[Acute coronary syndrome in older people]. / Akutes Koronarsyndrom beim älteren Menschen.

The acute coronary syndrome (ACS) is subdivided into ST segment elevation myocardial infarction (STEMI), non-ST segment elevation acute coronary syndrome (NSTE-ACS) and unstable angina pectoris. It poses a particular challenge in terms of diagnostics and treatment, especially in the elderly. Starting with the possibly difficult anamnesis, through the laboratory chemical findings up to special features in the electrocardiogram (ECG), echocardiography and angiography, these patients should be considered in some ways different to the younger population. Because of the mortality and morbidity after ACS, especially in old age, it is important to adhere to evident strategies in diagnostics and treatment and to employ specially trained personnel for people with acute chest pain in order to improve the prognosis and quality of life. A first important step is to provide certified chest pain units which ensure smooth diagnostics and treatment and thus positively influence the clinical decision-making processes.

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

Increased fear learning, spatial learning as well as neophobia in Rgs2-/- mice.

Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2-/- mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2-/- mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2-/- mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems.

Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice.

Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2-/-) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph+/-) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.

[Focal point emergency departments]. / Brennpunkt Notaufnahme.

The number of patients treated in hospital emergency departments in Germany has risen in recent years to approximately 20 million. This escalation also applies to the increasing numbers of patients presenting with neurological symptoms and diseases, which occur in approximately 20 % of emergency patients. In addition to patients with stroke, inflammatory or degenerative central nervous system (CNS) and peripheral nervous system (PNS) disorders who need urgent treatment, more and more patients with nonspecific complaints or conditions attend emergency departments for elective treatment, not least because timely appointments with specialist neurologists in practices could not be obtained. Neurological expertise and presence in emergency departments at the level of specialist standard are therefore indispensable for providing a professional level of treatment, which also corresponds to current legal requirements. The implementation of a generalist emergency physician in Germany, as introduced in some European countries, would mean a retrograde step for neurological expertise in emergency admission management. The discipline of neurology must work together with other emergency disciplines to improve the financing of emergency departments and provide neurologists working there with a substantive curriculum of further and continuing education in emergency-related aspects of neurology. The discipline of neurology has a responsibility to emergency patients within its range of competencies and must, therefore, strengthen and improve its role in healthcare politics and concerning organizational and personnel aspects of neurological emergencies.

Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a.

The effects of the Fc silencing mutations such as leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA) and the alanine (A) to asparagine (N) substitution at position 297 (N297A) are well investigated for human IgG. However, the effects of the same two silencing Fc mutations in a mouse IgG backbone are not yet well investigated in respect to binding to mouse Fc gamma receptors (FcγRs), complement and subsequent effector functions. By using a mouse IgG2a tool antibody directed against mouse OX40L, we demonstrate a strongly reduced binding of the two Fc mutants to high and low affinity recombinant and cell expressed mouse FcγRs, when compared to the mouse IgG2a with the wild type (wt) backbone. Reduced FcγR binding by the two investigated Fc mutants could further be confirmed on primary mouse macrophages expressing their native FcγRs. In addition, we reveal that the LALA and N297A mutations in the mIgG2a also slightly reduced binding to C1q of human origin. Thus, here we provide experimental evidence that the two investigated Fc mutations in the mouse IgG backbone lead to similar "silencing" properties as previously demonstrated for the human IgG and thus represent a useful method to alter effector functions in tool antibodies to be used in mouse models.

[Chest pain units or chest pain algorithm?]. / Chest Pain Units oder Chest-Pain-Algorithmus?

BACKGROUND: A large number of patients present to the emergency department (ED) for evaluation of acute chest pain. About 10-15% are caused by acute myocardial infarction (MI), and over 50% of cases are due to noncardiac reasons. Further improvement for chest pain evaluation appears necessary. OBJECTIVES: What are current options to improve chest pain evaluation in Germany? METHODS: A selective literature search was performed using the following terms: "chest pain", "emergency department", "acute coronary syndrome" and "chest pain evaluation". RESULTS AND DISCUSSION: A working group of the German Society of Cardiology published recommendations for infrastructure, equipment and organisation of chest pain units in Germany, which should be separated from the ED of hospitals and be under the leadership of a cardiologist. A symptom-based decision for acute care would be preferable if all differential diagnoses of diseases could be managed by one medical specialty: However, all four main symptoms of patients with acute MI (chest pain, acute dyspnea, abdominal pain, dizziness) are also caused by diseases of different specialties. Evaluation and treatment of acute chest pain by representatives of one specialty would lead to over- or undertreatment of affected patients. Therefore we suggest a multidisciplinary evaluation of patients with acute chest pain including representatives of emergency and critical care physicians, cardiologists, internists, geriatricians, family physicians, premedics and emergency nurses. Definition of key indicators of performance and institutionalized feedback will help to further improve quality of care.

