Ultrasound focusing using magnetic resonance acoustic radiation force imaging: application to ultrasound transcranial therapy.

PURPOSE: Magnetic resonance guided ultrasonic therapy is a promising minimally invasive technology for constantly growing variety of clinical applications. Delivery of focused ultrasound (FUS) energy to the targeted point with optimal intensity is highly desired; however, due to tissue aberrations, optimal focal intensity is not always achieved. Especially in transcranial applications, the acoustic waves are shifted and distorted mainly by the skull. In order to verify that magnetic resonance acoustic radiation force imaging (MR-ARFI) can be used as a focusing tool in transcranial treatments, such an imaging was applied in vivo on a porcine brain via ex vivo human skull. Then, by the use of MR-ARFI technique, an improved ultrasound focusing algorithm is proposed and demonstrated for both transcranial and none brain applications. METHODS: MR-ARFI images were acquired on a GE 1.5 T scanner equipped with InSightec FUS systems ExAblate 2000 and ExAblate 4000. Imaging was performed with MR-ARFI sequences of line-scan spin-echo and single-shot gradient-echo echo-planar. The in-plane resolution of both acquisitions was 0.9 x 0.9 mm2. The total acquisition time of MR-ARFI image was 31 s by the line-scan sequence and 1 s by the echo-planar sequence. An in vivo experiment was performed using FUS transducer, which is built out of 1024 ultrasound transmitting piezoelectric elements at 220 kHz frequency. The transducer was focused into the brain of a pig, which was wrapped in a human skull, in degassed water environment to resemble human treatments. The pig underwent a wide bilateral craniectomy to prevent a bone heating from the ultrasound beams. Two focusing experiments were performed in phantoms using 1 MHz and 710 kHz FUS transducers working with 208 and 225 elements, respectively. In the first experiment, aberration was added virtually to the apparatus by adding random phases to the phase map of the transducer. A simple focusing correction scheme was used, in which the corrected phase of a group of elements was chosen such that it maximizes the radiation force at the focal point. In the second experiment, aberrations made by a human skull were corrected using geometrical and phase based adjustments on segments of the transducer. RESULTS: A maximum displacement of 10 microm was obtained using 1.4 kW acoustic power on a live pig's head that its skull was removed and replaced by ex vivo human skull. Aberration correction using MR-ARFI resulted in near optimal focus, as the radiation force was similar to the nonaberration case. Transcranial, MR-ARFI based aberration correction performed better than CT based aberration correction, a technique that is currently used in brain FUS treatments. CONCLUSIONS: In the present work, the authors show for the first time a result of MR-ARFI in a live brain through ex vivo human skull. They have demonstrated that aberration correction could be done using MR-ARFI by measuring the radiation force at the focal point. Aberration correction using MR-ARFI is a promising noninvasive technique for transcranial focusing, which may result in near optimal focus and more reliable and safer brain FUS treatments.

Flares from a candidate Galactic magnetar suggest a missing link to dim isolated neutron stars.

Magnetars are young neutron stars with very strong magnetic fields of the order of 10(14)-10(15) G. They are detected in our Galaxy either as soft gamma-ray repeaters or anomalous X-ray pulsars. Soft gamma-ray repeaters are a rare type of gamma-ray transient sources that are occasionally detected as bursters in the high-energy sky. No optical counterpart to the gamma-ray flares or the quiescent source has yet been identified. Here we report multi-wavelength observations of a puzzling source, SWIFT J195509+261406. We detected more than 40 flaring episodes in the optical band over a time span of three days, and a faint infrared flare 11 days later, after which the source returned to quiescence. Our radio observations confirm a Galactic nature and establish a lower distance limit of approximately 3.7 kpc. We suggest that SWIFT J195509+261406 could be an isolated magnetar whose bursting activity has been detected at optical wavelengths, and for which the long-term X-ray emission is short-lived. In this case, a new manifestation of magnetar activity has been recorded and we can consider SWIFT J195509+261406 to be a link between the 'persistent' soft gamma-ray repeaters/anomalous X-ray pulsars and dim isolated neutron stars.

A photometric redshift of z = 6.39 +/- 0.12 for GRB 050904.

Gamma-ray bursts (GRBs) and their afterglows are the most brilliant transient events in the Universe. Both the bursts themselves and their afterglows have been predicted to be visible out to redshifts of z approximately 20, and therefore to be powerful probes of the early Universe. The burst GRB 000131, at z = 4.50, was hitherto the most distant such event identified. Here we report the discovery of the bright near-infrared afterglow of GRB 050904 (ref. 4). From our measurements of the near-infrared afterglow, and our failure to detect the optical afterglow, we determine the photometric redshift of the burst to be z = 6.39 - 0.12 + 0.11 (refs 5-7). Subsequently, it was measured spectroscopically to be z = 6.29 +/- 0.01, in agreement with our photometric estimate. These results demonstrate that GRBs can be used to trace the star formation, metallicity, and reionization histories of the early Universe.

Infection of fetal feline brain cells in culture with Bartonella henselae.

