Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

New ABO intron 1 variant alleles.

Unusual and discrepant ABO phenotypes are often due to genetic variants that lead to altered levels or activity of ABO transferases and consequently to altered expression of ABO antigens. This report describes eight genetic alterations found in 15 cases with reduced or undetectable expression of ABO antigens. Forward and reverse ABO grouping was performed by standard gel or tube methods. Adsorption-heat elution and saliva testing for H and A substances followed the AABB technical manual procedures. Genomic DNA extracted from whole blood was PCR-amplified to cover the entire ABO coding sequence, splice junctions, proximal promoter, and intron 1 enhancer. Amplification products were sequenced by next-generation or Sanger dideoxy methods, either directly or after cloning into a bacterial plasmid vector. Eight unreported alleles were found in the 15 cases analyzed. Alleles ABO*A(28+1C) and ABO*A(29-5G) harbor variants that alter the consensus sequence at the intron 1 donor and acceptor splice sites, respectively. The other alleles harbor variants that alter the consensus sequence at transcription factor-binding sites in the intron 1 enhancer: specifically, ABO*A(28+5792T), ABO*A(28+5859A), and ABO*A(28+5860G) at GATA-1 sites; ABO*B(28+5877T) and ABO*B(28+5878G) at a RUNX1 site; and ABO*A(28+5843A) at or near a C/EBP site. Molecular and serologic characterization of ABO alleles can help in their future identification and in the resolution of discrepancies.Unusual and discrepant ABO phenotypes are often due to genetic variants that lead to altered levels or activity of ABO transferases and consequently to altered expression of ABO antigens. This report describes eight genetic alterations found in 15 cases with reduced or undetectable expression of ABO antigens. Forward and reverse ABO grouping was performed by standard gel or tube methods. Adsorption-heat elution and saliva testing for H and A substances followed the AABB technical manual procedures. Genomic DNA extracted from whole blood was PCR-amplified to cover the entire ABO coding sequence, splice junctions, proximal promoter, and intron 1 enhancer. Amplification products were sequenced by next-generation or Sanger dideoxy methods, either directly or after cloning into a bacterial plasmid vector. Eight unreported alleles were found in the 15 cases analyzed. Alleles ABO*A(28+1C) and ABO*A(29­5G) harbor variants that alter the consensus sequence at the intron 1 donor and acceptor splice sites, respectively. The other alleles harbor variants that alter the consensus sequence at transcription factor­binding sites in the intron 1 enhancer: specifically, ABO*A(28+5792T), ABO*A(28+5859A), and ABO*A(28+5860G) at GATA-1 sites; ABO*B(28+5877T) and ABO*B(28+5878G) at a RUNX1 site; and ABO*A(28+5843A) at or near a C/EBP site. Molecular and serologic characterization of ABO alleles can help in their future identification and in the resolution of discrepancies.

The Italian Registry of GH Treatment: electronic Clinical Report Form (e-CRF) and web-based platform for the national database of GH prescriptions.

BACKGROUND: In Italy, the utilization and the reimbursement of Growth Hormone (rGH) therapy by the National Health System (Servizio Sanitario Nazionale) are regulated by the "Note #39" included in the "Notes for the use of drugs" by the Italian Medicines Agency (AIFA), which are published in the Official Gazette, thus having the force of law. The "Note #39" establishes the diagnosis for which the reimbursement is granted and confirms the assignment of the national health surveillance on the use of GH therapy to the Italian National Institute of Health, requesting its computerization. AIM: The aim of this work was to realize a dedicated electronic Clinical Report Form based on the mandatory data requested by the Note #39 and allowing the online reporting of the rGH prescriptions by the regional accredited centers. RESULTS AND CONCLUSIONS: This interface is at the base of the national database of the Italian Registry of GH Treatment, which allows obtaining and managing correct and complete data to provide public health surveillance on GH therapy, both at national and local levels, necessary for policymakers decisions. In addition, this national database could be a useful instrument for improving knowledge about aspects of this treatment still under discussion.

