Ultra-early evaluation of intracerebral hemorrhage

The authors evaluate eight patients with intracerebral hemorrhage (ICH) who underwent computerized tomography (CT) within 2 1/2 hours after symptom onset and then again several hours later. The second CT scan was performed within 12 hours after onset for seven of the patients and 100 hours after onset for the eighth patient. In four patients, the second CT scan was obtained prospectively. The mean percentage of increase in the volume of hemorrhage between the first and second CT scans was 107% (range 1% to 338%). In each of the six patients with a greater than 40% increase in hemorrhage volume, neurological deterioration occurred soon after the first CT. A systolic blood pressure of 195 mm Hg or greater was recorded during the first 6 hours in five of the same six patients. The data from this study indicate that, in ICH, bleeding may continue after the 1st hour post-hemorrhage, particularly in patients with early clinical deterioration.     

Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values.

Regional cerebral blood flow (CBF) was studied with O(15)-water positron emission tomography and anatomic region-of-interest analysis on co-registered magnetic resonance in patients with idiopathic (n = 12) and secondary (n = 5) normal pressure hydrocephalus (NPH). Mean CBF was compared with values obtained from healthy volunteers (n = 12) and with clinical parameters. Mean CBF was significantly decreased in the cerebrum and cerebellum of patients with NPH. The regional analysis demonstrated that CBF was reduced in the basal ganglia and the thalamus but not in white matter regions. The results suggest that the role of the basal ganglia and thalamus in NPH may be more prominent than currently appreciated. The implications for theories regarding the pathogenesis of NPH are discussed.     

Nonconvulsive status epilepticus in a patient with leptomeningeal cancer

A 56-year-old man sought medical assistance because of recurrent nonconvulsive status epilepticus without a history of prior seizure activity. Examination of the cerebrospinal fluid disclosed leptomeningeal cancer. To our knowledge, the association of partial complex status epilepticus and leptomeningeal cancer has not been reported previously. If the results of computed tomographic and magnetic resonance imaging studies are normal, examination of cerebrospinal fluid should be considered in patients with nonconvulsive status epilepticus.     

Search for Optimal Frequencies and Amplitudes of Therapeutic Electrical Carotid Sinus Nerve Stimulation by Application of the Evolution Strategy

In humans, electrical, bipolar, bilateral carotid sinus nerve stimulation (CSNS; impulse duration 0.35 ms) was applied, using frequencies between 10 and 110 Hz and voltages between individual thresholds and maximal amplitudes of stimulation. Ten anginal patients and two hypertensive patients were studied at an interval of up to 12 years after implantation of electrodes and a radiofrequency receiver for chronic therapeutic CSNS. In search of combinations of frequency and voltage of CSNS, eliciting largest ("optimal") depressor responses of blood pressure and heart rate in the individual patient, Rechenberg's evolution strategy was applied. This strategy simulates mutation and selection of biological evolution. In each patient and on each test stimulation, a value of quality was computed from actual heart rate and blood pressure values as a selection criterion for the strategy. Either responses to uninterrupted CSNS were investigated, while stimulation parameters were adjusted every 3 min, according to the strategy, or responses to 3 min of CSNS after a change in stimulation parameters were compared to intercalated 3-min control periods. In each patient, one or more combined settings of frequency and voltage elicited "optimal" responses. In principle, "optimal" CSNS frequencies ranged between 35 and 105 Hz with large interindividual differences. Due to chronic implantation of electrodes and technical features of radiofrequency transmitted stimulation energy, interindividually different voltages led to an optimal response to CSNS. Also according to the present results, the frequency of CSNS has to be determined individually. It is concluded that the evolution strategy was applied successfully, because voltage and frequency settings leading to "optimal" responses were found within 90-180 min, whereas intraindividual systematic investigations would not be feasible due to their necessarily very long duration. So far, only short-term responses have been evaluated. A broader use of the strategy in other applications is encouraged, as for example in pacemaker optimization and especially in functional electrostimulation.     

