Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.

Expanding the histopathological spectrum of CFL2-related myopathies.

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model.

Pharmacological functional MRI assessment of the effect of ibuprofen-arginine in painful conditions.

Pharmacological functional magnetic resonance imaging (phMRI) is a valuable tool for the investigation of pharmacological effects of a drug on pain processing. We hypothesized that the ibuprofen-arginine combination, in line with its characteristic analgesic properties, may influence the phMRI response at the central level, as compared to placebo. Ten healthy subjects underwent a double-blind, placebo-controlled, randomized, cross-over phFMRI study with somatosensory painful stimulation of the right median nerve. We measured the blood oxygen level dependent (BOLD) signal variations induced in conditions of pain after oral administration of either ibuprofen-arginine or placebo formulations. Independent component analysis (ICA) was used for the analysis of the fMRI data, without assuming a specific hemodynamic response function (HRF), which may be altered by drug administration. Median nerve electrical painful stimulation mainly activated the primary contralateral and the secondary somatosensory cortices, the insula, the supplementary motor area, and the middle frontal gyrus. Placebo and ibuprofen-arginine administration induced activation bilaterally in the premotor cortex, and an overall reduction in the other pain-related areas, which was more prominent in the left hemisphere. A task-related increase of BOLD signal between drug and placebo was observed bilaterally in the primary somatosensory area and the middle frontal gyrus without any changes in subjective pain scores. Overall, our findings show that ibuprofen-arginine, in line with the characteristic analgesic properties of ibuprofen, influences the BOLD response in specific pain-related brain areas with respect to placebo, with a vasoactive effect possibly due to arginine.

Indice de comorbilidad específico para trasplante alogénico de células progenitoras hematopoyéticas: cohorte retrospectiva de niños y adolescentes con enfermedad maligna / Specific comorbidity index for allogeneic hematopoietic stem cell transplantation: a retrospective cohort of children and adolescents with malignancies

Introducción: Entre las variables que afectan el riesgo de mortalidad relacionada (MRT) al trasplante alogénico de células progenitoras hematopoyéticas (TACPH) se incluyen las comorbilidades previas. Los índices de comorbilidad (IC) buscan mejorar la predicción de eventos combinando factores de riesgo independientes. Objetivos: 1) evaluar el uso de la versión breve y adaptada para niños, adolescentes y adultos jóvenes con enfermedad maligna del índice de comorbilidad específico para trasplante alogénico de células progenitoras hematopoyéticas (smyHCT-CI ); 2) evaluar el uso de los biomarcadores ferritina y albúmina en un índice de comorbilidad ampliado (smyHCT-CIa). Población y métodos: Diseño: cohorte retrospectiva. Periodo 2017- 2022. A cada p se le asignó nuevos puntajes utilizando el smyHCT-CI y el smyHCT-CIa. Los p se clasificaron en grupos de riesgo (GR) bajo (puntaje 0), intermedio (1-2) y alto (>3) con cada índice. Se comparó el n° de p asignado a cada GR grupo de riesgo y la MRT en cada grupo al usar el HCT-CI, el smyHCTCI y el smyHCT-CIa. Resultados: n 75. Frecuencia de p por GR según cada indicador (IC95): HCT-CI bajo 36 (25-47), intermedio 57 (56-69), alto 7 (1-12); smyHCT-CI: bajo 48 (37-59), intermedio 33 (23-44), alto 19 (10-27); smyHCT-CIa: bajo 43 (31-54), intermedio 36 (25-47), alto 21 (12-31). MRT por GR según indicador (IC95): HCT-CI: bajo 6,8 (14-28), intermedio 20,9 (9-33), alto 17,9 (0-55); smyHCT-CIa bajo 12,5 (1-24), intermedio 18,5 (4-33), alto 31,2 (9-54). Conclusión: El smyHCT-CI permitió identificar mejor los pacientes con mayor comorbilidad y riesgo de MRT. La ferritina resultó un biomarcador útil en la estimación del riesgo de MRT (AU)

