Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation

Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect

Racemic ketamine in adult head injury patients: use in endotracheal suctioning

INTRODUCTION: Endotracheal suctioning (ETS) is essential for patient care in an ICU but may represent a cause of cerebral secondary injury. Ketamine has been historically contraindicated for its use in head injury patients, since an increase of intracranial pressure (ICP) was reported; nevertheless, its use was recently suggested in neurosurgical patients. In this prospective observational study we investigated the effect of ETS on ICP, cerebral perfusion pressure (CPP), jugular oxygen saturation (SjO2) and cerebral blood flow velocity (mVMCA) before and after the administration of ketamine. METHODS: In the control phase, ETS was performed on patients sedated with propofol and remifentanil in continuous infusion. If a cough was present, patients were assigned to the intervention phase, and 100 \u3b3/kg/min of racemic ketamine for 10 minutes was added before ETS. RESULTS: In the control group ETS stimulated the cough reflex, with a median cough score of 2 (interquartile range (IQR) 1 to 2). Furthermore, it caused an increase in mean arterial pressure (MAP) (from 89.0\u2009\ub1\u200911.6 to 96.4\u2009\ub1\u200913.1 mmHg; P <0.001), ICP (from 11.0\u2009\ub1\u20096.7 to 18.5\u2009\ub1\u20098.9 mmHg; P <0.001), SjO2 (from 82.3\u2009\ub1\u20097.5 to 89.1\u2009\ub1\u20095.4; P\u2009=\u20090.01) and mVMCA (from 76.8\u2009\ub1\u200920.4 to 90.2\u2009\ub1\u200930.2 cm/sec; P\u2009=\u20090.04). CPP did not vary with ETS. In the intervention group, no significant variation of MAP, CPP, mVMCA, and SjO2 were observed in any step; after ETS, ICP increased if compared with baseline (15.1\u2009\ub1\u20099.4 vs. 11.0\u2009\ub1\u20096.4 mmHg; P <0.05). Cough score was significantly reduced in comparison with controls (P <0.0001). CONCLUSIONS: Ketamine did not induce any significant variation in cerebral and systemic parameters. After ETS, it maintained cerebral hemodynamics without changes in CPP, mVMCA and SjO2, and prevented cough reflex. Nevertheless, ketamine was not completely effective when used to control ICP increase after administration of 100 \u3b3/kg/min for 10 minutes

Acute febrile illness is associated with Rickettsia spp infection in dogs

BACKGROUND: Rickettsia conorii is transmitted by Rhipicephalus sanguineus ticks and causes Mediterranean Spotted Fever (MSF) in humans. Although dogs are considered the natural host of the vector, the clinical and epidemiological significance of R. conorii infection in dogs remains unclear. The aim of this prospective study was to investigate whether Rickettsia infection causes febrile illness in dogs living in areas endemic for human MSF. METHODS: Dogs from southern Italy with acute fever (n = 99) were compared with case–control dogs with normal body temperatures (n = 72). Serology and real-time PCR were performed for Rickettsia spp., Ehrlichia canis, Anaplasma phagocytophilum/A. platys and Leishmania infantum. Conventional PCR was performed for Babesia spp. and Hepatozoon spp. Acute and convalescent antibodies to R. conorii, E. canis and A. phagocytophilum were determined. RESULTS: The seroprevalence rates at first visit for R. conorii, E. canis, A. phagocytophilum and L. infantum were 44.8%, 48.5%, 37.8% and 17.6%, respectively. The seroconversion rates for R. conorii, E. canis and A. phagocytophilum were 20.7%, 14.3% and 8.8%, respectively. The molecular positive rates at first visit for Rickettsia spp., E. canis, A. phagocytophilum, A. platys, L. infantum, Babesia spp. and Hepatozoon spp. were 1.8%, 4.1%, 0%, 2.3%, 11.1%, 2.3% and 0.6%, respectively. Positive PCR for E. canis (7%), Rickettsia spp. (3%), Babesia spp. (4.0%) and Hepatozoon spp. (1.0%) were found only in febrile dogs. The DNA sequences obtained from Rickettsia and Babesia PCRs positive samples were 100% identical to the R. conorii and Babesia vogeli sequences in GenBank®, respectively. Febrile illness was statistically associated with acute and convalescent positive R. conorii antibodies, seroconversion to R. conorii, E. canis positive PCR, and positivity to any tick pathogen PCRs. Fourteen febrile dogs (31.8%) were diagnosed with Rickettsia spp. infection based on seroconversion and/or PCR while only six afebrile dogs (12.5%) seroconverted (P = 0.0248). The most common clinical findings of dogs with Rickettsia infection diagnosed by seroconversion and/or PCR were fever, myalgia, lameness, elevation of C-reactive protein, thrombocytopenia and hypoalbuminemia. CONCLUSIONS: This study demonstrates acute febrile illness associated with Rickettsia infection in dogs living in endemic areas of human MSF based on seroconversion alone or in combination with PCR