Benign pneumatosis intestinalis with massive portomesenteric venous gas in a very old man. A case report.

INTRODUCTION: Pneumatosis intestinalis (PI) is described as the presence of air within bowel wall. PI aetiology is various: it can be associated with non-urgent or life-threatening conditions. Clinical management is based on physical examination, blood tests and radiology, in particular abdominal CT. The cause of PI suggests the correct therapy. When PI is linked to gas in portal and mesenteric venae (PMVG), bowel ischemia or infarction is possible, and surgery needed. CASE REPORT: A 91 years-old man was admitted to Emergency Department reporting abdominal pain and vomit. Acute abdominal symptoms, radiological finding of small bowel PI with massive PMVG, severe neutrophilia, and high serum lactate forced us to perform exploratory laparotomy, from which it was observed a diffuse band-like pneumatosis of all the small bowel and mesentery without ischemic or peritonitis signs. The patient was imposed to fast and treated with oxygen, intravenous fluid and antibiotic therapy, without performing further surgery, and was discharged to a rehabilitation facility after symptomatology resolution. DISCUSSION: Scientific literature underlines the importance of PMVG to consider as critic a patient with PI, but it is always essential to assess also physical examination, vital parameters, and blood exams. In our case, several signs were suggestive for bowel infarction: its absence and the swift recovery of the patient were unexpected. CONCLUSION: Although non-surgical treatment is recommended for primary PI of unknown aetiology, in case physical examination and radiological signs aren't decisive surgery is necessary to rule out bowel infarction. This case stresses the difficulty of PI management.

Cell and matrix response of temporomandibular cartilage to mechanical loading.

OBJECTIVES: The generation of transgenic mice expressing green fluorescent proteins (GFPs) has greatly aided our understanding of the development of connective tissues such as bone and cartilage. Perturbation of a biological system such as the temporomandibular joint (TMJ) within its adaptive remodeling capacity is particularly useful in analyzing cellular lineage progression. The objectives of this study were to determine: (i) if GFP reporters expressed in the TMJ indicate the different stages of cell maturation in fibrocartilage and (ii) how mechanical loading affects cellular response in different regions of the cartilage. DESIGN/METHODS: Four-week-old transgenic mice harboring combinations of fluorescent reporters (Dkk3-eGFP, Col1a1(3.6 kb)-GFPcyan, Col1a1(3.6 kb)-GFPtpz, Col2a1-GFPcyan, and Col10a1-RFPcherry) were used to analyze the expression pattern of transgenes in the mandibular condylar cartilage (MCC). To study the effect of TMJ loading, animals were subjected to forced mouth opening with custom springs exerting 50 g force for 1 h/day for 5 days. Dynamic mineralization and cellular proliferation (EdU-labeling) were assessed in loaded vs control mice. RESULTS: Dkk3 expression was seen in the superficial zone of the MCC, followed by Col1 in the cartilage zone, Col2 in the prehypertrophic zone, and Col10 in the hypertrophic zone at and below the tidemark. TMJ loading increased expression of the GFP reporters and EdU-labeling of cells in the cartilage, resulting in a thickness increase of all layers of the cartilage. In addition, mineral apposition increased resulting in Col10 expression by unmineralized cells above the tidemark. CONCLUSION: The TMJ responded to static loading by forming thicker cartilage through adaptive remodeling.

Rise and fall of vector infectivity during sequential strain displacements by mosquito-borne dengue virus.