[Health care situation of patients with suspected sepsis in a German emergency department]. / Versorgungsprozesse von Patienten mit Verdacht auf Sepsis in einer deutschen Notaufnahme.

BACKGROUND: The in-hospital mortality of patients with severe sepsis and septic shock (ssss) is high. Of note, little is known about the health care situation of patients with sepsis in German emergency departments. The aim of the study was to analyze whether sepsis patients are treated according to current guidelines, to identify the treatment sites within the hospital and to evaluate the death rate of affected patients during index hospitalization. PATIENTS AND METHODS: In this single-centre, prospective and observational trial we analyzed consecutive patients with complaints of sepsis during August and September 2012. RESULTS: During the study period 151 patients presented with complaints of sepsis (age 68.3 ± 18 years, 54.3% men, 45% with ssss, in-hospital mortality of the overall cohort: 14.6%). The Surviving Sepsis Campaign three hour bundle (lactate, blood cultures, broad spectrum antibiotics, and volume) was carried out in 54.2% of patients with ssss. In case of ssss, broad spectrum antibiotics were initiated in the emergency department in 85.4%. Patients with ssss were admitted to wards with usual care in 67.2%, in 32.8% they were admitted to an intensive or intermediate care unit. The in-hospital mortality of patients with ssss during their index hospitalization was 27.8%. CONCLUSION: Despite the high in-hospital mortality rate, more than two thirds of the patients with ssss were admitted to wards with usual care. We call for action 1) to early identify affected patients, 2) to provide adequate risk stratification tools and 3) to realize an early disposition of patients to the appropriate care units.

Early venous drainage after successful endovascular recanalization in ischemic stroke -- a predictor for final infarct volume?

INTRODUCTION: Peri-ischemic early venous filling (PEVD) has been reported to occur at certain stages of brain infarction and has previously been termed as "luxury perfusion". We report on the significance of PEVD after a successful endovascular recanalization. METHODS: We retrospectively evaluated all patients who underwent endovascular stroke treatment from February 2006 to April 2010 in two centers. PEVD was rated as present or absent. Infarction was evaluated on computed tomography (CT) ≥ 18 h post-treatment. Localization of the PEVD and the infarction was noted for the anterior and posterior circulation; for the anterior circulation, also deep and superficial veins/brain regions were defined. RESULTS: A total of 151 of the 175 patients developed an infarct. Of these 151 patients, 118 had PEVD (sensitivity 78.1%); meanwhile, 20 of 24 patients without an infarction had no PEVD (specificity 83.3%). Consistent localization of the PEVD and the infarct was seen in 107/151 patients (70.9%); in 28 of these 107 cases, the territory of PEVD was smaller than the infarct (26.2%) and exceeded it in 7/107 patients (5.6%). Territorial congruency of the PEVD and the final infarct was 57.6-75% for deep/superficial brain regions of the anterior, but only 16.7% for the posterior circulation. Separate evaluation for the anterior circulation resulted in a 94.9% sensitivity and an 81.0% specificity. CONCLUSION: PEVD is a potential angiographic predictor for irreversible regional tissue damage and subsequent infarction despite successful recanalization. This finding deserves further studies and may influence therapeutic decisions such as post-treatment anticoagulative medication. It may also be considered in potential refined classifications of angiographic reperfusion success in the future.

Intravenous antiarrhythmic doses of lidocaine increase the survival rate of CA1 neurons and improve cognitive outcome after transient global cerebral ischemia in rats.

