Non-invasive monitoring of intracranial pressure changes: healthy volunteers study.

Objective: This research aims to evaluate the possible association between pulsatile near infrared spectroscopic waveform features and induced changes in intracranial pressure in healthy volunteers. Methods: An optical intracranial pressure sensor was attached to the forehead of 16 healthy volunteers. Pulsatile near infrared spectroscopic signals were acquired from the forehead during body position changes and Valsalva manoeuvers. Features were extracted from the pulsatile signals and analyses were carried out to investigate the presence of statistical differences in the features when intracranial pressure changes were induced. Classification models were developed utilizing the features extracted from the pulsatile near-infrared spectroscopic signals to classify between different body positions and Valsalva manoeuvre. Results: The presence of significant differences in the majority of the analyzed features (p < 0.05) indicates the technique's ability to distinguish between variations in intracranial pressure. Furthermore, the disparities observed in the optical signal features captured by the proximal and distal photodetectors support the hypothesis that alterations in back-scattered light directly correspond to brain-related changes. Further research is required to subtract distal and proximal signals and construct predictive models employing a gold standard measurement for non-invasive, continuous monitoring of intracranial pressure. Conclusion: The study investigated the use of pulsatile near infrared spectroscopic signals to detect changes in intracranial pressure in healthy volunteers. The results revealed significant differences in the features extracted from these signals, demonstrating a correlation with ICP changes induced by positional changes and Valsalva manoeuvre. Classification models were capable of identifying changes in ICP using features from optical signals from the brain, with a sensitivity ranging from 63.07% to 80% and specificity ranging from 60.23% to 70% respectively. These findings underscored the potential of these features to effectively identify alterations in ICP. Significance: The study's results demonstrate the feasibility of using features extracted from optical signals from the brain to detect changes in ICP induced by positional changes and Valsalva manoeuvre in healthy volunteers. This represents a first step towards the non-invasive monitoring of intracranial pressure.

Chemical engineering of molecular qubits.

We show that the electron spin phase memory time, the most important property of a molecular nanomagnet from the perspective of quantum information processing, can be improved dramatically by chemically engineering the molecular structure to optimize the environment of the spin. We vary systematically each structural component of the class of antiferromagnetic Cr(7)Ni rings to identify the sources of decoherence. The optimal structure exhibits a phase memory time exceeding 15 µs.

Electrically detected magnetic resonance of neutral donors interacting with a two-dimensional electron gas.

We have measured the electrically detected magnetic resonance of donor-doped silicon field-effect transistors in resonant X- (9.7 GHz) and W-band (94 GHz) microwave cavities. The two-dimensional electron gas resonance signal increases by 2 orders of magnitude from X to W band, while the donor resonance signals are enhanced by over 1 order of magnitude. Bolometric effects and spin-dependent scattering are inconsistent with the observations. We propose that polarization transfer from the donor to the two-dimensional electron gas is the main mechanism giving rise to the spin resonance signals.

Multiplexing Superconducting Qubit Circuit for Single Microwave Photon Generation.

We report on a device that integrates eight superconducting transmon qubits in λ / 4 superconducting coplanar waveguide resonators fed from a common feedline. Using this multiplexing architecture, each resonator and qubit can be addressed individually, thus reducing the required hardware resources and allowing their individual characterisation by spectroscopic methods. The measured device parameters agree with the designed values, and the resonators and qubits exhibit excellent coherence properties and strong coupling, with the qubit relaxation rate dominated by the Purcell effect when brought in resonance with the resonator. Our analysis shows that the circuit is suitable for generation of single microwave photons on demand with an efficiency exceeding 80%.

ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.

The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.

Nanoelectronic primary thermometry below 4 mK.

Cooling nanoelectronic structures to millikelvin temperatures presents extreme challenges in maintaining thermal contact between the electrons in the device and an external cold bath. It is typically found that when nanoscale devices are cooled to ∼ 10 mK the electrons are significantly overheated. Here we report the cooling of electrons in nanoelectronic Coulomb blockade thermometers below 4 mK. The low operating temperature is attributed to an optimized design that incorporates cooling fins with a high electron-phonon coupling and on-chip electronic filters, combined with low-noise electronic measurements. By immersing a Coulomb blockade thermometer in the (3)He/(4)He refrigerant of a dilution refrigerator, we measure a lowest electron temperature of 3.7 mK and a trend to a saturated electron temperature approaching 3 mK. This work demonstrates how nanoelectronic samples can be cooled further into the low-millikelvin range.

Investigation of co-amplification of the candidate genes ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box gene, DDX1, with N-myc in neuroblastoma. United Kingdom Children's Cancer Study Group.

