Low-Voltage Domain-Wall LiNbO3 Memristors.

Application of conducting ferroelectric domain walls (DWs) as functional elements may facilitate development of conceptually new resistive switching devices. In a conventional approach, several orders of magnitude change in resistance can be achieved by controlling the DW density using supercoercive voltage. However, a deleterious characteristic of this approach is high-energy cost of polarization reversal due to high leakage current. Here, we demonstrate a new approach based on tuning the conductivity of DWs themselves rather than on domain rearrangement. Using LiNbO3 capacitors with graphene, we show that resistance of a device set to a polydomain state can be continuously tuned by application of subcoercive voltage. The tuning mechanism is based on the reversible transition between the conducting and insulating states of DWs. The developed approach allows an energy-efficient control of resistance without the need for domain structure modification. The developed memristive devices are promising for multilevel memories and neuromorphic computing applications.

Hall effect in charged conducting ferroelectric domain walls.

Enhanced conductivity at specific domain walls in ferroelectrics is now an established phenomenon. Surprisingly, however, little is known about the most fundamental aspects of conduction. Carrier types, densities and mobilities have not been determined and transport mechanisms are still a matter of guesswork. Here we demonstrate that intermittent-contact atomic force microscopy (AFM) can detect the Hall effect in conducting domain walls. Studying YbMnO3 single crystals, we have confirmed that p-type conduction occurs in tail-to-tail charged domain walls. By calibration of the AFM signal, an upper estimate of ∼1 × 1016 cm-3 is calculated for the mobile carrier density in the wall, around four orders of magnitude below that required for complete screening of the polar discontinuity. A carrier mobility of∼50 cm2V-1s-1 is calculated, about an order of magnitude below equivalent carrier mobilities in p-type silicon, but sufficiently high to preclude carrier-lattice coupling associated with small polarons.

Immunovirological correlates in human rabies treated with therapeutic coma.

A 37-year-old woman was admitted to hospital and over the next 5 days developed a progressive encephalitis. Nuchal skin biopsy, analyzed using a Rabies TaqMan(c) PCR, demonstrated rabies virus RNA. She had a history in keeping with exposure to rabies whilst in South Africa, but had not received pre- or post-exposure prophylaxis. She was treated with a therapeutic coma according to the "Milwaukee protocol," which failed to prevent the death of the patient. Rabies virus was isolated from CSF and saliva, and rabies antibody was demonstrated in serum (from day 11 onwards) and cerebrospinal fluid (day 13 onwards). She died on day-35 of hospitalization. Autopsy specimens demonstrated the presence of rabies antigen, viral RNA, and viable rabies virus in the central nervous system.

Thrombotic thrombocytopenic purpura secondary to Streptococcus.

We describe a 16 year old female who developed thrombotic thrombocytopenic purpura (TTP) following infection due to Streptococcus. Initially presenting a fever and systemic upset she progressed to develop dialysis dependent acute renal failure, seizures, thrombocytopenia and a haemolytic anaemia--the pentad of features seen in TTP. Prior to the diagnosis she was found to have unexplained and previously undescribed MRI findings of diffuse increased signal intensity in the white matter of the left cerebellar hemisphere posteriorly and also increased signal intensity in the overlying cortex. She was commenced on plasmapheresis, and her anaemia, thrombocytopenia, creatinine and LDH all fully responded. In addition, she had no further seizures following plasmapheresis and has not relapsed to date. We review both the rare association of TTP and streptococcal infection, and the neuroradiological findings described in the literature. This is only the third case report describing TTP following streptococcal infection, and only the second in the era of plasmapheresis.

Clinical aspects of MuSK antibody positive seronegative MG.

Serum antibodies to muscle-specific receptor tyrosine kinase were detected in 12 of 32 patients with generalized seronegative MG. All were women, with onset between ages 21 and 59 years. Seven had prominent neck, shoulder, or respiratory muscle weakness and little or delayed ocular muscle involvement. The response to cholinesterase inhibitors was variable, and electromyographic findings suggested myopathy in several. None improved after thymectomy. All patients improved after plasma exchange, and most had a good response to selected immunotherapy. MuSK antibody status should help diagnose MG with atypical presentations and ensure appropriate patient treatment.

Effects of billing and documentation requirements on the quantity and quality of teaching by attending physicians.