Feeding microstructure in diet-induced obesity susceptible versus resistant rats: central effects of urocortin 2

With one billion people overweight worldwide, the need to identify risk factors and treatments for obesity is urgent. The present study determined whether rats genetically prone to diet-induced obesity (DIO) show preexisting differences in meal microstructure and are sensitive to central anorectic effects of corticotropin-releasing factor type 2 (CRF₂) receptor stimulation. Male, selectively bred DIO rats and their diet resistant (DR) counterparts ( n = 9/genotype) were weaned onto low-fat chow and compared as young adults for spontaneous or intracerebroventricular urocortin 2 administration-induced (0, 0.3, 1, 3 μg) differences in ingestion. DIO rats were hyperphagic selectively at the dark cycle onset, showing shorter latencies to initiate feeding, faster returns to eating following meal completion, and a lower satiety ratio than DR rats. At other times, DIO rats had briefer postmeal intervals, but ate smaller and briefer meals, resulting in normal intake. DIO rats also ate faster than DR rats. Urocortin 2 was less potent in DIO rats, ineffective at the 0.3 μg dose, but produced CRF₂ antagonist-reversible anorexia at higher doses. Though heavier, chow-maintained DIO rats were proportionately as or more lean than DR rats. Thus, DIO rats showed signs of a preexisting, heritable deficit in the maintenance of postmeal satiety and a reduced sensitivity to anorectic CRF₂ agonist stimulation. The meal patterns of DIO rats temporally resemble human 'snacking' behaviour, which predicts adult obesity. Because central CRF₂ stimulation retains full anorectic efficacy at higher doses in the DIO model, manipulating this neuropeptidergic system might yield new therapeutic approaches for diet-induced obesity.     

GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice

GM-CSF promotes homeostasis of myeloid cells. We report that GM-CSF upregulates mRNA and protein production of the soluble form of membrane bound VEGF receptor-1 (sVEGFR-1) in human monocytes. This sVEGFR-1 was biologically active, as cell-free supernatants from GM-CSF-stimulated monocytes blocked detection of endogenously expressed VEGF and inhibited endothelial cell migration and tube formation, even in the presence of exogenous rhVEGF. VEGF activity was recovered by neutralizing sVEGFR-1. To determine whether these events were important in vivo, Matrigel plugs were incubated with rhVEGF, rhGM-CSF, or rhGM-CSF/rhVEGF and injected into mice. Plugs containing GM-CSF or GM-CSF/VEGF had less endothelial cell invasion than plugs containing rhVEGF and were similar to plugs incubated with PBS alone. Neutralizing antibodies specific for sVEGFR-1 injected in these plugs reversed the effects of GM-CSF or GM-CSF/VEGF, while an isogenic antibody did not. Thus, GM-CSF and monocytes play a vital role in angiogenesis through the regulation of VEGF and sVEGFR-1.     

Antigen discovery and delivery of subunit vaccines by nonliving bacterial ghost vectors

The bacterial ghost (BG) platform system is a novel vaccine delivery system endowed with intrinsic adjuvant properties. BGs are nonliving Gram-negative bacterial cell envelopes which are devoid of their cytoplasmic contents, yet maintain their cellular morphology and antigenic structures, including bioadhesive properties. The main advantages of BGs as carriers of subunit vaccines include their ability to stimulate a high immune response and to target the carrier itself to primary antigen-presenting cells. The intrinsic adjuvant properties of BGs enhance the immune response to target antigens, including T-cell activation and mucosal immunity. Since native and foreign antigens can be carried in the envelope complex of BGs, combination vaccines with multiple antigens of diverse origin can be presented to the immune system simultaneously. Beside the capacity of BGs to function as carriers of protein antigens, they also have a high loading capacity for DNA. Thus, loading BGs with recombinant DNA takes advantage of the excellent bioavailability for DNA-based vaccines and the high expression rates of the DNA-encoded antigens in target cell types such as macrophages and dendritic cells. There are many spaces within BGs including the inner and outer membranes, the periplasmic space and the internal lumen which can carry antigens, DNA or mediators of the immune response. All can be used for subunit antigen to design new vaccine candidates with particle presentation technology. In addition, the fact that BGs can also carry piggyback large-size foreign antigen particles, increases the technologic usefulness of BGs as combination vaccines against viral and bacterial pathogens. Furthermore, the BG antigen carriers can be stored as freeze-dried preparations at room temperature for extended periods without loss of efficacy. The potency, safety and relatively low production cost of BGs offer a significant technical advantage over currently utilized vaccine technologies.     

Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.     

Factors associated with the provision of anti-smoking advice in general practice consultations.

Guidelines urge general practitioners (GPs) to discuss smoking with patients as frequently as possible. Using data collected before and after consultations, this study confirms that GPs are more likely to discuss smoking in the context of smoking-related problems. Encouraging GPs to make greater use of problem-orientated opportunities to discuss smoking may have more effect on rates of advice giving than urging them to advise all smokers.