Posttraumatic massive bleeding: a challenging multidisciplinary task

Massive bleeding is a key issue in the treatment of trauma and surgery. It does in fact account for more than 50% of all trauma-related deaths within the first 48 h following hospital admission, and it can significantly raise the mortality rate of any kind of surgery. Despite this great clinical relevance, evidence on the management of massive bleeding is surprisingly scarce, and its treatment is often based on empirical grounds. Successful treatment of massive haemorrhage depends on better understanding of the associated physiological changes as well as on good team work between the different specialists involved in the management of such a complex condition. The aim of this article is to provide an overview of the pathophysiology as well as of current treatment options of such a condition, including the new concept of “damage control resuscitation”, which integrates permissive hypotension, haemostatic resuscitation and damage control surgery.     

Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components

Gliosarcoma is a variant of glioblastoma multiforme characterized by two components displaying gliomatous or sarcomatous differentiation. We investigated 38 gliosarcomas for aberrations of tumor-suppressor genes and proto-oncogenes that are commonly altered in glioblastomas. Amplification of CDK4, MDM2, EGFR, and PDGFRA were found in 11% (4/35), 8% (3/38), 8% (3/38), and 3% (1/35) of the tumors, respectively. Nine of 38 gliosarcomas (24%) carried TP53 mutations. PTEN mutations were identified in 45% (9/20) of the investigated tumors. Twenty gliosarcomas were analyzed by comparative genomic hybridization (CGH). Chromosomal imbalances commonly detected were gains on chromosomes 7 (15/20; 75%), X (4/20; 20%), 9q, and 20q (3/20, 15% each); and losses on chromosomes 10 and 9p (7/20, 35% each), and 13q (3/20, 15%). Five different high-level amplifications were mapped to 4q12-q21 (1 case), 6p21 (1 case), 7p12 (2 cases), proximal 12q (4 cases), and 14q32 (1 case) by CGH. Southern blot and/or differential PCR analyses identified amplification of PDGFRA (4q12), CCND3 (6p21), EGFR (7p12), CDK4 (12q14) and/or MDM2 (12q14.3-q15), and AKT1 (14q32.3) in the respective tumors. Separate analysis of the gliomatous and sarcomatous components of eight gliosarcomas by CGH after microdissection and universal DNA amplification revealed that both components shared 57% of the chromosomal imbalances detected. Taken together, our data indicate that the genomic changes in gliosarcomas closely resemble those found in glioblastomas. However, the number of chromosomes involved in imbalances in gliosarcomas was significantly lower than that in glioblastomas, indicating a higher genomic stability in gliosarcomas. In addition, we provide further support for the hypothesis that the gliomatous and sarcomatous components are derived from a single precursor cell clone, which progressed into subclones with distinct morphological features during tumor evolution. According to our data, gain/amplification of genes on proximal 12q may facilitate the development of a sarcomatous phenotype.     

Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas

Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.     

Monitoring stroke progression: in vivo imaging of cortical perfusion,blood–brain barrier permeability and cellular damage in the rat photothrombosis model

Focal cerebral ischemia is among the main causes of death and disability worldwide. The ischemic core often progresses, invading the peri-ischemic brain; however, assessing the propensity of the peri-ischemic brain to undergo secondary damage, understanding the underlying mechanisms, and adjusting treatment accordingly remain clinically unmet challenges. A significant hallmark of the peri-ischemic brain is dysfunction of the blood–brain barrier (BBB), yet the role of disturbed vascular permeability in stroke progression is unclear. Here we describe a longitudinal in vivo fluorescence imaging approach for the evaluation of cortical perfusion, BBB dysfunction, free radical formation and cellular injury using the photothrombosis vascular occlusion model in male Sprague Dawley rats. Blood–brain barrier dysfunction propagated within the peri-ischemic brain in the first hours after photothrombosis and was associated with free radical formation and cellular injury. Inhibiting free radical signaling significantly reduced progressive cellular damage after photothrombosis, with no significant effect on blood flow and BBB permeability. Our approach allows a dynamic follow-up of cellular events and their response to therapeutics in the acutely injured cerebral cortex.     

The complete genome sequence of <Emphasis Type="Italic">Triticum</Emphasis> mosaic virus,a new wheat-infecting virus of the High Plains

The genome of Triticum mosaic virus (TriMV), a recently discovered mite-transmitted wheat potyvirus, was sequenced, characterized, and compared to other members of the family Potyviridae. TriMV has a single mRNA strand of 10,266 nucleotides with a predicted polyprotein consisting of 3,112 peptides. Protein alignments of the coat protein demonstrate that TriMV has 45.9% identity to Sugarcane streak mosaic virus strain AP (SCSMV-AP), but shares only 23.2% identity to Wheat streak mosaic virus. Although TriMV is mite-transmitted and could be placed in the genus Tritimovirus, it is significantly divergent and should be placed in the newly proposed genus Susmovirus.     

Biologic and molecular mechanisms for sex differences in pharmacokinetics,pharmacodynamics, and pharmacogenetics: Part II

There are specific pharmacology issues related to women's unique physiology, including the hormonal changes that occur throughout their life span. Studies have shown alterations in drug metabolism in relation to phase of menstrual cycle, during pregnancy, or after menopause. In the brain, hormones can alter the response to drugs through various mechanisms. Estrogen and other compounds can bind to the estrogen receptor and modulate a wide range of activities within the cell. In addition, animal studies have demonstrated sexual dimorphism in the brain in terms of both the type of response to estrogen and the response as related to timing of administration. Many normal physiological changes that occur during pregnancy can affect pharmacokinetics and pharmacodynamics. These changes during pregnancy are dramatic rises in levels of estrogen and progesterone, increases in maternal blood volume, altered protein binding resulting from a drop in albumin levels, and a rise in levels of other plasma proteins. The field of chronobiology offers a way to study these changes in biological functions. Chronopharmacology is the study of how biological rhythms, particularly 24-hour, menstrual cycle, and annual rhythms, impact the pharmacokinetics and pharmacodynamics of drugs as a function of their timing. Chronopharmacokinetics is the study of the absorption, distribution, metabolism, and elimination of medicines according to the time of day, menstrual cycle, or year. In addition to applying chronobiology to the study of drugs used in women, new technologies were addressed from computer modeling, pharmacogenetics (genetics of the response to drugs), and in vivo drug metabolism studies.