Although N-myc amplification is strongly associated with a poor prognosis, not all patients with neuroblastomas having N-myc amplification fare badly. To investigate whether genes other than N-myc are responsible for contributing to the prognosis, we examined seven cell lines and 87 primary tumours for co-amplification of candidate genes known to be present near the normal N-myc locus: ornithine decarboxylase (ODC), ribonucleotide reductase (RRM2), syndecan-1 and a DEAD box protein gene, DDX1. Sequence analysis of the pG21 cDNA clone previously reported to represent an expressed gene frequently co-amplified with N-myc, showed this to be from the DDX1 gene. No co-amplification with the first three genes was found in any of the cell lines or tumour samples. DDX1, however was found to be amplified along with N-myc in 4/6 (67%) cell lines and 6/16 (38%) of the N-myc amplified tumours. Co-amplification of DDX1 and N-myc was found more frequently in stage 4 or 4S tumours than lower stage (1-3) tumours. With the exclusion of a single 4S case, there was a highly significant reduction in the mean disease-free interval from 24.4 +/- 4.7 (SE, n = 10) months for cases with co-amplification of N-myc and DDX1 compared with 9.2 +/- 1.8 (SE, n = 5) months for those cases showing amplification of N-myc alone (P = 0.0056, Welch's unpaired t-test). No amplification of DDX1, ODC, RRM2, or syndecan-1 was found in the absence of N-myc amplification. These observation indicate that the N-myc amplicon is of varied size and/or position relative to the N-myc gene, with DDX1 representing at least one other gene frequently co-amplified with N-myc. Further studies are required to confirm the biological and prognostic significance of DDX1 co-amplification and to elucidate the role that DDX1 plays in tumour genesis and progression.

Analgesic effect of picenadol, codeine, and placebo in patients with postoperative pain.

A double-blind, parallel study was conducted to evaluate the analgesic effect and safety of a single 25 mg oral dose of picenadol, a centrally acting analgesic, and to compare it with a 60 mg dose of codeine and a placebo in patients with postoperative pain. Two sites using similar protocols enrolled a total of 178 inpatients with postoperative pain. Pain intensity, relief, and adverse experiences were then measured for up to 6 hours after administration of the test medications. Both picenadol and codeine were significantly more effective than placebo in reducing pain intensity (mean sum of pain intensity difference scores: picenadol 5.21, codeine 5.19, and placebo 2.82) and increasing total relief (mean total pain relief: picenadol 10.21, codeine 11.07, and placebo 6.96). Adverse experience profiles were similar among the three treatment groups.

Analysis of candidate gene co-amplification with MYCN in neuroblastoma.

Previous studies have revealed that the MYCN gene spans approximately 7kb, while the amplicon has been estimated to be 100 kb to 1 Mb long [1-3]. This implies that several other genes may be present on the MYCN amplicon. Such co-amplified genes could contribute to the malignant phenotype and might provide an explanation for why not all patients with MYCN amplification have a poor outcome. We investigated 7 neuroblastoma cell lines and 167 primary tumours for the co-amplification of candidate genes known to be present near the MYCN locus: ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box protein gene, DDX1. We also investigated further the pG21 expressed sequence previously reported to be co-amplified with MYCN. No co-amplification with the first 3 genes was found in any of the cell lines or tumour samples. DDX1 was found to be amplified along with MYCN in 4/6 (67%) cell lines and 18/38 (47%) of the MYCN amplified tumours. No amplification of DDX1, ODC1, RRM2 or syndecan-1 was found in the absence of MYCN amplification. DDX1 co-amplification was observed to occur mainly in stage 4 or 4S patients. With the exclusion of those with 4S disease, patients with DDX1 co-amplification had a significantly shorter mean (+/- SE) disease-free interval (4.1 +/- 1.4, n = 8 months) compared with patients with MYCN amplification alone (19.6 +/- 4.5, n = 17) (P = 0.04, Welch's unpaired t-test). The pG21 sequence was identical to part of the DDX1 gene. These observations indicate that there is at least 1 other gene co-amplified with MYCN in a proportion of cases and that those patients with DDX1 co-amplification tend to relapse more quickly. It also implies that the MYCN amplicon is of varied size and/or position relative to the MYCN gene.

Characteristics of an MM 22 medical microtron 21 MV photon beam.