Each of the four serotypes of mosquito-borne dengue virus (DENV-1-4) comprises multiple, genetically distinct strains. Competitive displacement between strains within a serotype is a common feature of DENV epidemiology and can trigger outbreaks of dengue disease. We investigated the mechanisms underlying two sequential displacements by DENV-3 strains in Sri Lanka that each coincided with abrupt increases in dengue haemorrhagic fever (DHF) incidence. First, the post-DHF strain displaced the pre-DHF strain in the 1980s. We have previously shown that post-DHF is more infectious than pre-DHF for the major DENV vector, Aedes aegypti. Then, the ultra-DHF strain evolved in situ from post-DHF and displaced its ancestor in the 2000s. We predicted that ultra-DHF would be more infectious for Ae. aegypti than post-DHF but found that ultra-DHF infected a significantly lower percentage of mosquitoes than post-DHF. We therefore hypothesized that ultra-DHF had effected displacement by disseminating in Ae. aegypti more rapidly than post-DHF, but this was not borne out by a time course of mosquito infection. To elucidate the mechanisms that shape these virus-vector interactions, we tested the impact of RNA interference (RNAi), the principal mosquito defence against DENV, on replication of each of the three DENV strains. Replication of all strains was similar in mosquito cells with dysfunctional RNAi, but in cells with functional RNAi, replication of pre-DHF was significantly suppressed relative to the other two strains. Thus, differences in susceptibility to RNAi may account for the differences in mosquito infectivity between pre-DHF and post-DHF, but other mechanisms underlie the difference between post-DHF and ultra-DHF.

Diets high in corn oil or extra-virgin olive oil differentially modify the gene expression profile of the mammary gland and influence experimental breast cancer susceptibility.

PURPOSE: Nutritional factors, especially dietary lipids, may have a role in the etiology of breast cancer. We aimed to analyze the effects of high-fat diets on the susceptibility of the mammary gland to experimental malignant transformation. METHODS: Female Sprague-Dawley rats were fed a low-fat, high-corn-oil, or high-extra-virgin olive oil (EVOO) diet from weaning or from induction. Animals were induced with 7,12-dimethylbenz[a]anthracene at 53 days and euthanized at 36, 51, 100 and 246 days. Gene expression profiles of mammary glands were determined by microarrays. Further molecular analyses were performed by real-time PCR, TUNEL and immunohistochemistry. Carcinogenesis parameters were determined at 105 and 246 days. RESULTS: High-corn-oil diet increased body weight and mass when administered from weaning. The EVOO diet did not modify these parameters and increased the hepatic expression of UCP2, suggesting a decrease in intake/expenditure balance. Both diets differentially modified the gene expression profile of the mammary gland, especially after short dietary intervention. Corn oil down-regulated the expression of genes related to immune system and apoptosis, whereas EVOO modified the expression of metabolism genes. Further analysis suggested an increase in proliferation and lower apoptosis in the mammary glands by effect of the high-corn-oil diet, which may be one of the mechanisms of its clear stimulating effect on carcinogenesis. CONCLUSIONS: The high-corn-oil diet strongly stimulates mammary tumorigenesis in association with modifications in the expression profile and an increased proliferation/apoptosis balance of the mammary gland.

DIAGNOSTIC PERFORMANCE OF WAIST CIRCUMFERENCE MEASUREMENTS FOR PREDICTING CARDIOMETABOLIC RISK IN MEXICAN CHILDREN.

OBJECTIVE: The accumulation of abdominal fat is associated with cardiometabolic abnormalities. Waist circumference (WC) measurements allow an indirect evaluation of abdominal adiposity. However, controversy exists over which WC reference values are the most suitable for identifying the pediatric population at risk. The aim of the study was to evaluate the ability of various WC indices to identify abdominal obesity as diagnostic tools for predicting cardiometabolic risk in Mexican children and adolescents. METHODS: Anthropometric measurements were performed and biochemical profiles determined in a crosssectional study that included 366 children and adolescents. Four parameters were used to evaluate abdominal obesity in our study group: (1) WC >90th percentile, according to the Fernández reference in a Mexican-American population measured by the National Center for Health Statistics (NCHS) technique; (2) WC >90th percentile, according to the Klünder reference in a Mexican population (measured by the World Health Organization [WHO] technique); (3) waist-to-height ratio (WHtR) >0.5 according to WHO; and (4) WHtR >0.5 according to NCHS. The ability of each of the indices to discriminate cardiometabolic abnormalities (fasting plasma glucose, dyslipidemia, and hypertension) was assessed. RESULTS: WHtR >0.5 according to WHO or NCHS references showed greater sensitivity to detect metabolic abnormalities compared to percentile reference parameters (74.3 to 100% vs. 59.0 to 88.9%; P<.05). However, the percentiles displayed more specificity to identify these alterations (46.2 to 62.2 vs. 21.3 to 46.9; P<.05). Area under the curve analysis showed that WHtR >0.5 can more readily detect hypertriglyceridemia (0.642), hypoalphalipoproteinemia (0.700), and a combination of two or more metabolic abnormalities (0.661), whereas WC >90th percentile, according to Klünder, better detected hyperglycemia (0.555). CONCLUSION: WHtR >0.5 is a sensitive measure to identify pediatric patients with cardiometabolic alterations, despite its low specificity, and is a useful diagnostic tool to detect populations at risk. Based on the results of this study, we recommend preferential use of the Klünder waist circumference references over the Fernández method in Mexican pediatric populations. ABBREVIATIONS: AUC = area under the curve BMI = body mass index HDL = high-density lipoprotein IDF = International Diabetes Federation LDL = low-density lipoprotein MS = metabolic syndrome NCHS = National Center for Health Statistics ROC = receiver operating characteristic WC = waist circumference WHO = World Health Organization WHtR = waist-to-height ratio.

