White matter microstructure in chronic moderate-to-severe traumatic brain injury: Impact of acute-phase injury-related variables and associations with outcome measures.

This study examines how injury mechanisms and early neuroimaging and clinical measures impact white matter (WM) fractional anisotropy (FA), mean diffusivity (MD), and tract volumes in the chronic phase of traumatic brain injury (TBI) and how WM integrity in the chronic phase is associated with different outcome measures obtained at the same time. Diffusion tensor imaging (DTI) at 3 T was acquired more than 1 year after TBI in 49 moderate-to-severe-TBI survivors and 50 matched controls. DTI data were analyzed with tract-based spatial statistics and automated tractography. Moderate-to-severe TBI led to widespread FA decreases, MD increases, and tract volume reductions. In severe TBI and in acceleration/deceleration injuries, a specific FA loss was detected. A particular loss of FA was also present in the thalamus and the brainstem in all grades of diffuse axonal injury. Acute-phase Glasgow Coma Scale scores, number of microhemorrhages on T2*, lesion volume on fluid-attenuated inversion recovery, and duration of posttraumatic amnesia were associated with more widespread FA loss and MD increases in chronic TBI. Episodes of cerebral perfusion pressure <70 mmHg were specifically associated with reduced MD. Neither episodes of intracranial pressure >20 mmHg nor acute-phase Rotterdam CT scores were associated with WM changes. Glasgow Outcome Scale Extended scores and performance-based cognitive control functioning were associated with FA and MD changes, but self-reported cognitive control functioning was not. In conclusion, FA loss specifically reflects the primary injury severity and mechanism, whereas FA and MD changes are associated with objective measures of general and cognitive control functioning.

Intensive care and traumatic brain injury after the introduction of a treatment protocol: a prospective study.

BACKGROUND: Traumatic brain injury (TBI) treatment protocols have been introduced in the intensive care unit (ICU) to avoid secondary brain injury. In this study, we aimed to evaluate the deviations from such a treatment protocol and the frequency of extracranial complications, and relate these findings to outcome. METHODS: During a 5-year period (2004-2009), 133 patients with severe TBI [Glasgow Coma Scale (GCS) score ≤ 8] were prospectively included. The following deviations from treatment goals were studied: intracranial pressure (ICP), blood pressure, haemoglobin, blood glucose, serum sodium, serum albumin, body temperature and extracranial complications during the ICU stay. Outcome was assessed using Glasgow Outcome Scale Extended score at 12 months. RESULTS: The frequencies of deviations from the treatment goals were: episodes of intracranial hypertension 69.5% (of monitored patients), hypotension 20.3%, anaemia 77.4%, hyperglycaemia 42.9%, hyponatremia 34.6%, hypoalbuminemia 30.8% and hyperthermia 54.9%. Pulmonary complications were common (pneumonia 72.2%, acute respiratory distress syndrome/acute lung injury 31.6%). Thrombocytopenia (4.5%), severe sepsis (3.0%), renal failure (0.8%) and liver failure (0.8%) were infrequent. Twenty-six (19.5%) patients died within the first 12 months due to the head injury. Age, GCS score, pupil dilation, Injury Severity Score (ISS), ICP > 25 mmHg, hyperglycaemia and pneumonia predicted a worse outcome. CONCLUSIONS: Deviations from the TBI treatment protocol were frequent. Pneumonia was the most frequent extracranial complication. Age, GCS score, pupil dilation, ISS, high ICP, hyperglycaemia and pneumonia predicted a worse outcome.

Incidence of hospital-admitted severe traumatic brain injury and in-hospital fatality in Norway: a national cohort study.

AIMS: The aims of this study were to assess the incidence of hospital-admitted severe traumatic brain injury (TBI) in the adult population in Norway, and to determine whether there were differences in the epidemiological characteristics of severe TBI between rural and urban regions. METHODS: A prospective population-based study on adults with severe TBI admitted to the Norwegian Trauma Referral Centres during the 2-year period (2009-2010). The electronic patient register was searched weekly for ICD-10 diagnoses of intracranial injuries (S06.0-S06.9) to identify patients. Severe TBI was defined as lowest unsedated Glasgow Coma Scale Score ≤8 during the first 24 h after injury. RESULTS: The annual age-adjusted incidence was estimated at 5.2/100,000 in 2009 and 4.1/100,000 in 2010. The highest frequency of hospitalized patients was found among the youngest and the oldest age groups. The most common causes of injury were falls and transport accidents. The highest in-hospital case-fatality rate was found among the oldest patients. There were consistent epidemiological characteristics of severe TBI from both rural and urban regions. CONCLUSIONS: The incidence of hospital-admitted patients with severe TBI in this national study supports the declining incidence of TBI reported internationally. No major differences were found in epidemiological characteristics between the urban and rural parts of Norway.

Severe head injury: control of physiological variables, organ failure and complications in the intensive care unit.

