Experimental quantum speed-up in reinforcement learning agents.

As the field of artificial intelligence advances, the demand for algorithms that can learn quickly and efficiently increases. An important paradigm within artificial intelligence is reinforcement learning1, where decision-making entities called agents interact with environments and learn by updating their behaviour on the basis of the obtained feedback. The crucial question for practical applications is how fast agents learn2. Although various studies have made use of quantum mechanics to speed up the agent's decision-making process3,4, a reduction in learning time has not yet been demonstrated. Here we present a reinforcement learning experiment in which the learning process of an agent is sped up by using a quantum communication channel with the environment. We further show that combining this scenario with classical communication enables the evaluation of this improvement and allows optimal control of the learning progress. We implement this learning protocol on a compact and fully tunable integrated nanophotonic processor. The device interfaces with telecommunication-wavelength photons and features a fast active-feedback mechanism, demonstrating the agent's systematic quantum advantage in a setup that could readily be integrated within future large-scale quantum communication networks.

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Although the aetiology of schizophrenia is complex and multifactorial, with estimated heritabilities as high as 80%, genetic factors are the most compelling. Childhood-onset schizophrenia (COS), defined as onset of schizophrenia before the age of 13 years, is a rare and malignant form of the illness that may have more salient genetic influence. The first known case of paternal segmental uniparental isodisomy (iUPD) on 5q32-qter in a patient with COS is described, which adds to the previously known high rates of chromosomal abnormalities reported in this sample. iUPD is a rare genetic condition in which the offspring receives two chromosomal homologues from one parent. Segmental UPD is defined as UPD on a portion of a chromosome with biparental inheritance seen in the rest of the homologous pair. Complications owing to this abnormality may arise from malfunctioning imprinted genes or homozygosity of recessive disease-causing mutations. This aberration became apparent during whole-genomic screening of a COS cohort and is of particular interest because 5q has been implicated in schizophrenia by several genomewide linkage studies and positive gene associations. This report, therefore, presents more evidence that schizophrenia susceptibility gene, or genes, may be found on distal 5q.

Fibre-optic array for curvature assessment: application in otitis diagnosis.

A contact-free sensor consisting of two parallel optical-fibre arrays was designed to assess surface shapes of diffusely scattering media. By sequentially illuminating objects using one fibre array and detecting the diffusely back-scattered photons by the other, a source-detector intensity matrix was formed, where the matrix element (i, j) was the intensity at detector j when light source i was excited. Experimental data from convex and concave polyacetal plastic surfaces were recorded. A mathematical model was used for simulating source-detector intensity matrices for the surfaces analysed in the experiments. Experimental results from the system were compared with the theoretically expected results provided by the mathematical model. The shape and relative amplitude showed similar behaviour in the experiments and simulations. A convex/concave discriminator index D, representing the detected intensity difference between two source-detector separations, was defined. The relative dynamic range of D, defined as the difference between the maximum and the minimum divided by the mean of the index, was 1.37 for convex surfaces and 0.68 for concave surfaces, at a measuring distance of 4.5 mm. The index D was positive for convex surfaces and negative for concave surfaces, which showed that the system could distinguish between convex and concave surfaces, an important result for the diagnosis of otitis media.

Diffuse reflectance spectroscopy of the human tympanic membrane in otitis media.

We have investigated if features in the diffuse reflectance spectra from in vivo spectroscopic measurements of the tympanic membrane could aid the diagnosis of otitis media in children. Diffuse reflectance spectroscopy, in the visible wavelength range, was used in 15 ears from children with otitis media with effusion before and after myringotomy and in 15 healthy ears as a reference. Two previously published erythema detection algorithms yielded numerical quantities of haemoglobin content. With a combination of the algorithms, induced erythema (after myringotomy) was distinguished from healthy ears using Student's t-test (p < 0.01). Otitis media with mucous effusion was distinguished from (1) otitis media with serous effusion, (2) induced erythema and (3) healthy ears, (p < 0.05) using Student's t-test for independent groups and the paired t-test for dependent groups. Our results imply that reflectance spectroscopy is a promising technique to be used for the diagnosis of otitis media.