"Osservatorio territoriale droga e tossicodipendenze. Il fenomeno delle dipendenze nel territorio della ASL MI 2. Anno 2009- X Rapporto"

Report on the state of legal and illegal substances use in the territory of the Local Healthcare Service-MI 2, Province of Milan.Il Report analizza il fenomeno delle dipendenze nel territorio della ASL Milano 2. La descrizione del fenomeno si sviluppa intorno all\u27analisi degli indicatori individuati dall\u27Osservatorio Europeo delle Dipendenze di Lisbona (OEDT): 1-uso di sostanze nella popolazione generale (questo indicatore va a rilevare i comportamenti nei confronti di alcol e sostanze psicoattive da parte della popolazione generale); 2-prevalenza d\u27uso problematico delle sostanze psicoattive; 3-domanda di trattamento degli utilizzatori di sostanze; 4-mortalit? degli utilizzatori di sostanze; 5-malattie infettive. Altri due importanti indicatori che si stanno sviluppando, e che vengono qui illustrati, sono l\u27analisi delle Schede di Dimissione Ospedaliera (SDO) e gli indicatori relativi alle conseguenza sociali dell\u27uso di droghe (criminalit? droga correlata). Inoltre sono state applicate diverse metodologie standard di stima sia per quantificare la quota parte sconosciuta di utilizzatori di sostanze che non afferiscono ai servizi, sia per identificarne alcune caratteristiche

Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53

Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2/M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibitor UCN-01, we successfully abrogated IO-induced G2/M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC50 values. Likewise, overexpression of an inducible wild-type p53 in cells natively presenting a mutant protein decreased their IC50 for IO. These results were also confirmed in primary CD22-positive cells derived from B-ALL patients at diagnosis and from patients with r/r B-ALL. Furthermore, co-treatment with IO and UCN-01 significantly increased cell death in primary cells expressing mutant p53. In summary, our findings suggest that p53 status may represent a biomarker predictive of IO efficacy in patients diagnosed with CD22-positive malignancies

Mine, Yours, Ours? Sharing Data on Human Genetic Variation

The achievement of a robust, effective and responsible form of data sharing is currently regarded as a priority for biological and bio-medical research. Empirical evaluations of data sharing may be regarded as an indispensable first step in the identification of critical aspects and the development of strategies aimed at increasing availability of research data for the scientific community as a whole. Research concerning human genetic variation represents a potential forerunner in the establishment of widespread sharing of primary datasets. However, no specific analysis has been conducted to date in order to ascertain whether the sharing of primary datasets is common-practice in this research field. To this aim, we analyzed a total of 543 mitochondrial and Y chromosomal datasets reported in 508 papers indexed in the Pubmed database from 2008 to 2011. A substantial portion of datasets (21.9%) was found to have been withheld, while neither strong editorial policies nor high impact factor proved to be effective in increasing the sharing rate beyond the current figure of 80.5%. Disaggregating datasets for research fields, we could observe a substantially lower sharing in medical than evolutionary and forensic genetics, more evident for whole mtDNA sequences (15.0% vs 99.6%). The low rate of positive responses to e-mail requests sent to corresponding authors of withheld datasets (28.6%) suggests that sharing should be regarded as a prerequisite for final paper acceptance, while making authors deposit their results in open online databases which provide data quality control seems to provide the best-practice standard. Finally, we estimated that 29.8% to 32.9% of total resources are used to generate withheld datasets, implying that an important portion of research funding does not produce shared knowledge. By making the scientific community and the public aware of this important aspect, we may help popularize a more effective culture of data sharing

Residuals of Intelligent Design in Contemporary Theories about Language Nature and Origins

Some contemporary theories about the origin and the nature of language resort to concepts with no bearing on Darwinian evolutionary hypothesis or evo-devo perspective which are both based on the reconstruction of species morphological structure transformation. These theories, which evoke qualitative leap, cultural evolution, structure/function coevolution as esplicative principles for human evolution, in our opinion, result compatible in some points with the most recent Intelligent Design (ID) accounts. Attempting to substantiate itself as a scientific theory, the contemporary ID is ready to give up (or suspend) creationist explanation just to impeding Darwin’s fundamental idea according to which it’s possible to explain evolution only through a gradual material modification of structures. For comprehending a complex phenomenon as human language – according to ID – it’s necessary appealing to a second substance, whatever it is. This idea seems to be at the bottom of all those theories which have rejected monistic structural explanation (modification of physiological structures) for embracing functional, psychological or cultural accounts. We consider these kinds of explanation real unresolved residuals of ID, residuals nested in the heart of the most accredited scientific theories

Hsp90: A New Player in DNA Repair?

Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted