Neural Networks for Cause of Hospitalization and Final Cause of Death Extraction from Discharge Summaries.

Determining the cause of death of hospitalized patients with cardiovascular disease is of the utmost importance. This is usually recorded in free text form. In this study we aimed to develop a series of supervised natural language processing algorithms to extract cardiovascular causes of hospitalization and final causes of death.

Transcriptomic and genomic structural variation analyses on grape cultivars reveal new insights into the genotype-dependent responses to water stress.

Grapevine (Vitis vinifera L.) is importantly cultivated worldwide for table grape and wine production. Its cultivation requires irrigation supply, especially in arid and semiarid areas. Water deficiency can affect berry and wine quality mostly depending on the extent of plant perceived stress, which is a cultivar-specific trait. We tested the physiological and molecular responses to water deficiency of two table grape cultivars, Italia and Autumn royal, and we highlighted their different adaptation. Microarray analyses revealed that Autumn royal reacts involving only 29 genes, related to plant stress response and ABA/hormone signal transduction, to modulate the response to water deficit. Instead, cultivar Italia orchestrates a very broad response (we found 1037 differentially expressed genes) that modifies the cell wall organization, carbohydrate metabolism, response to reactive oxygen species, hormones and osmotic stress. For the first time, we integrated transcriptomic data with cultivar-specific genomics and found that ABA-perception and -signalling are key factors mediating the varietal-specific behaviour of the early response to drought. We were thus able to isolate candidate genes for the genotype-dependent response to drought. These insights will allow the identification of reliable plant stress indicators and the definition of sustainable cultivar-specific protocols for water management.

Alopecia neoplastica as a sign of visceral malignancies: a systematic review.

Alopecia neoplastica (AN) from visceral tumours is a rare form of cutaneous metastasis in which internal malignancies spread to the scalp. The diagnosis of AN may be very challenging, especially when its onset precedes the diagnosis of the primary tumour. We aimed to improve the knowledge on AN, highlighting that in case of scarring localized alopecia, a differential diagnosis with metastasis should always be considered. We performed a systematic review to describe the main demographic and clinical features associated with AN from visceral malignancies; a survival analysis was also performed. In 118 reports, accounting for 123 patients, we found that women were more affected by AN than men (53.7% vs. 46.3%). The most frequent site of the primary tumour was the gastrointestinal tract (24.4%), followed by breast (17.9%), kidney (8.1%), lung (7.3%), thyroid (7.3%), uterus (6.5%), central nervous system (6.5%), liver (3.3%) and other anatomic areas for 18.7% of cases. Furthermore, in more than half of the cases (66.1%), AN lesions were single and were mainly diagnosed after the primary visceral tumour (71.5%). Finally, survival analysis highlighted a lower progression-free survival in men; while, no significant differences in overall survival were reported among genders. In conclusion, metastatic skin disease should always be taken into consideration when dealing with patients with localized scarring alopecia.

Melilotus, Rutin and Bromelain in primary and secondary lymphedema.

As reported in the literature, benzopyrones (alpha and gamma) have important effects on the microcirculation through various mechanisms. Coumarins are an alpha-benzopyrone as derivatives of Melilotus Officinalis, while bioflavonoids are a gamma-benzopyrone and include Rutin. Alpha-benzopyrones have two fundamental pharmacological effects: they have pro-lymphokinetic action by activating contractility of lymphangions; and the activation of macrophages to provide a proteolytic effect. Gamma-benzopyrones, such as Rutin, have an important anti-exuding and membrane stabilizing effect. Bromelain is known for its anti-inflammatory effect. The present study enrolled 52 patients with primary and/or secondary lymphedema in clinical stages I or II (according to the ISL classification) with 31 cases involving the lower limbs and 21 cases involving the upper limbs. All subjects were given for six months a natural compound consisting of 100 mg of natural Melilotus, that contains 20 grams of Coumarin, 300 mg of Rutin and 100 mg of Bromelain. The following parameters were studied at zero time (T0), after three months (T1), and after six months of treatment (T2): pitting, Stemmer's sign, measurement of limb circumferences, measurement of superficial tissue thickness in the affected limbs using ultrasound, and blood tests to evaluate hepatic function (ALT, AST, GGT, total and fractional bilirubin). At the end of the treatment (T2), the following results were observed: disappearance of pitting in 72% of the cases; unchanged Stemmer's sign; average decrease in limb circumferences of 4.2 cm; and average reduction of the superficial thickness of 29%. There was no variation in the liver function parameters examined. The combination of natural compounds (Melilotus, Rutin, and Bromelain) has been shown to be a valuable aid in the clinical control of both primary and secondary lymphedema of clinical stages I and II as well as in control of inflammatory phenomena related to chronic stasis. There were no side effects and no alteration of liver function parameters found.