Beam quality, surface doses, depths of maximum dose, peak dose rates, beam profiles, and central axis percentage depth doses of a medical microtron's 21 MV photon beam were measured. The half-value layer of lead was 1.35 cm, the half-value layer of water was 23 cm, and the nominal acceleration potential was 17.7 MV. For a 10 X 10 cm2 field at 100 cm SSD, the maximum dose occurred at a depth of 3 g X cm-2 and the surface dose was 18% of the maximum. The highest dose rate at isocenter was approximately 800 cGy X min-1. The worst horns on beam profiles occurred at a depth of 5 cm for the 35 X 35 cm2 field where the dose rate 4 cm from the edge of the beam was 3% higher than that on the central ray. No horns were apparent for fields 25 X 25 cm2 or smaller.

Characteristics of an MM 22 medical microtron 6-MV photon beam.

Instrument AB Scanditronix offers a 6-MV therapeutic photon beam as an option with the 22-MeV medical microtron (MM 22). The method of acceleration, target assembly, and use of two flattening filters produce beams having several characteristics (e.g., field flatness, penetration, and intensity) that are superior to many 6-MV Linac beams. Characteristics of the microtron's 6-MV photon beams including quality, surface dose, depth of maximum dose, peak dose rates, peak scatter factors, central axis percentage depth doses, tissue maximum ratios, and beam profiles are described.

Characteristics of electron beams from a medical microtron.

The Instrument AB Scanditronix MM22 medical microtron provides ten electron beam energies from approximately 3 to 22 MeV. Isodose curves, depth dose curves, field uniformity, and other characteristics were measured in water and in polystyrene. The method of acceleration, dual scattering foil system, and collimation technique produce beams having features superior to many other medical electron accelerators. Maximum dose rates at isocenter varied from about 500 to over 900 cGy min-1, photon contamination from 0.6% to 4.1%, and surface doses from 70% to 95% of the maximum. Depth dose curves were indistinguishable from those with identical practical ranges of a scanned beam linac at energies less than 18 MeV, and field flatness was clearly superior to the scanned beam linac at standard treatment distances.

Picenadol in a large multicenter dental pain study.

STUDY OBJECTIVE: To estimate the analgesic dose of picenadol hydrochloride equal to codeine 60 mg in a dental pain model. DESIGN: Randomized, double-blind, parallel, dose-response study. SETTING: Four university-based dental clinics. PATIENTS: Four hundred eight adult patients with moderate or severe pain after extraction of one or more impacted molar teeth plus bone removal. INTERVENTIONS: Patients received orally administered single doses of picenadol 15 and 30 mg, codeine phosphate 30 and 90 mg, or placebo. METHODS: Single oral doses of picenadol 15 and 30 mg, an opioid agonist-antagonist, were compared with codeine 30 and 90 mg and placebo in 408 patients with moderate or severe pain from third molar extraction in a randomized, double-blind, parallel study. Assessments were performed for pain intensity, pain relief, and adverse events for up to 6 hours after drug administration. MAIN RESULTS: Picenadol 30 mg and codeine 90 mg were more effective than placebo based on sum of pain intensity differences, total pain relief, peak pain relief, and duration of analgesia (p < 0.05). Compared with placebo, the frequency of adverse events was highest for patients receiving codeine 90 mg (p < 0.05). No patients discontinued due to adverse events, and all such events resolved spontaneously. CONCLUSIONS: Picenadol 22 mg was estimated to be equianalgesic to codeine 60 mg, and picenadol 30 mg was safe in this dental pain model.

Low-grade astrocytoma of the tectal region as an unusual cause of knee pain: case report.

A 12-year-old boy was investigated for knee pain and contractures, and was found to have an intraspinal tumor of a lumbar nerve root and a tumor in the tectal region, both low-grade astrocytomas. We postulated that the tectal region astrocytoma metastasized to the lumbar intraspinal region. After surgery, the child underwent focal irradiation to the posterior fossa supplemented by craniospinal irradiation and a boost dose to the region of the lumbar spinal tumor. A low-grade astrocytoma rarely presents as spinal metastasis. This case may represent the first of a primary tectal low-grade astrocytoma manifesting as a symptomatic spinal mass.

In vitro cytolysis of primitive neuroectodermal tumors of the posterior fossa (medulloblastoma) by lymphokine-activated killer cells.