Brain ischemia is often a consequence of cardiac or neurologic surgery. Prophylactic pharmacological neuroprotection would be beneficial for patients undergoing surgery to reduce brain damage due to ischemia. We examined the effects of two antiarrhythmic doses of lidocaine (2 or 4 mg/kg) on rats in a model of transient global cerebral ischemia. The occlusion of both common carotid arteries combined with hypotension for 10 min induced neuronal loss in the CA1 region of the hippocampus (18±12 vs. 31±4 neurons/200 µm linear distance of the cell body layer, X±SD; P<0.01). Lidocaine (4 mg/kg) 30 min before, during and 60 min after ischemia increased dorsal hippocampal CA1 neuronal survival 4 weeks after global cerebral ischemia (30±9 vs. 18±12 neurons/200 µm; P<0.01). There was no significant cell loss after 10 min of ischemia in the CA3 region, the dentate region or the amygdalae; these regions were less sensitive than the CA1 region to ischemic damage. Lidocaine not only increased hippocampal CA1 neuronal survival, but also preserved cognitive function associated with the CA1 region. Using an active place avoidance task, there were fewer entrances into an avoidance zone, defined by relevant distal room-bound cues, in the lidocaine groups. The untreated ischemic group had an average, over the nine sessions, of 21±12 (X±SD) entrances into the avoidance zone per session; the 4 mg/kg lidocaine group had 7±8 entrances (P<0.05 vs. untreated ischemic) and the non-ischemic control group 7±5 entrances (P<0.01 vs. untreated ischemic). Thus, a clinical antiarrhythmic dose of lidocaine increased the number of surviving CA1 pyramidal neurons and preserved cognitive function; this indicates that lidocaine is a good candidate for clinical brain protection.

Furin cleavage of bacterial expressed glutathione-S-transferase-pro-transforming growth factor beta1 fusion protein in vitro.

To investigate the processing of transforming growth factor beta1 (TGFbeta1) pro-protein by furin protease we expressed a GST-pro-TGFbeta1 fusion protein in bacteria. Analysis of the furin digestion pattern revealed the liberation of 12.5 kDa TGFbeta1 monomers. There was no evidence for cleavage of an alternative furin site within the pro-protein.

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes.

The role of UVA-radiation-the major fraction in sunlight-in human skin carcinogenesis is still elusive. We here report that different UVA exposure regime (4 x 5 J/cm(2) per week or 1 x 20 J/cm(2) per week) caused tumorigenic conversion (tumors in nude mice) of the HaCaT skin keratinocytes. While tumorigenicity was not associated with general telomere shortening, we found new chromosomal changes characteristic for each recultivated tumor. Since this suggested a nontelomere-dependent relationship between UVA irradiation and chromosomal aberrations, we investigated for alternate mechanisms of UVA-dependent genomic instability. Using the alkaline and neutral comet assay as well as gamma-H2AX foci formation on irradiated HaCaT cells (20-60 J/cm(2)), we show a dose-dependent and long lasting induction of DNA single and double (ds) strand breaks. Extending this to normal human skin keratinocytes, we demonstrate a comparable damage response and, additionally, a significant induction and maintenance of micronuclei (MN) with more acentric fragments (indicative of ds breaks) than entire chromosomes particularly 5 days post irradiation. Thus, physiologically relevant UVA doses cause long-lasting DNA strand breaks, a prerequisite for chromosomal aberration that most likely contribute to tumorigenic conversion of the HaCaT cells. Since normal keratinocytes responded similarly, UVA may likewise contribute to the complex karyotype characteristic for human skin carcinomas.

Sevoflurane immediate preconditioning alters hypoxic membrane potential changes in rat hippocampal slices and improves recovery of CA1 pyramidal cells after hypoxia and global cerebral ischemia.

