Human 3-D aVOR with and without otolith stimulation

We describe in detail the frequency response of the human three-dimensional angular vestibulo-ocular response (3-D aVOR) over a frequency range of 0.05-1 Hz. Gain and phase of the human aVOR were determined for passive head rotations in the dark, with the rotation axis either aligned with or perpendicular to the direction of gravity (earth-vertical or earth-horizontal). In the latter case, the oscillations dynamically stimulated both the otolith organs and the semi-circular canals. We conducted experiments in pitch and yaw, and compared the results with previously-published roll data. Regardless of the axis of rotation and the orientation of the subject, the gain in aVOR increased with frequency to about 0.3 Hz, and was approximately constant from 0.3 to 1 Hz. The aVOR gain during pitch and yaw rotations was larger than during roll rotations. Otolith and canal cues combined differently depending upon the axis of rotation: for torsional and pitch rotations, aVOR gain was higher with otolith input; for yaw rotations the aVOR was not affected by otolith stimulation. There was a phase lead in all three dimensions for frequencies below 0.3 Hz when only the canals were stimulated. For roll and pitch rotations this phase lead vanished with dynamic otolith stimulation. In contrast, the horizontal phase showed no improvement with additional otolith input during yaw rotations. The lack of a significant otolith contribution to the yaw aVOR was observed when subjects were supine, prone or lying on their sides. Our results confirm studies with less-natural stimuli (off-vertical axis rotation) that the otoliths contribute a head-rotation signal to the aVOR. However, the magnitude of the contribution depends on the axis of rotation, with the gain in otolith-canal cross-coupling being smallest for yaw axis rotations. This could be because, in humans, typical yaw head movements will stimulate the otoliths to a much lesser extent then typical pitch and roll head movements.     

Genetic heterogeneity of Usher syndrome type II.

Usher syndrome is an autosomal recessive disorder characterised by retinitis pigmentosa and congenital sensorineural hearing loss. A gene for Usher syndrome type II (USH2) has been localised to chromosome 1q32-q41. DNA from a family with four of seven sibs affected with clinical characteristics of Usher syndrome type II was genotyped using markers spanning the 1q32-1q41 region. These included D1S70 and D1S81, which are believed to flank USH2. Genotypic results and subsequent linkage analysis indicated non-linkage of this family to these markers. The A test analysis for heterogeneity with this family and 32 other Usher type II families was statistically significant at p < 0.05. Further clinical evaluation of this family was done in light of the linkage results to determine if any phenotypic characteristics would allow for clinical identification of the unlinked type. No clear phenotypic differences were observed; however, this unlinked family may represent a previously unreported subtype of Usher type II characterised by a milder form of retinitis pigmentosa and mild vestibular abnormalities. Heterogeneity of Usher syndrome type II complicates efforts to isolate and clone Usher syndrome genes using linkage analysis and limits the use of DNA markers in early detection of Usher type II.     

Stimulus-dependence and time-course of histamine and leukotriene release from chopped and dispersed human lung tissue

The calcium ionophore A23187 and anti-human IgE provoked a dose-dependent release of histamine and cysteinyl-leukotrienes (LTC₄, LTD₄ and LTE₄) from dispersed human lung cells. Optimal release of histamine peaked at 3 min after challenge whereas the release of cysteinyl-leukotrienes peaked at 30 min. The molar ratio between released histamine and cysteinyl-leukotrienes was approximately 1001. The ionophore, but not anti-IgE caused additional formation of LTB₄ in the dispersed cells or the chopped lung, indicating that this chemoattractant is formed from cells not primarily activated by IgE-dependent mechanisms. Indomethacin failed to alter release of histamine or leukotrienes from dispersed cells, whereas further inhibition of lipoxygenases by NDGA abolished leukotriene formation and reduced the release of histamine.     