PURPOSE: The Health Care Financing Administration's guidelines for billing and documentation by attending physicians have increased the amount of time that attending physicians spend documenting the services that they provide for patients. This study assessed the impact of these guidelines on attending physicians' teaching of housestaff on inpatient medical wards. METHOD: A survey of 92 housestaff from the department of medicine at one teaching hospital was conducted in 1998 to determine how attending physicians' billing and documentation requirements, clinic responsibilities, teaching styles, and inpatient census affected the quantity and quality of their teaching. The questionnaire included a rank-order analysis of factors affecting quantity and quality of attending physicians' teaching, as well as a five-point Likert scale assessing the quality of attending physicians' teaching. RESULTS: All housestaff responded. A total of 39% of housestaff perceived billing and documentation requirements to be the major detriment to quantity of teaching by attending physicians, and 30% perceived these requirements to be the major detriment to quality of teaching by attending physicians. Housestaff perceived more teaching and higher-quality teaching on services where attending physicians did not perform billing and documentation during teaching rounds. CONCLUSION: Billing and documentation requirements are a major detriment to the quantity of teaching on inpatient services, especially when faculty attempt to meet these requirements during teaching rounds.

Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.

Use of a novel modified TSI for the evaluation of controlled-release aerosol formulations. I.

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.

Mutagenesis analysis of human SM22: characterization of actin binding.

SM22 is a 201-amino acid actin-binding protein expressed at high levels in smooth muscle cells. It has structural homology to calponin, but how SM22 binds to actin remains unknown. We performed site-directed mutagenesis to generate a series of NH(2)-terminal histidine (His)-tagged mutants of human SM22 in Escherichia coli and used these to analyze the functional importance of potential actin binding domains. Purified full-length recombinant SM22 bound to actin in vitro, as demonstrated by cosedimentation assay. Binding did not vary with calcium concentration. The COOH-terminal domain of SM22 is required for actin affinity, because COOH terminally truncated mutants [SM22-(1-186) and SM22-(1-166)] exhibited markedly reduced cosedimentation with actin, and no actin binding of SM22-(1-151) could be detected. Internal deletion of a putative actin binding site (154-KKAQEHKR-161) partially prevented actin binding, as did point mutation to neutralize either or both pairs of positively charged residues at the ends of this region (KK154LL and/or KR160LL). Internal deletion of amino acids 170-180 or 170-186 also partially or almost completely inhibited actin cosedimentation, respectively. Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding. Substitution of Ser-181 to aspartic acid (to mimic serine phosphorylation) also reduced actin binding. Immunostains of transiently transfected airway myocytes revealed that full-length NH(2)-terminal FLAG-tagged SM22 colocalizes with actin filaments, whereas FLAG-SM22-(1-151) does not. These data confirm that SM22 binds to actin in vitro and in vivo and, for the first time, demonstrate that multiple regions within the COOH-terminal domain are required for full actin affinity.

Physiological control of smooth muscle-specific gene expression through regulated nuclear translocation of serum response factor.

Prolonged serum deprivation induces a structurally and functionally contractile phenotype in about 1/6 of cultured airway myocytes, which exhibit morphological elongation and accumulate abundant contractile apparatus-associated proteins. We tested the hypothesis that transcriptional activation of genes encoding these proteins accounts for their accumulation during this phenotypic transition by measuring the transcriptional activities of the murine SM22 and human smooth muscle myosin heavy chain promoters during transient transfection in subconfluent, serum fed or 7 day serum-deprived cultured canine tracheal smooth muscle cells. Contrary to our expectation, SM22 and smooth muscle myosin heavy chain promoter activities (but not viral murine sarcoma virus-long terminal repeat promoter activity) were decreased in long term serum-deprived myocytes by at least 8-fold. Because serum response factor (SRF) is a required transcriptional activator of these and other smooth muscle-specific promoters, we evaluated the expression and function of SRF in subconfluent and long term serum-deprived cells. Whole cell SRF mRNA and protein were maintained at high levels in serum-deprived myocytes, but SRF transcription-promoting activity, nuclear SRF binding to consensus CArG sequences, and nuclear SRF protein were reduced. Furthermore, immunocytochemistry revealed extranuclear redistribution of SRF in serum-deprived myocytes; nuclear localization of SRF was restored after serum refeeding. These results uncover a novel mechanism for physiological control of smooth muscle-specific gene expression through extranuclear redistribution of SRF and consequent down-regulation of its transcription-promoting activity.

Endovascular aortic repair is associated with greater hemodynamic stability compared with open aortic reconstruction.