Pretreatment with anesthetics before but not during hypoxia or ischemia can improve neuronal recovery after the insult. Sevoflurane, a volatile anesthetic agent, improved neuronal recovery subsequent to 10 min of global cerebral ischemia when it was present for 1 h before the ischemia. The mean number of intact hippocampal cornus ammonis 1 (CA1) pyramidal neurons in rats subjected to cerebral ischemia without any pretreatment was 17+/-5 (neurons/mm+/-S.D.) 6 weeks after the ischemia; naïve, non-ischemic rats had 177+/-5 neurons/mm. Rats pretreated with either 2% or 4% sevoflurane had 112+/-57 or 150+/-15 CA1 pyramidal neurons/mm respectively (P<0.01) 6 weeks after global cerebral ischemia. In order to examine the mechanisms of protection we used hypoxia to generate energy deprivation. Intracellular recordings were made from CA1 pyramidal neurons in rat hippocampal slices; the recovery of resting and action potentials after hypoxia was used as an indicator of neuronal survival. Pretreatment with 4% sevoflurane for 15 min improved neuronal recovery 1 h after the hypoxia; 90% of the sevoflurane-pretreated neurons recovered while none (0%) of the untreated neurons recovered. Pretreatment with sevoflurane enhanced the hypoxic hyperpolarization(-6.4+/-0.6 vs. -3.3+/-0.3 mV) and reduced the final level of the hypoxic depolarization (-39+/-6 vs. -0.3+/-2 mV) during hypoxia. Chelerythrine (5 muM), a protein kinase C/protein kinase M inhibitor, blocked both the improved recovery (10%) and the electrophysiological changes with 4% sevoflurane preconditioning. Two percent sevoflurane for 15 min before hypoxia did not improve recovery (0% recovery both groups) and did not enhance the hypoxic hyperpolarization or reduce the final depolarization during hypoxia. However if 2% sevoflurane was present for 1 h before the hypoxia then there was significantly improved recovery, enhanced hypoxic hyperpolarization, and reduced final depolarization. Thus we conclude that sevoflurane preconditioning improves recovery in both in vivo and in vitro models of energy deprivation and that preconditioning enhances the hypoxic hyperpolarization and reduces the hypoxic depolarization. Anesthetic preconditioning may protect neurons from ischemia by altering the electrophysiological changes a neuron undergoes during energy deprivation.

Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells.

Aneuploidy is a fundamental principle of many cancer cells and is mostly related to defects in mitotic segregation of chromosomes. Many solid tumors as well as some preneoplastic lesions have been shown to contain polyploid chromosome numbers. The exact mechanisms behind whole-genome duplications are not known but have been linked to compromised mitotic checkpoint genes. We now report that the telomere checkpoint plays a key role for polyploidy in colon cancer cells. Telomerase suppression by a dominant-negative mutant of hTERT and consecutive telomere dysfunction in wild-type HCT116 colon cancer cells resulted in only minor stable chromosomal alterations. However, higher ploidy levels with up to 350 chromosomes were found when the cell-cycle checkpoint proteins p53 or p21 were absent. These findings indicate that telomere dysfunction in the absence of cell-cycle control may explain the high frequency of alterations in chromosome numbers found in many solid tumors.

Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation.

Non-melanoma skin cancers, in particular keratoacanthomas (KAs) and squamous cell carcinomas (SCCs), have become highly frequent tumor types especially in immune-suppressed transplant patients. Nevertheless, little is known about essential genetic changes. As a paradigm of 'early' changes, that is, changes still compatible with tumor regression, we studied KAs by comparative genomic hybridization and show that gain of chromosome 11q is not only one of the most frequent aberration (8/18), but in four tumors also the only aberration. Furthermore, 11q gain correlated with amplification of the cyclin D1 locus (10/14), as determined by fluorescence in situ hybridization, and overexpression of cyclin D1 protein (25/31), as detected by immunohistochemistry. For unraveling the functional consequence, we overexpressed cyclin D1 in HaCaT skin keratinocytes. These cells only gained little growth advantage in conventional and in organotypic co-cultures. However, although the control vector-transfected cells formed a well-stratified and orderly differentiated epidermis-like epithelium, they showed deregulation of tissue architecture with an altered localization of proliferation and impaired differentiation. The most severe phenotype was seen in a clone that additionally upregulated cdk4 and p21. These cells lacked terminal differentiation, exhibited a more autonomous growth in vitro and in vivo and even formed tumors in two injection sites with a growth pattern resembling that of human KAs. Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth.

Lidocaine attenuates apoptosis in the ischemic penumbra and reduces infarct size after transient focal cerebral ischemia in rats.