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months

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Influence of acetylcholine, peptides, and other vasodilators on endogenous noradrenaline overflow and vasoconstriction in canine blood perfused gracilis muscle

The effects of acetylcholine, substance P and vasoactive intestinal polypeptide (VIP) on the endogenous noradrenaline (NA) overflow were compared to those of two other vasodilators, nitroglycerin and felodipine, neither of which are thought to influence NA neurotransmission in blood perfused skeletal muscle. The lack of prejunctional effects of nitroglycerin was verified in vitro. The sympathetic nerve stimulation (SNS) evoked NA overflow was reduced by 37 +/- 9% by a dose of acetylcholine which reduced the perfusion pressure at rest by 44 +/- 6%. Conversely, atropine tended to enhance SNS evoked NA overflow. Acetylcholine reduced the vasoconstrictor responses to SNS when compared to the responses observed with an equipotent vasodilatory dose of, e.g. nitroglycerin. The SNS evoked NA overflow was not influenced by a moderate mechanical blood flow reduction or by pronounced reductions of vascular resistance induced by either substance P, VIP, nitroglycerin or felodipine, supporting the idea that the transport of NA from nerve terminal to blood is not importantly influenced by moderate decreases in blood flow or vascular tone. Prejunctional muscarinic inhibition of NA release in skeletal muscle was verified under in vivo conditions, but the other substances tested did not influence sympathetic neurotransmission. Endogenous NA overflow appears to mirror NA release in vivo also when diffusion is influenced by changes in blood flow or vascular tone in this experimental model.     

Differential diagnosis of chordoma, chondroid, and ependymal tumors as aided by anti-intermediate filament antibodies.

Six chordomas, nine chondrosarcomas, and three myxopapillary ependymomas of the filum terminale were evaluated immunohistochemically for the expression of intermediate filament proteins by the use of monospecific antibodies against intermediate filament proteins of keratin, vimentin, and glial fibrillary acidic protein (GFAP) type. All chordomas were positive for keratin but negative for GFAP, whereas chondrosarcomas and ependymomas were negative for keratin. Chondrosarcomas showed strong vimentin positivity, whereas ependymomas were positive for GFAP. Chordomas showed desmosomelike junctions by electron microscopy, whereas chondrosarcomas of different types showed no junctions or only primitive ones. By electron microscopy chordomas often showed prominent intermediate filaments also associated with desmosomes, and poorly differentiated chondrosarcomas also showed prominent intermediate filaments. Keratin positivity of chordomas suggests their epithelial nature, while vimentin positivity of chondrosarcomas is in line with their mesenchymal derivation. The results also show that antibodies against different intermediate filament proteins can be applied as diagnostic aids in making the distinction between chordomas, chondroid tumors, and ependymal tumors.     

Association of Lyn tyrosine kinase to the GM-CSF and IL-3 receptor common betac subunit and role of Src tyrosine kinases in DNA synthesis and anti-apoptosis

BACKGROUND: After GM-CSF or IL-3 stimulation, the activation of JAK2 tyrosine kinase and members of the Src family of tyrosine kinases takes place, followed by phosphorylation of betac tyrosine residues and the recruitment of SH2 containing molecules to the receptor complex. The exact role of Src kinases such as Lyn in this and other downstream signal transduction events remains unclear. RESULTS: We investigated the association of Lyn kinase with betac using synthetic peptides derived from the eight betac tyrosine residues and the Box 1 motif. We found that Lyn kinase GST fusion proteins bind to peptides corresponding to the membrane proximal region of betac and to peptides containing specific betac derived phosphorylated tyrosine residues. We also determined that betac tyrosine residues Y1,2 as well as Y7 and Y8 can act as substrates of Lyn. We further analysed the role of the Src kinases in DNA synthesis and anti-apoptosis downstream of GM-CSF by using the Src kinase inhibitor PP1 in murine BA/F3 cells stably expressing a series of mutant betac receptors. CONCLUSIONS: Lyn binds to betac derived peptides through multiple interactions, and may play an important role in betac phosphorylation. Src family kinases also play an essential role in GM-CSF mediated DNA synthesis, as well as an important role in anti-apoptosis in response to GM-CSF.     

Electronic patient-provider communication: will it offset office visits and telephone consultations in primary care?