Exhaled breath temperature in children: reproducibility and influencing factors.

OBJECTIVE: This study will investigate the reproducibility and influencing factors of exhaled breath temperature measured with the tidal breathing technique in asthmatic patients and healthy children. METHODS: Exhaled breath temperature, fractional exhaled nitric oxide, and spirometry were assessed in 124 children (63 healthy and 61 asthmatic), aged 11.2 ± 2.5 year, M/F 73/51. A modified version of the American Thoracic Society questionnaire on the child's present and past respiratory history was obtained from parents. Parents were also asked to provide detailed information on their child's medication use during the previous 4 weeks. Ear temperature, ambient temperature, and relative-ambient humidity were also recorded. RESULTS: Exhaled breath temperature measurements were highly reproducible; the second measurement was higher than the first measurement, consistent with a test-retest situation. In 13 subjects, between-session within-day reproducibility of exhaled breath temperature was still high. Exhaled breath temperature increased with age and relative-ambient humidity. Exhaled breath temperature was comparable in healthy and asthmatic children; when adjusted for potential confounders (i.e. ambient conditions and subject characteristics), thermal values of asthmatic patients exceeded those of the healthy children by 1.1 °C. Normalized exhaled breath temperature, by subtracting ambient temperature, was lower in asthmatic patients treated with inhaled corticosteroids than in those who were corticosteroid-naive. CONCLUSION: Measurements of exhaled breath temperature are highly reproducible, yet influenced by several factors. Corrected values, i.e. normalized exhaled breath temperature, could help us to assess the effect of therapy with inhaled corticosteroids. More studies are needed to improve the usefulness of the exhaled breath temperature measured with the tidal breathing technique in children.

Molecular identification of Borrelia and SFG Rickettsia spp. in hard ticks parasitizing domestic and wild animals in southeastern Spain.

Lyme disease and the spotted fever group rickettsiosis, involve bacteria belonging to the genus Borrelia and Rickettsia, respectively. These infections are the most important tick-borne zoonotic diseases involving ticks as vectors. Descriptive and epidemiological studies are essential to determine the animal hosts involved in the maintenance of these diseases. In the present study, 94 tick pool samples from 15 different host species located in the Region of Murcia (southeastern, Spain) were analysed. Ticks were morphologically identified as: Dermacentor marginatus, Hyalomma lusitanicum, Ixodes Ricinus, and Rhipicephalus sanguineus. Our results showed that 5.3% of the tick pool samples carried Borrelia spp. DNA, and 20.2% carried SFG Rickettsia DNA. In every hard tick pool Spot Fever Group (SFG) Rickettsia spp. DNA were detected, except for H. lusitanicum. Likewise, D. marginatum was the only species in which Borrelia spp. DNA was not detected. Barbary sheep and wild boar were the host species in which tick pools showed DNA presence of both pathogens. This study increases the knowledge about the presence of Borrelia spp. DNA and SFG Rickettsia spp. DNA in different hard tick species from this geographical area.