Proprioception sense in lymphedema affected upper limb.

This study aimed to provide information on proprioception alterations in lymphedema-affected limbs. Blindfolded subjects sat at a table with their forearms positioned on paddles. The hinges of the paddles were aligned with the elbow joint and an electronic goniometer was positioned to measure the angle of the forearm. Paddles were moved by an electric servomotor with a slow angular speed that was barely appreciated by the subjects. Subjects were then asked to guess the position of the affected arm in comparison with the unaffected arm to study the position sense of the lymphedema-affected arm. The study investigated 50 women affected by secondary upper limb lymphedema by measuring the difference in terms of degrees of arch of movement in comparison with the unaffected arm and also both duration of lymphedema and the circumference of the forearm. Results were matched with a control group of 50 unaffected women providing proof of compromised proprioception in lymphedema-affected arms. In addition, results also showed a correlation with duration of lymphedema but not with size (stage) of the lymphedematous arm.

The molecular characterization by SSRs reveals a new South Italian kinship and the origin of the cultivar Uva di Troia.

Vitis vinifera L. varieties were spread through cuttings following historic migrations of people, trades, or after biological crises due to pests outbreaks. Some today's varieties could be more than a 1000 years old and, although over the centuries these varieties generated most of the remaining cultivars, their origin could be impossible to track back. The Italian grapevine biodiversity is one of most important, most likely due to its strategic position in the middle of the Mediterranean sea. Unravelling of its structure is challenging because of its complexity and the lack of historical documentation. In this paper molecular data are compared with historical documentations. Simple Sequence Repeats fingerprinting are molecular markers best suited to investigate genetic relationships and identify pedigrees. South-Italian germplasm was studied with 54 nuclear microsatellites. A family was identified, consisting of two parents and three siblings and further genetically characterized with six nuclear and five chloroplast microsatellites and described with ampelographic and phylometric analysis. Although these latter were not informative for the kinship identification. The common Bombino bianco was the female parent and the previously unknown Uva rosa antica was the male parent. Bombino nero, Impigno and the popular Uva di Troia, all typical of the south-east Italy, were the offspring. Further research showed that the Uva rosa antica was a synonym of Quagliano and Bouteillan noir, both minor varieties. Quagliano was considered to be autochthonous of some alpine valleys in the north-west of Italy and Bouteillan noir is a neglected variety of Vancluse in France. This finding uncovers the intricate nature of Italian grape cultivars, considered peculiar of an area, but possibly being the remains of ancient latin founding varieties. Consequently, intriguing new hypotheses are discussed and some conclusions are drawn, based on the peculiar geographical origin of the parents, on the distribution of the offspring, on the chance of a single, and perhaps intentional, crossing event.

Dermoscopy and methyl aminolevulinate: A study for detection and evaluation of field cancerization.