Lidocaine is a local anesthetic and antiarrhythmic agent. Although clinical and experimental studies have shown that an antiarrhythmic dose of lidocaine can protect the brain from ischemic damage, the underlying mechanisms are unknown. In the present study, we examined whether lidocaine inhibits neuronal apoptosis in the penumbra in a rat model of transient focal cerebral ischemia. Male Wistar rats underwent a 90-min temporary occlusion of middle cerebral artery. Lidocaine was given as an i.v. bolus (1.5 mg/kg) followed by an i.v. infusion (2 mg/kg/h) for 180 min, starting 30 min before ischemia. Rats were killed and brain samples were collected at 4 and 24 h after ischemia. Apoptotic changes were evaluated by immunohistochemistry for cytochrome c release and caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) for DNA fragmentation. Cytochrome c release and caspase-3 activation were detected at 4 and 24 h after ischemia and DNA fragmentation was detected at 24 h. Double-labeling with NeuN, a neuronal marker, demonstrated that cytochrome c, caspase-3, and TUNEL were confined to neurons. Lidocaine reduced cytochrome c release and caspase-3 activation in the penumbra at 4 h and diminished DNA fragmentation in the penumbra at 24 h. Lidocaine treatment improved early electrophysiological recovery and reduced the size of the cortical infarct at 24 h, but had no significant effect on cerebral blood flow in either the penumbra or core during ischemia. These findings suggest that lidocaine attenuates apoptosis in the penumbra after transient focal cerebral ischemia. The infarct-reducing effects of lidocaine may be due, in part, to the inhibition of apoptotic cell death in the penumbra.

Isochromosome 1q as an early genetic event in a child with intracranial ependymoma characterized by molecular cytogenetics.

Data concerning cytogenetic features of childhood ependymoma are rare. In this article, a gain of 1q was identified as the sole alteration in a primary childhood infratentorial ependymoma by comparative genomic hybridization (CGH). A recurrence of this brain tumor was studied using multiplex-fluorescence in situ hybridization (M-FISH) in addition to CGH and G-banding analysis. In accordance with the primary tumor, a gain of 1q corresponding to an isochromosome 1q was observed indicating an early event in the tumor development. Furthermore, M-FISH classified several other rearranged chromosomes including 6q and 17p that have previously been found to be involved in the development and progression of childhood ependymoma.

Chromosomal aberrations in sporadic pituitary tumors.

Pituitary adenomas are common intracranial neoplasms that may be hormone-secreting or nonfunctional. Genetic defects associated with some pituitary tumors have been identified, although our understanding of the underlying molecular mechanisms remains incomplete. We have studied 75 sporadic pituitary tumors, representing the major clinical subtypes, by comparative genomic hybridization (CGH) with the aim of assessing for DNA copy number changes. CGH revealed chromosomal imbalances in 34 adenomas (45.3%), whereby gains were 4.9 times more frequently observed than losses. Most of the genetic alterations detected by CGH affected entire chromosomes (108/131, 82.4%). Gain of genetic material was observed predominantly on chromosomes X (24/75, 32%), 19 (12/75, 16%), 12 (6/75, 6.7%), 7 and 9 (5/75, 6.7%), whereas loss of DNA sequences most frequently affected chromosomes 11 (4/75, 5.3%), 13 and 10 (3/75, 4%). There were no significant differences in the CGH results for the individual clinical subtypes of pituitary tumors. These results reveal a nonrandom pattern of chromosomal alterations in pituitary tumors, in particular gains of entire chromosomes, and this may contribute to the development of such neoplasms.

Comparative genomic hybridization in childhood acute lymphoblastic leukemia: correlation with interphase cytogenetics and loss of heterozygosity analysis.

We used comparative genomic hybridization (CGH) to study DNA copy number changes in 71 children with acute lymphoblastic leukemia (ALL) including 50 B-lineage and 21 T-ALLs. Forty-two patients (59%) showed genomic imbalances whereby gains were more frequently observed than losses (127 vs. 29). Gains most commonly affected the entire chromosomes 21 and 10 (19.7% each), 6, 14, 18, X (15.5% each), 17 (14.1%) and 4 (11.3%). Highly hyperdiploid karyotypes (chromosome number >50) occurred more frequently in B-lineage than in T-lineage ALL (24% vs. 4.8%). In both cell lineages deletions were mainly detected on 9p (14.1%) and 12p (8.4%), and on 6q in T-lineage ALL (4.2%). These findings were compared with loss of heterozygosity (LOH) of 6q, 9p, 11q, and 12p previously performed in 56 of the 71 patients. Among 54 sites of LOH, CGH revealed losses of the respective chromosome arms in 17 LOH-positive regions (31.5%). G-banding analysis and interphase cytogenetics with subregional probes for 14 loci confirmed the presence of genomic imbalances as detected by CGH. We, therefore, conclude that, in the absence of cytogenetic data, CGH represents a suitable method for identifying hyperdiploid karyotypes as well as prognostically relevant deletions in ALL patients.