Introduction: Variables affecting allogeneic hematopoietic stem cell transplantation (HCT) related mortality risk (TMR) include prior comorbidities. Comorbidity indices (CI) aim to improve event prediction by combining independent risk factors. Objectives: 1) to evaluate the use of the brief and adapted version of the HCT-specific comorbidity index for children, adolescents and young adults with malignancies (ymHCT-CI); 2) to evaluate the use of the biomarkers ferritin and albumin in an expanded comorbidity index (expanded ymHCT-CI). Population and methods: Design: retrospective cohort. Period 2017- 2022. Each patient was assigned new scores using the ymHCTCI and expanded ymHCT-CI. The p were classified into low (score 0), intermediate (1-2) and high (>3) risk groups (RG) with each index. The number of patients assigned to each RG and the TMR in each group were compared using the HCTCI, the ymHCT-CI, and the expanded ymHCT-CI. Results: n 75. Frequency of patients per RG according to each indicator (95%CI): HCT-CI low 36 (25-47), intermediate 57 (56-69), high 7 (1-12); ymHCT-CI: low 48 (37-59), intermediate 33 (23-44), high 19 (10-27); expanded ymHCT-CI: low 43 (31-54), intermediate 36 (25-47), high 21 (12-31). TMR by RG according to indicator (95%CI): HCT-CI: low 6.8 (14-28), intermediate 20.9 (9-33), high 17.9 (0-55); expanded ymHCT-CI low 12.5 (1-24), intermediate 18.5 (4-33), high 31.2 (9-54). Conclusion: ymHCT-CI allowed better identification of patients with higher comorbidity and risk of TMR. Ferritin proved to be a useful biomarker to estimate TMR risk (AU)

National Italian Guidelines for caries prevention in 0 to 12 years-old children.

AIM: Oral and dental health improved tremendously over the last fifty years in Italy but still prevalence of dental caries in children remains a significant clinical problem. This report describes the National Italian Guidelines for caries prevention. METHODOLOGY: A panel of experts coordinated by the Italian Society of Paediatric Dentistry (SIOI) planned to elaborate the national Italian guidelines for caries prevention in children. The structure of the guidelines has been planned to follow the principles of modern caries treatment and management as well as science based dentistry. The main procedure was based on a hierarchic evaluation of literature. CONCLUSION: The guidelines are planned for dentist working in primary dental care, however, they are also designed to be of interest for other care professionals such as paediatricians, gynecologists, pharmacists and general medical practitioners and also for parents and/or guardians of the children.

The antral mucosa as a new site for endocrine tumors in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndromes.

Carcinoid tumors were identified in the antro-pyloric mucosa of four patients with multiple endocrine neoplasia type 1 (MEN-1)/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic Zollinger-Ellison syndrome (P < 0.001), indicating a prominent role for the MEN-1 gene defects in tumor development. Immunohistochemically the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, two of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT-2), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In one of these patients a second antral VMAT-2-positive carcinoid was seen 21 months after the first diagnosis. The other two antral carcinoids were unreactive for VMAT-2. Multiple ECL cell tumors were found in the gastric body-fundus mucosa of the two patients with VMAT-2-positive, but not in those with VMAT-2-negative, antral carcinoids. In one case, the former tumors were diagnosed 22 months after the detection of the antral tumor. We conclude that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN-1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least two cases, were identified as ectopic ECL cell carcinoids.

p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior.

The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53. p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors. p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling (P =.02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases. Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors.

Polymerization shrinkage of microfilled composites determined by laser beam scanning.

An He-Ne scanning laser beam was used to measure for the first time the linear shrinkage of light-cured microfilled composites. A low-power beam, which has a wavelength (632.8 nm) different from the polymerization wavelength (approximately 450 nm), was used. In these conditions no shrinkage is induced by the laser light. This method of measurement makes it possible to analyse small samples with a very low error (1.1 microns). Five different materials were tested using 10-20 mg specimens, and the shrinkage process was examined in detail over 2 days. All these materials showed shrinkage of more than 50% of their original length after 1 min of irradiation and approximately 99% of the total shrinkage occurred 4 h after irradiation.

Polymerization of dental composite resins using plasma light.

Five visible light-cured composite resins used as restoration or adhesive materials in dentistry, were irradiated with high energy plasma light (1300 mW/cm2), and contraction, rate of contraction, irradiation-induced temperature were analysed. A comparison was carried out with the same materials irradiated with a conventional halogen light (400 mW/cm2). The exposure to the photoactivating lights was either continuously or sequentially in three or more intervals with 10 min between intervals. Comparing the lengths of exposure of both lights, which induced the same contraction in a given material, it was found that the exposure length to the plasma light was greatly reduced, when compared with the exposure length of the halogen light (1:10). Frequently, the final contraction of plasma-irradiated materials was lower, whereas the rate of contraction, as indicated by the linear dimensional variation curves obtained by laser beam scanning method, did not show significant differences between the two lights. The temperature increase induced by plasma light on the material did not exceed the temperature induced by conventional light.