BACKGROUND AND AIM: Electronic patient-provider communication promises to improve efficiency and effectiveness of clinical care. This study aims to explore whether a secure web-based messaging system is an effective way of providing patient care in general practices. METHOD: We conducted a randomised controlled trail and recruited 200 patients from the waiting area in one primary clinic in Norway. Participants were randomised to either the intervention group, which received access to a secure messaging system, or the control group receiving standard care without such access. Primary outcome measures were number of online consultations, telephone consultations and office visits in the two groups. Data were derived from patient records and collected 1 year prior to (baseline), and 1 year after the intervention. RESULTS: Forty-six percent of the patients who were given access to the messaging system (n=99) used the online communication system on at least one occasion (ranging from 1 to 17 messages per patient per year). A total of 147 electronic messages were sent to six general practitioners during a 1-year trial period. Eleven percent of the messages were to schedule an appointment. In 10% of the messages, the GP was unable to respond adequately and recommended an office visit. The reduction in office visits over time was greater for the intervention group than for the control group (P=0.034). There was however no significant difference in the number of telephone consultations between the groups during the study (P=0.258). CONCLUSION: The use of a secure electronic messaging system reduced the number of office visits at the general practice, but not phone consultations.     

Human X-chromosomal lineages in Europe reveal Middle Eastern and Asiatic contacts

Within Europe, classical genetic markers, nuclear autosomal and Y-chromosome DNA polymorphisms display an east-west frequency gradient. This has been taken as evidence for the westward migration of Neolithic farmers from the Middle East. In contrast, most studies of mtDNA variation in Europe and the Middle East have not revealed clinal distributions. Here we report an analysis of dys44 haplotypes, consisting of 35 polymorphisms on an 8 kb segment of the dystrophin gene on Xp21, in a sample of 1203 Eurasian chromosomes. Our results do not show a significant genetic structure in Europe, though when Middle Eastern samples are included a very low but significant genetic structure, rooted in Middle Eastern heterogeneity, is observed. This structure was not correlated to either geography or language, indicating that neither of these factors are a barrier to gene flow within Europe and/or the Middle East. Spatial autocorrelation analysis did not show clinal variation from the Middle East to Europe, though an underlying and ancient east-west cline across the Eurasian continent was detected. Clines provide a strong signal of ancient major population migration(s), and we suggest that the observed cline likely resulted from an ancient, bifurcating migration out of Africa that influenced the colonizing of Europe, Asia and the Americas. Our study reveals that, in addition to settlements from the Near East, Europe has been influenced by other major population movements, such as expansion(s) from Asia, as well as by recent gene flow from within Europe and the Middle East.     

Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia

We studied the risk of the development of acute myeloid leukemia (AML) during initial remission in 733 consecutive children with acute lymphoid leukemia (ALL) who were treated with intensive chemotherapy. This complication was identified according to standard morphologic and cytochemical criteria in 13 patients 1.2 to 6 years (median, 3.0) after the diagnosis of ALL. At three years of follow-up, the cumulative risk of secondary AML during the first bone marrow remission was 1.6 percent (95 percent confidence limits, 0.7 and 3.5 percent); at six years, it was 4.7 percent (2 and 10 percent). The development of secondary AML was much more likely among patients with a T-cell than a non-T-cell immunophenotype (cumulative risk, 19.1 percent [6 and 47 percent] at six years). Sequential cytogenetic studies in 10 patients revealed entirely different karyotypes in 9, suggesting the induction of a second neoplasm. In eight of these patients, the blast cells had abnormalities of the 11q23 chromosomal region, which has been associated with malignant transformation of a pluripotential stem cell. There was no evidence of loss of DNA from chromosome 5 or 7, a karyotypic change commonly observed in cases of AML secondary to treatment with alkylating agents, irradiation, or both. We conclude that there is a substantial risk of AML in patients who receive intensive treatment for ALL, especially in those with a T-cell immunophenotype, and that 11q23 chromosomal abnormalities may be important in the pathogenesis of this complication.