OBJECTIVE: Examination of overall hemodynamic stability in patients undergoing endovascular aortic repair (EAR) compared with open aortic repair (OAR). DESIGN: Retrospective study. SETTING: University hospital setting. PARTICIPANTS: Seventy-two patients undergoing OAR and 17 patients undergoing EAR were studied. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Physiologic parameters were extracted every 15 seconds from computerized anesthesia records. Median values were calculated for every 2-minute epoch, and the absolute value of the fractional change in median (|FCM|) from epoch to epoch was calculated for a maximum of 5 hours during the intraoperative period. The incidence of extremes in hemodynamic parameters was compared. Data are presented as median and interquartile ranges. The frequency of |FCM| greater than 0.06 for mean arterial pressure (MAP) was significantly greater in the OAR compared with the EAR group (0.37 [0.30, 0.46] vs 0.14 [0.11, 0.21], p < 0.0001), implying greater stability in MAP during EAR. Similarly, the mean pulmonary artery pressures (MPAPs) were significantly more stable during EAR compared with OAR (frequency of |FCM| > 0.07: EAR, 0.20 [0.16, 0.27] vs OAR, 0.32 [0.26, 0.391; p < 0.01). No intergroup differences were detected in heart rate (HR), systolic (SPAP) or diastolic pulmonary artery pressures (DPAP), or central venous pressures (CVPs). With the exception of a greater incidence of low CVP during EAR, there were no significant differences in the frequency of extremes of hemodynamic values between groups. CONCLUSION: These results show improved hemodynamic stability during EAR compared with OAR.

Neurological examination is possible using telemedicine.

To compare the reliability of neurological examination performed by telemedicine and face to face, a junior doctor examined 23 patients face to face, these examinations being witnessed either by one or by two telemedicine observers using a telemedicine video-link at 384 kbit/s. The gold standard was a face-to-face examination from a panel of six consultant neurologists. Power, deep tendon reflexes, plantar responses, coordination, sensation, eye movements, facial strength, tongue movements, sitting balance and gait were studied. Seventeen patients satisfied the inclusion criteria, and a total of 1,084 matched pairs of observations were made. The reliability of the telemedicine examination ranged from fair to moderate for deep tendon reflexes, coordination and eye movement, to near perfect for plantar responses. Overall, examination by telemedicine compared favourably with face-to-face examination. Telemedicine examination was more sensitive in detecting abnormalities than face-to-face examination for all the neurological tests studied and more specific for all but one (plantar responses). The study showed that neurological examination using telemedicine is at least as good as face-to-face examination performed by a junior doctor.

Attitudes towards, and utility of, an integrated medical-dental patient-held record in primary care.

BACKGROUND: The need for closer coordination between primary care medical and dental services has been recognized. AIM: To assess the attitudes of general medical practitioners (GMPs), general dental practitioners (GDPs), and patients to an integrated medical-dental patient-held record (integrated medical-dental PHR); to examine patients' use of these records, and the utility of the records for doctors and dentists. METHOD: A three-phase study was carried out: (1) postal survey of GMPs and GDPs; (2) randomized trial of patients, using postal questionnaires before and one year after the issue of integrated medical-dental PHRs to cases; (3) assessment by doctors and dentists of anonymized integrated medical-dental PHRs from this trial. The study was carried out in medical and dental practices in affluent and deprived areas in Greater Glasgow Health Board. Two hundred and thirteen GMPs, 183 GDPs, and 369 patients registered with GMPs and GDPs were surveyed. Eighteen GDPs and GMPs assessed the integrated medical-dental PHRs. RESULTS: Eighty per cent of dentists had contacted a doctor and 16% of doctors had contacted a dentist in the previous three months; 87% of dentists and 68% of doctors thought an integrated medical-dental PHR would be of some use. Twenty-one per cent of dentists and 85% of doctors had practice computers. Most patients wanted to be able to see and read their own records. Twenty-four per cent of patients said there were mistakes and 30% noticed omissions in the integrated medical-dental PHR issued. Experience of having an integrated medical-dental PHR made patients more positive towards the idea of having a patient-held record and being able to check the accuracy of records. Integrated medical-dental PHRs contained important information for half the GDPs and one-third of the GMPs. CONCLUSION: Both professionals and patients have reasonably positive attitudes towards the use of patient-held records. Among patients, the experience of having the integrated medical-dental PHR led to greater enthusiasm towards the idea. Dentists in particular would benefit from the transfer of information from doctors, but better methods are needed to ensure that patients take the integrated medical-dental PHR with them. Given the current lack of ability to easily produce an integrated medical-dental PHR, further examination of the routine issue of a copy of their medical summary, by GMPs, to all patients would be worthwhile.