Expression and function of chemokine receptors in human multiple myeloma.

Multiple myeloma (MM) is a B cell tumor characterized by its selective localization in the bone marrow. The mechanisms that contribute to the multiple myeloma cell recruitment to the bone marrow microenvironment are not well understood. Chemokines play a central role for lymphocyte trafficking and homing. In this study we have investigated expression and functional importance of chemokine receptors in MM-derived cell lines and primary MM cells. We found that MM cell lines express functional CCR1, CXCR3 and CXCR4 receptors, and some also CCR6. Although only a minority of the cell lines responded by calcium mobilization after agonist stimulation, a migratory response to the CCR1 ligands RANTES and MIP-1 alpha was obtained in 5/6 and 4/6, respectively, of the cell lines tested. Five out of six cell lines showed a response to the CXCR4 ligand SDF-1. In addition, 3/6 cell lines migrated in response to MIP-3 alpha and IP-10, ligands for CCR6 and CXCR3, respectively. The expression of CXCR4 and CCR1 and the migration to their ligands, SDF-1, and RANTES and MIP-1 alpha, respectively, were also demonstrated in primary MM cells. These findings suggest that chemokine receptor expression and the migratory capacity of MM cells to their ligands are relevant for the compartmentalization of MM cells in the bone marrow.

Hepatocyte growth factor may accelerate healing in chronic leg ulcers: a pilot study.

BACKGROUND: Hepatocyte growth factor (HGF) is a heparin-binding protein with mitogenic, motogenic and morphogenic activities for various cell types. The regenerative properties of HGF have been the object of several animal and in vitro studies in recent years. OBJECTIVE: To investigate the physiological and therapeutic effects of HGF on chronic leg ulcers. METHODS: HGF in gel form was locally applied, once daily for 7 days, to 15 of 19 chronic leg ulcers in 11 elderly patients. All patients had previously been treated by conventional methods and their leg ulcers had been in stable conditions for between 1 and 14 years. Any signs of allergy, discomfort or pain were reported daily. Microcirculation perfusion in the ulcers, compared to the intact contiguous skin, was determined by laser Doppler at the beginning of the study, after 1 week and again after 3 months (in seven patients). Ulcer size and characteristics were also documented. RESULTS: It was observed that microcirculatory perfusion, which might reflect the angiogenic effect of HGF, was statistically significantly correlated (r = 0.94, p < 0.002) to ulcer area reduction in the treated ulcers. Excellent (84-100% area reduction) or partial healing (58-59%) was seen in eight out of 11 patients. No control group was included in this pilot study, which must be completed by proper control studies. CONCLUSION: This study suggests that HGF may heal chronic leg ulcers, possibly by improving the microcirculation. Proper control studies need to be performed.

Spectral signature and heterodyne efficiency for different wavelengths in laser Doppler flowmetry.

Laser Doppler perfusion monitoring and imaging technologies generate time traces and two-dimensional flow maps of the microcirculation. With the goal of reaching different tissue depths, these technologies are equipped with lasers operating at different wavelengths lambda. The fact that the average scattering angle, at a single scattering event, between a photon and a red blood cell increases with lambda is compensated for by a 1/lambda effect in the scattering vector, rendering the average frequency shift virtually independent of the choice of wavelength. Monte Carlo simulations showed that the corresponding spectral signature of the Doppler signals for lambda = 632.8 nm and 780 nm were close to identical. The theoretical predictions were verified by calculating the centre-of-gravity (COG) frequency of the laser Doppler power spectral density for the two wavelengths from forearm and finger skin, representing a low and high perfusion area, respectively (forearm COG= 123 against 121 Hz, finger COG = 220 against 212 Hz). When the wavelength changes from 632.8 nm to 780 nm, the heterodyne efficiency of the detector and, thereby, the inherent system amplification increase. For tissues with identical microvascular flow conditions, the output signal therefore tends to increase in magnitude when shifting to longer wavelengths.

Multiple myeloma cells are killed by syndecan-1-directed superantigen-activated T cells.