BACKGROUND: In patients with severe head injury, control of physiological variables is important to avoid intracranial hypertension and secondary injury to the brain. The aims of this retrospective study were to evaluate deviations of physiological variables and the incidence of extracranial complications in patients with severe head injury. We also studied if these deviations could be related to outcome. PATIENTS AND METHODS: One hundred and thirty-three patients were included during a 5-year period (1998-2002). Deviations from treatment goals for the following physiological variables were studied: blood pressure, haemoglobin, blood sugar, serum sodium, serum albumin and temperature. Extra cerebral organ complications were also recorded as well as outcome at 6 months. RESULTS: The median age was 32 years (range; 1-88 years). Median Glasgow Coma Scale (GCS) before intubation was 6 (range; 3-14). The frequencies of severe deviations from the desired values of the physiological variables for at least one treatment day were: hypotensive episodes (systolic BP < 90 mmHg) - 20%, anaemia (hgb < 8 g/dL) - 22%, blood glucose > 10 mmol/l - 26%, serum sodium concentration < 130 mmol/l - 10%, serum albumin < 25 g/l(-1)- 31% and hyperthermia > 39 degrees C - 24%. Pneumonia was diagnosed in 71% and Acute Lung Injury (ALI)/Adult Respiratory Distress Syndrome (ARDS) in 26% of the patients. Other complications such as severe sepsis (6%), renal failure (1.5%), a coagulation disorder (6%) and liver failure (one patient) were infrequent. Age, GCS, hypotension during the first day of treatment, elevated blood sugar and low albumin predicted an unfavourable outcome. CONCLUSIONS: Deviations of key physiological variables and pulmonary complications were frequent in patients suffering from severe head injury. During intensive care treatment, hypotension, elevated blood sugar and hypoalbuminemia are possible independent predictors of an unfavourable outcome.

Neuroacanthocytosis--the variability of presenting symptoms in two siblings.

Neuroacanthocytosis is a progressive multisystem disease with a wide range of symptoms. The involuntary movements mainly include chorea and orofaciolingual dyskinesias. The descriptive name of the disease refers to the presence of abnormal erythrocytes in peripheral blood. Two siblings are presented. One young female had dystonia, self-mutilating behaviour, lip biting and eating difficulties. Her brother had repeated generalized epileptic seizures several years before developing choreatic movements and neuropsychiatric symptoms. Both had clinical signs of sensorimotor axonal polyneuropathy. Fresh blood smears in each patient contained between 15 and 20% acanthocytes compared to less than 2% in normal controls. Neuroacanthocytosis must be kept in mind in young adult patients without heredity for Huntington's disease and the diagnosis is easily confirmed when making a fresh blood smear.

Polysomy of chromosome 7 is associated with amplification and overexpression of the EGF-receptor gene in a human carcinoma cell line derived from a brain metastasis.

Overexpression of the EGF-receptor gene is associated with the malignant nature of some tumors. We have recently reported the establishment of a human carcinoma cell line (T-CAR1), derived from a brain metastasis, that had 7 million EGF receptors per cell and was growth inhibited by EGF. The present study was carried out in order to further characterize the EGF-receptor protein in T-CAR1 cells, and to see if the overexpression of the EGF-receptor gene in these cells was associated with abnormalities at the genomic level. We have compared the T-CAR1 cells with the human glioblastoma cell line T-MG1, which has 135,000 EGF-receptors and is growth stimulated by EGF. The MW of the EGF receptors in T-CAR1 cells and T-MG1 cells was estimated to be 170 kDa, equal to the normal EGF-receptor. However, in T-CAR1 cells an additional protein reacted with the monoclonal antibody directed against the internal domain of the EGF receptor. The levels of EGF receptor-related RNAs in T-CAR1 cells and T-MG1 cells reflected the number of EGF receptors in these cell lines. The EGF-receptor gene was amplified ten-fold in T-CAR1 cells, while it was not amplified in T-MG1 cells. No restriction fragment length polymorphism of DNA digested with various restriction enzymes was seen in either of the cell lines. Chromosomal analysis of T-CAR1 cells showed polysomy of chromosome 7 and marker chromosomes derived partly from chromosome 7. Thus, in the T-CAR1 cell line it was an association between polysomy of chromosome 7 and EGF-receptor gene amplification.

Tumor necrosis factor-alpha regulates mRNA for urokinase-type plasminogen activator and type-1 plasminogen activator inhibitor in human neoplastic cell lines.

Tumor necrosis factor-alpha (TNF-alpha) was found to induce type-1 plasminogen activator inhibitor (PAI-1) antigen in the human fibrosarcoma cell line HT-1080, and PAI-1 and urokinase-type plasminogen activator (u-PA) antigens in the human carcinoma cell line T-CAR1; tissue-type plasminogen activator (t-PA) antigen was not affected or slightly decreased. The effects in HT-1080 and T-CAR1 cells were preceded by increases in the cellular levels of the corresponding mRNAs. Cycloheximide caused an increase of PAI-1 mRNA in T-CAR1 cells, but not in HT-1080 cells; during this increase the relative abundance of the two PAI-1 mRNA species, of 2.3 kb and 3.4 kb, respectively, changed strongly in favor of the longer transcript. We conclude that TNF-alpha may affect proteolytic activity in the microenvironment of cells in malignant tumors by affecting gene expression of u-PA and PAI-1.

Transforming growth factor-beta 1 is a potent inducer of plasminogen activator inhibitor type-1 in human glioblastoma and carcinoma cell lines.

Transforming growth factor-beta 1 has been shown to suppress the urokinase activity in the glioblastoma cell line T-MG1 and the carcinoma cell line T-CAR1. The molecular mechanisms behind the decrease in the proteolyic activity is shown to be at least partly due to increased synthesis of plasminogen activator inhibitor type-1 and not by decreased synthesis of urokinase.

Amplification of the epidermal growth factor receptor gene in biopsy specimens from human intracranial tumours.

Amplification and overexpression of proto-oncogenes are associated with the malignant nature of some human tumours. In this study we have determined the prevalence of amplification of the proto-oncogenes c-erb B1 (= epidermal growth factor receptor gene), c-erb B2 and c-myc in 44 human intracranial tumours (27 gliomas, six metastases to the brain and 11 meningiomas). None of the tumours had an amplified c-erb B2 gene and only two tumours had an amplified c-myc gene. Nineteen per cent (five out of 27) of the gliomas, 50% (three out of six) of the brain metastases and 0% (0 out of 11) meningiomas had an amplified EGF-receptor gene. Amplification of the EGF-receptor gene appeared to give a growth advantage when single-cell suspensions of the tumours were grown in agarose.