Bartonella henselae is known to cause central nervous system (CNS) disease in humans, and neurological signs have been observed in experimentally infected cats. However, the pathogenesis of CNS disease remains unclear. This study was undertaken to determine whether B. henselae infects feline fetal brain cells in vitro. Microglial-cell- and astrocyte-enriched cultures were inoculated with B. henselae. Giménez staining identified bacterial organisms within microglial cells by day 7 postinoculation. The viability of the intracellular bacteria was demonstrated by incubating cultures with gentamicin and plating cell lysate on agar. Electron microscopy identified intracellular organisms with characteristic Bartonella morphology but identified no ultrastructural abnormalities within infected microglial cells. No evidence of infection was seen in Bartonella-inoculated astrocyte cultures. These findings suggest a role for microglia in the pathogenesis of B. henselae-associated neurological disease.

Characterization of a human gene conferring sensitivity to infection by gibbon ape leukemia virus.

Gibbon ape leukemia virus (GALV) enters cells following interaction with a specific receptor protein. We have isolated human complementary DNAs (cDNAs) encoding a protein which, when expressed in normally uninfectable mouse NIH3T3 cells, confers on these cells specific sensitivity to infection by GALV. This was done by transfection into mouse cells of human DNA and selection of putative receptor gene transfectants using infection with a retrovirus carrying a drug resistance gene. Transfected genomic sequences were then cloned through their association with repetitive DNA, and these were used to isolate cDNA clones. The predicted 679-amino acid sequence encoded in these cDNAs is characteristic of an integral membrane protein in that multiple potential transmembrane domains are present. Searches of DNA and protein data banks failed to reveal homologies to other known sequences. It thus appears that the sequence isolated is novel and represents the human receptor for GALV. As expected from the wide host range of the virus, closely related homologues of the gene were found in several other vertebrate species tested.

Absence of mutation in the beta-amyloid cDNAs cloned from the brains of three patients with sporadic Alzheimer's disease.

Using an oligonucleotide probe, we isolated cDNA clones corresponding to the precursor of the beta-amyloid peptide (BAP) from brain libraries of 3 patients with sporadic Alzheimer's disease (AD). DNA sequencing showed that the largest cDNA clone encompasses 83% of the open reading frame proposed by Kang et al. to encode the BAP precursor (APP). cDNA clones from each of the 3 AD brain libraries were identical to the sequence of the APP-cDNAs cloned from normal adult human and fetal brain. An antisense-radiolabeled RNA copy of one of the AD clones detected a pattern of 3 gene transcripts measuring 3.5, 3.2 and 1.6 kilobases (kb) in both normal and AD brain RNAs. These data suggest that there are no mutations in or about the 42 amino acid (aa) sequence of BAP and that the accumulation of amyloid consistently found in AD may result from altered post-translational processing of APP.

Multiple forms of beta-amyloid peptide precursor RNAs in a single cell type.

The longest open reading frames (ORFs) of three different cDNAs ([10, 12, 18, 26], and this report) contain the exact 42 amino acid (aa) sequence of the beta-amyloid peptide (BAP) which is selectively deposited in Alzheimer's diseased (AD) brains. Each of the three cDNAs for the putative amyloid peptide precursor (APP) has been cloned from a different cell type. Using an HL 60 library, we have cloned two of these three APP cDNAs from a single cell type. The sequences of the HL 60 cDNAs are identical to the APP 751 and to the APP 770 forms of APP cDNAs. Northern blots show that oligonucleotide probes drawn from unique regions of the APP 751 and APP 770 cDNAs both hybridize to 4.0 Kilobase (Kb) and to 1.6 Kb APP RNAs from HL 60 cells. In human adult brain, an oligonucleotide probe drawn from the unique region of the APP 751 cDNA hybridizes to a 3.5 Kb APP RNA. However, a DNA probe drawn from the BAP region, which is common to the 695, 751, and 770 forms of APP cDNAs, hybridizes to 3.5, 3.2 and 1.6 Kb APP RNAs. Taken together, these results show that at least two forms of APP RNAs can exist within a single cell type and that the diversity of possible APP RNAs and complexity of their expression may have been underestimated. Thus, in addition to identifying the cells which produce BAP, a new challenge consists of determining which form of forms of APP RNAs and hence APP proteins are associated with BAP deposition in AD and Down syndrome (DS).

Increased levels of myosin mRNAs in spontaneously hypertensive rat heart.

RNAs isolated from normal and spontaneously hypertensive (SHR) rat heart tissues were examined by direct hybridization assay using cloned DNA probes containing chicken cardiac myosin light chain and heavy chain specific cDNA sequences. In 7 weeks old SHR heart, the level of mRNA hybridizable to these probes is the same as in normal rat heart. However, at 18 weeks of age, when hypertrophy in SHR is well established as a consequence of age-related increase in blood pressure and cardiac mass, there is an increase in SHR mRNA levels consistent with the increase in the corresponding proteins. Thus, the increase in mRNAs for major myofibrillar proteins and the onset of hypertrophic state in SHR appear to occur simultaneously.