Actinic keratosis (AK) is a keratinocyte intraepidermal neoplasia UV light-induced that frequently appears in sun-exposed areas of the skin. Although historically AK was defined as "precancerous", actually it is considered as the earliest stage of squamous cell carcinoma (SCC) in situ. Since AKs can progress into invasive SCC, their treatment is recommended. AKs rarely develop as a single lesion; usually multiple lesions commonly affect an entire area of chronically actinic damaged skin. This has led to the concept of "field cancerization", an area chronically sun-exposed that surrounds peripherally visible lesions, in which are individualized subclinical alterations. One of the main principles endpoint in the management of AKs is the evaluation and the treatment of field cancerization. In this view, in order to detect and quantify field cancerization, we employed a method based on the topical application of methyl aminolevulinate (MAL) and the detection of the fluorescence emitted by its metabolite Protoporphyrin IX (PpIX); then, considering the extension and the intensity of measured fluorescence, we create a score of field cancerization. The results show that patients underwent to daylight PDT had a reduction of total score, from T0 to T2. Whereas in the group untreated we observed a stability of total score or a slightly worse. So, the method and the score used allows to evaluate with a good approximation the dimension of field cancerization and show the modification of it after treatment.

A case of Scalp Rosacea treated with low dose doxycycline and probiotic therapy and literature review on therapeutic options.

Rosacea is a common chronic inflammatory disorder showing a wide range of clinical features such as telangiectasia, erythema, papules, and pustules primarily involving the central part of face (forehead, cheeks and nose) although extra facial manifestation have been described. We describe a case of rosacea with predominant scalp involvement successfully treated with a 8-week-course of doxycycline 40 mg once a day and probiotic therapy twice a day (Bifidobacterium breve BR03, Lactobacillus salivarius LS01 1 × 10(9) UFC/dose).

A Rare Case of Emberger Syndrome Caused By a De Novo Mutation in the GATA2 Gene.

Emberger syndrome, or primary lymphedema with myelodysplasia, is a severe rare disease characterized by early primary lymphedema and blood anomalies including acute childhood leukemia. The syndrome is associated with heterozygous mutations in the GATA2 gene. We report on a 13-year-old boy who developed lymphedema of the right lower limb at age 6 years which was accompanied by severe panleukopenia and repeated episodes of erysipelas. The suspicion of Emberger syndrome was confirmed by detection of a new germinal line GATA2 mutation c.414_417del, p.Ser139Cysfs*78. Clinical treatment included a bone marrow transplant from the father.This case is one of a very limited number of Emberger syndrome cases documented in the literature, and genetic testing proved fundamental for definition of the condition and its association with a de novo mutation in the GATA2 which is reported here for the first time.

Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach.

Primary lymphedema is a rare inherited condition characterized by swelling of body tissues caused by accumulation of fluid, especially in the lower limbs. In many patients, primary lymphedema has been associated with variations in a number of genes involved in the development and maintenance of the lymphatic system. In this study, we performed a genetic screening in patients affected by primary lymphedema using a next generation sequencing (NGS) approach. With this technology, based on a custom-made oligonucleotide probe library, we were able to analyze simultaneously in each patient all the coding exons of 10 genes (FLT4, FOXC2, CCBE1, GJC2, MET, HGF, GATA2, SOX18, VEGFC, KIF11) associated with primary lymphedema. In the study population, composed of 45 familial and 71 sporadic cases, we identified the presence of rare variants with a potential pathogenic effect in 33% of subjects. Overall, we found a total of 36 different rare nucleotidic alterations, 30 of which had not been previously described. Among these, we identified 23 mutations that we considered most likely to be disease causing. Patients with an FLT4 or FOXC2 alteration accounted for the largest percentage of the sample, followed by MET, HGF, KIK11, GJC2 and GATA2. No alterations were identified in SOX18, VEGFC, and CCBE1 genes. In conclusion, we showed that NGS technology can be successfully applied to perform molecular screening of lymphedema-associated genes in large cohort of patients with a reasonable effort in terms of cost, work, and time.

BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies.

Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.

Clinical and genetic study of 46 Italian patients with primary lymphedema.