Multiple myeloma (MM) is an incurable plasma cell/plasmablast malignancy with a great need for innovative treatment strategies. Since experimental immunotherapy with targeted superantigens (SAg) proved to be effective in other haematopoietic tumours, we investigated whether this would also hold true for MM. We used the bacterial SAg Staphylococcus enterotoxin A (SEA), a potent activator of T cell cytotoxicity by means of its binding to particular T cell receptor Vbeta sequences on effector cells and MHC class II molecules on target cells. To eliminate potentially unspecific binding via MHC class II, SEA was point mutated (SEAm). In a second step SEAm was genetically fused to protein A (PA), resulting in a fusion protein (PA-SEAm). This fusion protein was used together with four different plasma-cell-specific/associated mAbs to direct T cells towards 10 MM target cell lines. Three of these mAbs were directed against syndecan-1/CD138, known to be highly expressed on MM and plasma cells, but absent on other haematopoietic cells. All MM cell lines proved to be sensitive to SAg-activated T cell killing (15-50% lysis), as measured in a 51Cr-release assay. This effect was clearly mediated via the plasma-cell-reactive antibodies, as control antibodies only conferred a low background lysis. MM therapy based on targeted SAgs could in theory be hampered by dysfunctional T cells in MM patients. However, we show that T cells from MM patients and healthy controls responded equally well to activation by SAg.

Reflection spectroscopy of analgesized skin.

Analgesized skin, when subjected to heat stimuli, responds by increasing skin perfusion. This response does not originate from increased perfusion in superficial capillaries, but rather in the deeper lying vessels. The aim of this study was to assess changes in blood chromophore content, measured by reflection spectroscopy, in relation to the perfusion increase, especially regarding the chromophores oxyhemoglobin and deoxyhemoglobin. Eleven normal subjects were treated with analgesic cream (EMLA) and placebo for 20, 40, 60, 120, and 180 min. Individual reactions to local heating were classified as responses if the change in reflection data or the change in perfusion, as measured by laser Doppler blood flowmetry, exceeded 2 standard deviations of normal variation. The increase in blood perfusion or in blood content gave rise to an increased absorption, interpreted as an increase due mainly to the chromophore oxyhemoglobin. The number of responses increased with increased treatment time for EMLA-treated areas. In general, there was a good agreement between both methods; 44 of 55 classifications coincided for the two methods used. In conclusion, analgesized forearm skin, which had been exposed to local heating, responded with an elevated perfusion consisting of oxygenated blood. This strengthens the hypothesis that the flow increase occurs through dilatation of larger deeper lying skin vessels and not in the capillaries.

Respiratory drive during carbachol challenge in allergic sheep.

Diaphragmatic activity is the standard assessment of respiratory neural output but is difficult to measure and cannot be used for long-term clinical monitoring. The tidal breathing minute ventilation (V') and mean inspiratory flow (VT/tI) reflect respiratory drive and can be monitored non-invasively using respiratory inductive plethysmography (RIP). Recent findings indicate that peak inspiratory acceleration (PIA) correlates to diaphragmatic activity during CO2 rebreathing in piglets. The aim of the present study was to assess whether tidal breathing peak inspiratory acceleration reflects respiratory drive during carbachol challenge. Aerosolized carbachol was administered to 15 allergic sheep until pulmonary resistance increased by at least 400%. After threshold dose, slight increases in V' and VT/tI were seen (8 and 5%, respectively; P=NS), while PIA increased by 30% (P<0.05). The change in PIA was closely correlated to changes in V'[bar over] and VT/tI (r=0.73, P<0.01 and r=0.88, P<0.001, respectively). In conclusion, peak inspiratory acceleration reflected respiratory drive during bronchoprovocation. Further, this new measure of drive has the potential to accurately estimate drive in chronic obstructive lung disease where intrinsic positive end expiratory pressure prevents accurate selection of beginning inspiration necessary for computation of, e.g. VT/tI.

Skin capillary appearance and skin microvascular perfusion due to topical application of analgesia cream.