Leader-follower formation control based on non-inertial frames for non-holonomic mobile robots.

A chain formation strategy based on mobile frames for a set of n differential drive mobile robots is presented. Considering two consecutive robots in the formation, robots Ri and Ri+1. It is intended that robot Ri+1 follows the delayed trajectory, τ units of time, of the leader robot Ri. In this way, the follower robot Ri+1 becomes the leader robot for robot Ri+ 2 in the formation and so on. With this formation policy, the trailing distance between two consecutive robots varies accordingly to the velocity of the Ri leader robot. Mobile frames are located on the body of the vehicles, in such a way that the position of robot Ri is determined with respect to the frame located on Ri+1 robot. The strategy relies on the fact that the general leader robot R1 describes any trajectory generated by bounded linear v1(t) and angular ω1(t) velocities. For the remaining vehicles in the string, the strategy considers a desired trajectory for the follower robot Ri+1 obtained by an estimation of the delayed trajectory of the leader robot Ri. This desired estimated trajectory is obtained under the knowledge of the actual and past input velocities of the Ri robot. To formally prove the convergence of the formation strategy, the equations describing the time variation of the relative posture between any pair of consecutive vehicles in the formation are obtained, and a feedback law based on local measurements is proposed to get the convergence of robot Ri+1 to the delayed trajectory, τ units of time, of the trajectory previously described by robot Ri. Lyapunov techniques are considered for this fact. The effectiveness of the chain formation solution is evaluated by means of numerical simulations and real time experiments showing an adequate convergence.

Highly correlated ab initio study of the low frequency modes of propane and various monosubstituted isotopologues containing D and 13C.

With the purpose of providing some clues that could encourage the spectral recordings of propane and various monodeuterated and (13)C isotopologues and also to explore their far infrared spectra at low temperatures, the energy levels corresponding to their three lowest frequency modes are determined variationally using a flexible model in three dimensions. Five vibrationally corrected potential energy surfaces are computed using CCSD(T) ab initio calculations. In spite of the quality of these highly correlated potentials in molecules with similar structures, it was proven that an empirical adjustment of the surfaces would enclose accurately the experimental and theoretical frequency residuals and therefore it is also used in the present work. Interacting terms, energy levels and tunneling splittings are provided for CH3CH2CH3, CH3(13)CH2CH3, (13)CH3CH2CH3, CH2DCH2CH3 and CH3CHDCH3. Infrared and Raman transitions of CH3CH2CH3 are assigned. Correlation between symmetry species of the five isotopologue symmetry groups (G36, G36, G18, G6 and G'18, respectively) is established for the classification of the levels and torsional splittings. The rotational constants are determined with CCSD(T)/CBS (A0 = 29263.46 MHz, B0 = 8454.10 MHz and C0 = 7466.64 MHz) using a non-relativistic procedure. Fundamental anharmonic frequencies corresponding to the high and medium amplitude modes are computed for all the isotopologues. The adjusted parameters are accurate enough to be employed in further spectral analysis.

The high-resolution infrared spectrum of DC4H from 450 to 1100 cm-1: overtone, combination, and hot bands.

The high-resolution infrared spectrum of monodeuterated diacetylene has been recorded in the 450-1100 cm(-1) spectral region by Fourier transform infrared spectroscopy. Seven new bands have been identified: the ν3 fundamental (C-C stretch), and the ν8 + ν9, ν7 + ν8, 2ν7, 2ν8, ν8 + ν9 - ν9, and ν6 + ν9 - ν9 combination, overtone, and hot bands. The assigned transitions, together with those previously reported for the fundamental bands [F. Tamassia, L. Bizzocchi, C. Degli Esposti, L. Dore, M. Di Lauro, L. Fusina, M. Villa, and E. Canè, Astron. Astrophys. 549, A38 (2013)], form a comprehensive data set which comprises more than 2500 ro-vibrational transitions, and involves all singly and most doubly excited vibrational states of DC4H lying below 1000 cm(-1). Rotational and vibrational l-type resonance effects among the sub-levels of excited bending states were considered in the analysis, which also included a careful treatment of the various anharmonic interactions coupling many vibrational states lying above 600 cm(-1). Reliable and unambiguous spectroscopic parameters were obtained for each investigated state, including the rotational and centrifugal distortion constants Bv and Dv, the l-type doubling parameter qt, the anharmonicity constants xL(89), xL(69), and the vibrational l-type terms r89, r69 for the v8 = v9 = 1 and v6 = v9 = 1 bend-bend combination states.