Primary lymphedema is characterized by altered morphological development of lymphatic vessels causing fluid accumulation in interstitial spaces. In familial forms, it is primarily transmitted as a dominant Mendelian trait with heterozygous mutations in genes involved in lymphangiogenesis. We used PCR and direct sequencing to analyze the region of the fms-related tyrosine kinase 4 (FLT4) gene encoding the "tyrosine-kinase domain" and the single exon of the forkhead box C2 (FOXC2) gene in 46 Italian probands with primary lymphedema, 42 of whom had familial forms. We identified 12 mutations in 12 patients (12/46, 26%), six in the FLT4 gene and six in the FOXC2 gene. Most of the mutations (9/12, 75%) were new, and none were identified in 100 healthy subjects or listed in the NCBI dbSNP. A clear relation emerged between genotype and phenotype because 4/5 (80%) probands with onset at birth showed FLT4 mutations and 4/5 (80%) probands without distichiasis and with FOXC2 mutations had an amino-acid substitution outside the forkhead domain. Besides the allelic heterogeneity shown by unique mutations in each proband, the absence of mutations in almost 75% of familial cases of primary lymphedema also suggests genetic heterogeneity.

New insights into centromere organization and evolution from the white-cheeked gibbon and marmoset.

The evolutionary history of alpha-satellite DNA, the major component of primate centromeres, is hardly defined because of the difficulty in its sequence assembly and its rapid evolution when compared with most genomic sequences. By using several approaches, we have cloned, sequenced, and characterized alpha-satellite sequences from two species representing critical nodes in the primate phylogeny: the white-cheeked gibbon, a lesser ape, and marmoset, a New World monkey. Sequence analyses demonstrate that white-cheeked gibbon and marmoset alpha-satellite sequences are formed by units of approximately 171 and approximately 342 bp, respectively, and they both lack the high-order structure found in humans and great apes. Fluorescent in situ hybridization characterization shows a broad dispersal of alpha-satellite in the white-cheeked gibbon genome including centromeric, telomeric, and chromosomal interstitial localizations. On the other hand, centromeres in marmoset appear organized in highly divergent dimers roughly of 342 bp that show a similarity between monomers much lower than previously reported dimers, thus representing an ancient dimeric structure. All these data shed light on the evolution of the centromeric sequences in Primates. Our results suggest radical differences in the structure, organization, and evolution of alpha-satellite DNA among different primate species, supporting the notion that 1) all the centromeric sequence in Primates evolved by genomic amplification, unequal crossover, and sequence homogenization using a 171 bp monomer as the basic seeding unit and 2) centromeric function is linked to relatively short repeated elements, more than higher-order structure. Moreover, our data indicate that complex higher-order repeat structures are a peculiarity of the hominid lineage, showing the more complex organization in humans.

Primate chromosome evolution: ancestral karyotypes, marker order and neocentromeres.

In 1992 the Japanese macaque was the first species for which the homology of the entire karyotype was established by cross-species chromosome painting. Today, there are chromosome painting data on more than 50 species of primates. Although chromosome painting is a rapid and economical method for tracking translocations, it has limited utility for revealing intrachromosomal rearrangements. Fortunately, the use of BAC-FISH in the last few years has allowed remarkable progress in determining marker order along primate chromosomes and there are now marker order data on an array of primate species for a good number of chromosomes. These data reveal inversions, but also show that centromeres of many orthologous chromosomes are embedded in different genomic contexts. Even if the mechanisms of neocentromere formation and progression are just beginning to be understood, it is clear that these phenomena had a significant impact on shaping the primate genome and are fundamental to our understanding of genome evolution. In this report we complete and integrate the dataset of BAC-FISH marker order for human syntenies 1, 2, 4, 5, 8, 12, 17, 18, 19, 21, 22 and the X. These results allowed us to develop hypotheses about the content, marker order and centromere position in ancestral karyotypes at five major branching points on the primate evolutionary tree: ancestral primate, ancestral anthropoid, ancestral platyrrhine, ancestral catarrhine and ancestral hominoid. Current models suggest that between-species structural rearrangements are often intimately related to speciation. Comparative primate cytogenetics has become an important tool for elucidating the phylogeny and the taxonomy of primates. It has become increasingly apparent that molecular cytogenetic data in the future can be fruitfully combined with whole-genome assemblies to advance our understanding of primate genome evolution as well as the mechanisms and processes that have led to the origin of the human genome.