Short-term stimulation of nonantigen-primed peripheral blood mononuclear leukocytes with interleukin-2 generates a population of oncolytic effectors designated "lymphokine-activated killer" (LAK) cells. These LAK cells express potent lytic activity against a wide spectrum of fresh or cultured autochthonous (patient's own) and allogeneic (unrelated) tumors, yet specifically spare normal tissues. In this study, cells derived from primitive neuroectodermal tumors of the posterior fossa (PNET-PF) were examined for their sensitivity to LAK cytolysis utilizing an in vitro 4-hour chromium-51-release assay. Five early-passage cell lines, derived from primary PNET-PF, demonstrated significant sensitivity to LAK cell cytolysis. Lysis was equally effective in culture medium and cerebrospinal fluid. Three freshly excised PNET-PF exhibited similar susceptibility to lysis by autochthonous LAK cells. Greatly increased expansion of LAK cell cultures could be achieved by short-term stimulation with monoclonal anti-CD3 antibodies in addition to interleukin-2 activation. These findings constitute the preliminary in vitro foundations for potential intrathecal adoptive immunotherapy of PNET-PF with LAK cells.

Stannous-ion quantitation in pyrophosphate and polyphosphate radiopharmaceutical kits using differential pulse polarography.

Stannous salts are used as reducing agents in many radiopharmaceutical kits. Differential pulse polarography, with 1 M sulfuric acid as the supporting electrolyte, is a relatively simple and effective technique for stannous quantitation and can be used in the quality assurance testing of pyrophosphate and polyphosphate radiopharmaceutical kits.

Correlations between laparoscopic and hysteroscopic findings in 497 women with otherwise unexplained infertility.

Laparoscopy and hysteroscopy were undertaken simultaneously in 497 women presenting with otherwise unexplained infertility. Of them, 285 complained of primary infertility and 212 of secondary infertility. Laparoscopic evidence of pelvic inflammatory disease in the absence of endometriosis was noted in 103 patients with primary and in 108 women with secondary infertility. Lesions were noted on hysteroscopy in both groups as well as in 34% of women with normal laparoscopic examinations. No specific dependency could be demonstrated between any laparoscopically detected lesion and hysteroscopically detected lesion. A significant dependency was demonstrated only between a history of secondary infertility and uterine adhesions (chi 2 = 12.03, 1 df, p less than 0.01). While the combined endoscopic findings did not demonstrate any dependency, the findings of this study demonstrate the importance of hysteroscopy in assessing all patients with infertility, especially those with secondary infertility.

Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma.

Heterozygous germline mutations in PHOX2B, a transcriptional regulator of sympathetic neuronal differentiation, predispose to diseases of the sympathetic nervous system, including neuroblastoma and congenital central hypoventilation syndrome (CCHS). Although the PHOX2B variants in CCHS largely involve expansions of the second polyalanine repeat within the C-terminus of the protein, those associated with neuroblastic tumors are nearly always frameshift and truncation mutations. To test the hypothesis that the neuroblastoma-associated variants exert their effects through loss or gain of protein-protein interactions, we performed a large-scale yeast two-hybrid screen using both wild-type (WT) and six different mutant PHOX2B proteins against over 10 000 human genes. The neuronal calcium sensor protein HPCAL1 (VILIP-3) exhibited strong binding to WT PHOX2B and a CCHS-associated polyalanine expansion mutant but only weakly or not at all to neuroblastoma-associated frameshift and truncation variants. We demonstrate that both WT PHOX2B and the neuroblastoma-associated R100L missense and the CCHS-associated alanine expansion variants induce nuclear translocation of HPCAL1 in a Ca(2+)-independent manner, while the neuroblastoma-associated 676delG frameshift and K155X truncation mutants impair subcellular localization of HPCAL1, causing it to remain in the cytoplasm. HPCAL1 did not appreciably influence the ability of WT PHOX2B to transactivate the DBH promoter, nor did it alter the decreased transactivation potential of PHOX2B variants in 293T cells. Abrogation of the PHOX2B-HPCAL1 interaction by shRNA knockdown of HPCAL1 in neuroblastoma cells expressing PHOX2B led to impaired neurite outgrowth with transcriptional profiles indicative of inhibited sympathetic neuronal differentiation. Our results suggest that certain PHOX2B variants associated with neuroblastoma pathogenesis, because of their inability to bind to key interacting proteins such as HPCAL1, may predispose to this malignancy by impeding the differentiation of immature sympathetic neurons.

Electrically detected magnetic resonance in a W-band microwave cavity.

We describe a low-temperature sample probe for the electrical detection of magnetic resonance in a resonant W-band (94 GHz) microwave cavity. The advantages of this approach are demonstrated by experiments on silicon field-effect transistors. A comparison with conventional low-frequency measurements at X-band (9.7 GHz) on the same devices reveals an up to 100-fold enhancement of the signal intensity. In addition, resonance lines that are unresolved at X-band are clearly separated in the W-band measurements. Electrically detected magnetic resonance at high magnetic fields and high microwave frequencies is therefore a very sensitive technique for studying electron spins with an enhanced spectral resolution and sensitivity.