Radionuclide activities and metal concentrations in sediments of the Sebou Estuary, NW Morocco, following a flooding event.

This study presents metal concentrations (Fe, Mg, Mn, Co, Cu, Zn, Pb, As, Sr and V) and radionuclide activities ((40)K, (137)Cs, (210)Pb, (226)Ra, (228)Ac, (234)Th and (212)Pb) in surface deposits and a sediment core from the Sebou Estuary, Northwest Morocco. Samples were collected in April 2009, about 2 months after a flooding event, and analysed using a well-type coaxial gamma-ray detector and inductively coupled plasma-quadrupole mass spectrometry. Activities of radionuclides and concentrations of almost all elements in surface samples displayed only moderate spatial variation, suggesting homogenous deposition of eroded local soil in response to intense precipitation. Excess (210)Pb displayed relatively constant activity throughout the sediment core, preventing dating and precluding determination of the historical accumulation rates of pollutants at the core site. Some elements showed non-systematic trends with depth and displayed local maxima and minima. Other elements presented relatively systematic concentration trends or relatively constant levels with discrete maxima and/or minima. Except for Mn, Sr and Cr, all metal concentrations in sediment were below levels typical of polluted systems, suggesting little human impact or losses of metals from sediment particles.

Conjugate treatment with high concentration normobaric oxygen and hyaluronic acid for vaginal atrophy: a prospective study.

OBJECTIVE: Vulvovaginal atrophy is a condition closely related to low circulating estrogen levels, with post-menopause being the main cause. However, patients of childbearing age may also present with these symptoms due to treatments that reduce estrogen production. Local estrogen therapy is the causal treatment of local symptoms, but it is not always accepted and is often abandoned by patients. In recent years, alternative therapies have been proposed: fractional CO2 laser or the conjugate treatment with normobaric oxygen and hyaluronic acid, the latter being the subject of this study. The study aimed to evaluate the effectiveness of conjugate topical treatment with normobaric oxygen and hyaluronic acid. PATIENTS AND METHODS: 50 patients were evaluated and treated with 5 applications of 15 minutes each, every 15 days, with Caressflow®. All patients presented at least one of the symptoms related to vulvovaginal atrophy: dryness, burning, and dyspareunia. In all cases, vulvoscopy, colposcopy, and cervicovaginal cytology were performed. The patients were interviewed with an analogic scale (VAS) concerning the severity of symptoms before and after the treatment. Colposcopy and PAP-smear were assessed by mean of Vaginal Health Index Score (VHI) at baseline and at the end of the treatment. RESULTS: All patients completed the treatment scheme and presented with a significant improvement in subjective symptoms. The colposcopy and PAP-smear performed 10 days after the end of the last treatment showed a significant improvement in the appearance and elasticity of the vaginal epithelium and the cytological picture, which showed, in the sample taken after treatment, hyaluronic acid vesicles within the cell cytoplasm. CONCLUSIONS: This study corroborates the data presented in the latest published papers on the effectiveness of treatment with normobaric O2 and hyaluronic acid on vaginal atrophy. Efficacy has been confirmed both in terms of subjective symptoms reported by the patients and objective improvement at colposcopy and PAP-smear cytology.

Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia.

Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⁻² had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⁻² (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL.

CCSD(T) study of CD3-O-CD3 and CH3-O-CD3 far-infrared spectra.