[11 cases of erythema multiforme. The etiological correlations and therapy]. / Undici casi di eritema multiforme. Correlazioni etiologiche e terapia.

Erythema multiforme (EM) is characterised by a polymorphous eruptive complex which many involve the cutis and oral, genital and conjunctival mucous. Its etiopathogenesis is unclear: it is thought to be associated with various viral or bacterial infective agents (herpes virus, Coxsackie virus, mycoplasmas, etc.), numerous drugs, physical therapy, systemic pathologies of various types. The authors report their experience in relation to 11 patients suffering from EM; the clinical characteristics of each case are reported, together with the course of disease, and the diagnostic and therapeutic protocol adopted. The discussion examines the possible cause of disease: in 5 patients the etiology was traced back to viral infections (4 herpes and 1 coxsackie) and to the administration of drugs in the remaining cases (4 in relation to anti-phlogistic agents and 2 regarding antibiotics).

[Headaches and craniofacial pains with dental involvement in the classification of the International Headache Society (1988)]. / Cefalee e algie cranio-facciali di interesse stomatologico nella classificazione della International Headache Society (1988).

Facial pain often presents complex diagnosis, requiring other specialists' consultation. The use of different terminology and protocols can affect the information exchange negatively. These problems in the field of headache, cranial neuralgias and facial pain lead the International Headache Society to introduce a new classification in 1988. The chief difference with the previous ones is the presence of strictly codified diagnostic principles. Its target is research, but it can help the general practice as well. We discuss the most interesting points to the stomatologist.

Hard and soft tissue management for the restoration of traumatized anterior teeth.

The restoration of coronally fractured anterior teeth without surgical invasion is contingent upon several factors. Specifically, the biologic width of the tooth should not be violated by the apical extent of the fracture, and the residual root structure must possess an adequate ferrule. In patients with these conditions, it is possible to prosthetically restore the tooth following orthodontic extrusion. This article describes a technique in which orthodontic extrusion is utilized to provide adequate tooth structure for the prosthetic restoration of patients who presented with fractured anterior teeth.

Expression pattern of squamous cell carcinoma antigen in oesophageal dysplasia and squamous cell carcinoma.

The aim of the present study was to evaluate the tissue expression of squamous cell carcinoma antigen (SCCA) in oesophageal dysplasia and squamous cell carcinoma (SCC) with reference to its clinico-pathologic and prognostic significance. Immunohistochemistry using SCCA polyclonal antibody was performed on SCCs from 61 surgical oesophagectomies. Fifteen cases of low-grade dysplasia (LGD) and 37 non-coexistent high-grade dysplasia (HGD) were also sampled from these materials, together with sixteen chronic cases of oesophagitis. SCCA immunoreactivity was present in the maturative compartments of all normal epithelia and oesophagitis. LGDs showed no SCCA immunoreactivity in the dysplastic proliferative component but only in the superficial normal layers. In 94.6% of HGDs, no SCCA immunoreactivity was detected throughout the thickness of the epithelium. In SCCs, SCCA expression higher than 25% was found in 54% of cases. SCCA positivity showed an inverse correlation with histological grade, whereas no statistically significant correlation was found with TNM classifications, stage, or survival. SCCA is not expressed in early oesophageal carcinogenesis but, in SCC, it represents an indicator of histologic differentiation. In differentiated SCC, SCCA may represent a negative factor for cancer invasiveness, through inhibition of proteases.

RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours.

The Ras-association domain family 1A (RASSF1A) tumour suppressor gene is inactivated in a variety of solid tumours, usually by epigenetic silencing of the promoter and/or allelic loss of its locus at 3p21.3. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, 62 endocrine tumours from different sites in the gut were investigated for methylation of the RASSF1A promoter using the polymerase chain reaction, the presence of 3p21.3 deletions by loss of heterozygosity analysis, and cyclin D1 expression by immunohistochemistry. Methylation was found in 20/62 (32%) cases and was restricted to foregut tumours; deletion at 3p21.3 was found in 15/58 (26%) informative cases and restricted to malignant foregut tumours; cyclin D1 hyper-expression was found in 31/58 (53%) cases and correlated with RASSF1A methylation. Our data suggest that RASSF1A is involved in the development of endocrine tumours derived from the foregut only, and that the presence of both RASSF1A methylation and 3p21.3 deletion is associated with malignancy. These results may provide a rationale for foregut-targeted therapy for aggressive endocrine carcinomas entailing the use of demethylating agents.