[Neonatal group B Streptococcus infection: an integrated approach (of clinical pathologists, gynecologists, midwives, pediatricians-neonatologists) of the functional area of Cuneo (Italy)]. / Infezione neonatale da Streptococco B: un approccio multidisciplinare integrato (di laboratoristi, ginecologi, ostetriche e pediatri-neonatologi) del Quadrante di Cuneo.

The frequency of early-onset neonatal sepsis without prophylaxis is 1-5/1.000 live births. Since year '70 the most frequent causative microorganism is the group B Streptococcus (S. agalactiae, GBS), followed by Escherichia coli. The mortality rate is now reduced to 4% due to the improvement of neonatal intensive care. In the USA, the incidence of GBS early-onset neonatal sepsis has been markedly reduced by the application of the guidelines released by the Centers for Disease Control (CDC). This strategy, however, is not effective on occurrence of late-onset neonatal group B streptococcal disease. In Italy, the application of CDC guidelines is not customary, and different, often complex, protocols of obstetrical-neonatological integrated approach are applied. The frequency of infectious risk has made the GBS a paramount problem for the neonatologist, even for the legal responsibility issues resulting from the multiplicity of possible options. To reach the best level of protection of the newborn against early-onset GBS infection, the working group of providers of prenatal, obstetric, and neonatal care of the functional area of Cuneo issued an integrated protocol, in order to perform the GBS screening with the optimal culture method suggested by CDC guidelines in the highest possible number of pregnant women, and to standardize the obstetrical and neonatal management.

Glioblastoma cell death induced by asiatic acid.

Asiatic acid (AA), a triterpene, is known to be cytotoxic to several tumor cell lines. AA induces dose- and time-dependent cell death in U-87 MG human glioblastoma. This cell death occurs via both apoptosis and necrosis. The effect of AA may be cell type-specific as AA-induced cell death was mainly apoptotic in colon cancer RKO cells. AA-induced glioblastoma cell death is associated with decreased mitochondrial membrane potential, activation of caspase-9 and -3, and increased intracellular free Ca2+. Although treatment of glioblastoma cells with the caspase inhibitor zVAD-fmk completely abolished AA-induced caspase activation, it did not significantly block AA-induced cell death. AA-induced cell death was significantly prevented by an intracellular Ca2+ inhibitor, BAPTA/AM. Taken together, these results indicate that AA induces cell death by both apoptosis and necrosis, with Ca2+-mediated necrotic cell death predominating.

The boundary of macaque rDNA is constituted by low-copy sequences conserved during evolution.

In Macaca mulatta, the single rDNA array is flanked by a patchwork of sequences including subregions of human Yp11.2, 4q35.2, and 10p15.3. This composite DNA region is characterized by unique or low-copy sequences, resembling a potentially transcribed region. The analysis of Cercopithecus aethiops, Presbytis cristata, and Hylobates lar suggests that this complex sequence organization could be shared by Old World monkey and lesser ape species. After the lesser apes/great apes divergence, the unique or nonduplicated DNA region underwent amplification and spreading, preferentially marking the p arm of acrocentric chromosomes bearing the rDNA. The molecular analysis of human acrocentric chromosomes revealed some extent of remodeling of the rDNA boundary: near the human NOR, a large 4q35.2 duplication partially resembles that found in MMU; conversely, infrequently represented Yp11.2 sequences totally differed from those of the macaque, and 10p15.3 sequences were lacking. Thus, although evolutionary events modified the sequence organization of the MMU rDNA boundary, its overall sequence feature and the preferential location in vicinity to the NOR have been conserved.

Otorhinolaryngology-related tuberculosis.

Data from personal case histories, from 1984 to 2000 inclusive, are reported in order to contribute to a better understanding of some of the clinical and epidemiological ENT associated TB aspects. Analysis of these data shows that: (1) Like the pulmonary form, ENT localizations are increasing due to the traditional risk factors (immigration, poverty, immunodeficiency, drug addiction). (2) They are generally clinically primitive forms (which are found in extrapulmonary regions as the first expression of tubercular disease) and typically affect young people with a slight prevalence among females. Lymph gland localizations are the most frequent.