From a vibrationally corrected 3D potential energy surface determined with highly correlated ab initio calculations (CCSD(T)), the lowest vibrational energies of two dimethyl-ether isotopologues, (12)CH(3)-(16)O-(12)CD(3) (DME-d(3)) and (12)CD(3)-(16)O-(12)CD(3) (DME-d(6)), are computed variationally. The levels that can be populated at very low temperatures correspond to the COC-bending and the two methyl torsional modes. Molecular symmetry groups are used for the classification of levels and torsional splittings. DME-d(6) belongs to the G(36) group, as the most abundant isotopologue (12)CH(3)-(16)O-(12)CH(3) (DME-h(6)), while DME-d(3) is a G(18) species. Previous assignments of experimental Raman and far-infrared spectra are discussed from an effective Hamiltonian obtained after refining the ab initio parameters. Because a good agreement between calculated and experimental transition frequencies is reached, new assignments are proposed for various combination bands corresponding to the two deuterated isotopologues and for the 020 → 030 transition of DME-d(6). Vibrationally corrected potential energy barriers, structural parameters, and anharmonic spectroscopic parameters are provided. For the 3N - 9 neglected vibrational modes, harmonic and anharmonic fundamental frequencies are obtained using second-order perturbation theory by means of CCSD and MP2 force fields. Fermi resonances between the COC-bending and the torsional modes modify DME-d(3) intensities and the band positions of the torsional overtones.

Diversity of Flavobacterium psychrophilum and the potential use of its phages for protection against bacterial cold water disease in salmonids.

Flavobacterium psychrophilum causes rainbow trout fry syndrome (RTFS) and cold water disease (CWD) in salmonid aquaculture. We report characterization of F. psychrophilum strains and their bacteriophages isolated in Chilean salmonid aquaculture. Results suggest that under laboratory conditions phages can decrease mortality of salmonids from infection by their F. psychrophilum host strain. Twelve F. psychrophilum isolates were characterized, with DNA restriction patterns showing low diversity between strains despite their being obtained from different salmonid production sites and from different tissues. We isolated 15 bacteriophages able to infect some of the F. psychrophilum isolates and characterized six of them in detail. DNA genome sizes were close to 50 Kbp and corresponded to the Siphoviridae and Podoviridae families. One isolate, 6H, probably contains lipids as an essential virion component, based on its chloroform sensitivity and low buoyant density in CsCl. Each phage isolate rarely infected F. psychrophilum strains other than the strain used for its enrichment and isolation. Some bacteriophages could decrease mortality from intraperitoneal injection of its host strain when added together with the bacteria in a ratio of 10 plaque-forming units per colony-forming unit. While we recognize the artificial laboratory conditions used for these protection assays, this work is the first to demonstrate that phages might be able protect salmonids from RTFS or CWD.

Rapid maxillary expansion in children with Obstructive Sleep Apnoea Syndrome (OSAS).

AIM: to evaluate the effects of rapid maxillary expansion (RME) in a group of OSAS preschool children. MATERIALS AND METHODS: Lateral cephalograms of 15 OSAS children (8 boys and 7 girls, age mean ± SD: 5.94 ± 1.64 years) were analysed at the start of treatment with RME (T0). All subjects were revaluated after a mean period of 1.57 ± 0.58 years (T1). At this time the sample was divided into 2 groups according to the change in the respiratory disturbance index (RDI): an improved group (I: 8 subjects) and a stationary/worsened group (SW: 7 subjects). Differences between I and SW children with respect to values of cephalometric variables at T0 and to variations between T0 and T1 were evaluated using Mann-Whitney U test. Differences between T0 and T1 values in the overall group of children and separately in I and SW groups were assessed using Wilcoxon test. RESULTS: At the start of treatment, the I group was characterised by more retrognathic jaws with lower values of SNA (p=0.055) and SNB (p=0.020) and higher age values (p=0.093) when compared to SW group. After treatment, the I group showed an increase in SNA and SNB angle significantly higher than SW group (p=0.004 and p=0.003, respectively). On the contrary, I and SW groups did not differ as for variation in the skeletal divergency and in the total facial height. CONCLUSION: OSAS preschool children with retrognathic jaws could benefit from RME treatment.