Enfermedad por adenovirus en niños receptores de trasplante alogénico de células progenitoras hematopoyéticas / Adenovirus disease in children undergoing allogeneic hematopoietic stem cell transplantation

Introducción: Las infecciones virales son una causa conocida de morbi-mortalidad en pacientes receptores de trasplante alogénico de células progenitoras hematopoyéticas (TACPH). Los avances en la prevención y tratamiento de la infecciones por los virus del grupo Herpes obliga a centrar la atención en virus emergentes como el Adenovirus (Adv). Objetivos: Analizar la incidencia, evolución y factores de riesgo de la enfermedad por Adv en pacientes pediátricos trasplantados en un mismo centro. Métodos: Cohorte retrospectiva. Se analizaron los TACPH realizados entre abril/94 y abril/10. Se comparó la frecuencia de enfermedad por Adv antes y después del inicio del programa de TACPH con donantes no relacionados, en el año 2008. Resultados: n TCPH: 303. Incidencia enfermedad por Adv: 18p (5,4%), según período: 1994-2007: 2,8% vs 2008-2010: 18,9% (p<0,001). Pacientes con Adv: 61% varones, mediana edad: 8 años (r 0,6 - 18), días del trasplante: 55 (r 4- 295). La enfermedad por Adv tuvo una mortalidad del 22% y fue causa del 5,6% de la mortalidad relacionada con el trasplante. Los factores de riesgo para enfermedad por Adv fueron el antecedente de TACPH no relacionado (OR 6,6 IC95% 1,6-27,8) y la enfermedad por CMV (OR 12,3 IC95% 3,4- 44,5). Doce pacientes con viremia y/o enfermedad grave por Adv que recibieron tratamiento con Cidofovir (75%) tuvieron toxicidad renal moderada-severa y 33% de mortalidad por Adv. Conclusión: La enfermedad por Adv representa una causa importante de morbi-mortalidad en el TACPH. Los pacientes con factores de riesgo requieren estrategias de diagnóstico temprano y tratamiento oportuno (AU)

Introduction: Viral infections are a well-known cause of morbidity and mortality in patients who underwent allogeneic hematopoietic stem cell transplantation (AHSCT). Advances in the prevention and treatment of herpes virus infections have led to increased focus on other emerging viruses such as the adenovirus (ADV). Objectives: To analyze the incidence, evolution, and risk factors for ADV disease in pedia - tric patients who underwent AHSCT in a single center. Methods: All patients who underwent HSCT between April 1994 and April 2010 were retrospectively analyzed. Incidence rates of ADV disease before and after the introduction of the program of AHSCT from non-related donors in 2008 were compared. Results: HSCT n = 303. Incidence of ADV disease: 18p (5.4%), 1994-2007: 2.8% vs 2008-2010: 18.9% (p<0,001). Patients with ADV: 61% boys, mean age: 8 years (r 0.6 - 18), mean days after transplantation: 55 (r 4- 295). Mortality due to ADV disease was 22% and ADV was de cause of 5.6% of transplant-related mortality. Risk factors for disease due to ADV were AHSCT from a non-related donor (OR 6.6 CI 95% 1.6-27.8) and CMV disease (OR 12.3 CI 95% 3.4- 44.5). Twelve patients with viremia and/or severe disease due to ADV who received treatment with Cidofovir (75%) developed moderate- to-severe kidney toxicity and mortality due to ADV was 33%. Conclusion: ADV disease is an important cause of morbidity and mortality in AHSCT. At-risk Patients require early diagnostic strategies and adequate treatment (AU)

[Experimental measurement of force exerted by palatal bars. 1]. / Misurazione sperimentale delle forze esercitate dalle barre palatali--parte I.

The Authors have prepared a protocol of research to evaluate the forces of lateral expansion expressed by the palatal bar et different degrees of activation. A special instrument has been built to this purpose. The forces expressed at the different degrees of activation are then evaluated and confronted in relation to the following variables: --length of the bar;--the presence or the absence of a U loop; --the more or less bowed conformation given to the bar. It is shown how, on the same terms, the presence of the U loop reduces the force made by the bar by about the half and that the more or less bowed conformation of the bar influences the force in the same way.