Local topical analgesia changes basal skin perfusion and its regulation. In particular, the response induced by local heating, which in nontreated skin comprises a rapidly increased perfusion followed by a normalization within 30 s, is altered to a delayed and persistent perfusion increase. The response dependency to the analgesia cream application time, that is, the intradermal penetration of the analgesics and in which vascular plexa the response occurs, is not known. The aim of this study was to assess changes in the appearance of superficial skin capillaries and skin microvascular perfusion changes due to different application periods of topical analgesia cream (EMLA). Twelve subjects were treated with EMLA and placebo applied to the volar side of each forearm, respectively. The treatment areas were assigned different application times (20 min, 40 min, 1 h, 2 h, and 3 h). The areas were cleared from the creams and shortly thereafter provoked during 9 s with a probe heated to 45 degrees C. To assess capillary number density and skin perfusion, capillary microscopy, and Laser Doppler perfusion imaging (LDPI), respectively, were used. The number density of physiologically active capillary was significantly decreased with longer application times of EMLA (P < 0.005). The LDPI-signal showed a persistent perfusion increase after provocation associated with increasing application time of the cream. This perfusion pattern was not seen after 20 min of treatment, but was present in 9 of 12 subjects after 3 h of treatment. No significant relationship between changes in the capillary number density and the LDF measurement was found. In conclusion, a longer application time and therefore a higher intradermal concentration and a deeper penetration of the analgesics was associated with a delayed and persistent perfusion increase after local heating. There was a discrepancy between changes in capillary number density and skin perfusion, indicating that the perfusion increase does not occur in the capillaries but in the deeper lying vessels. Hence, the contribution of the capillary perfusion to the LDF-signal is smaller than previously anticipated. Capillary number density and presumably their perfusion were decreased with longer application times.

Effects on skin blood flow by provocation during local analgesia.

Although topical analgesia cream has been used for several years, little is known about its effects on the microcirculation. Previous studies have shown a vasoconstrictive effect after short application times and a vasodilatation after longer application. It has also been shown that vasomotion does not occur in the analgesized skin. The present study was undertaken to investigate the alterations in skin blood perfusion following local cooling, local heating and pin-pricking after the establishment of analgesia. In 11 healthy volunteers, skin analgesia was attained by use of a eutectic mixture of lidocaine and prilocaine (EMLA, Astra Pain Control AB, Sweden) applied to the skin three hours prior to provocation. The changes in skin blood perfusion, after applying three different provocation methods, were studied using the laser Doppler technique. Local cooling and heating to temperatures of +10 and +45 degrees C, respectively, were applied for 9 s by use of a copper probe (O12 mm). In the pin-prick provocation method, a combined effect of deflection and penetration of the skin to in total 3 mm was attained. Identical provocation methods were applied to placebo treated and untreated skin areas. After heat provocation, significant differences in the perfusion response between the treatments were seen (P < 0.0001). Skin areas treated with analgesia cream responded with a slow increase in perfusion that persisted beyond the four minute measurement period. Placebo and untreated areas decreased their perfusion over time. After cooling a significant reduction in skin perfusion was seen, irrespective of the treatment. Similarly, after pin-pricking a perfusion increase was seen for all treatments. The findings indicate that topical analgesia influences the myogenic control of the blood flow in those vascular plexa measured by laser Doppler following heat provocation. No differences could be seen in the response to pin-pricking and cooling for the different treatments.

Influence of tidal volume and thoraco-abdominal separation on the respiratory induced variation of the photoplethysmogram.

OBJECTIVE: The present study was aimed at determining the relative influences of tidal volume and thoraco-abdominal separation (relative thoracic and abdominal contribution to the tidal volume) on the respiratory induced intensity variation (RIIV) of the photoplethysmographic signal. The effects were studied in two body positions. METHODS: Respiratory inductive plethysmography was used for quantifying thoraco-abdominal separation and for assessing tidal volumes. 10 subjects were trained to perform widely varying degrees of thoraco-abdominal separation at different tidal volumes. The relationship between the RIIV signal peak-to-peak value (measured at the forearm), and the tidal volume and thoraco-abdominal separation was investigated in two body positions with the use of multiple linear regression. RESULTS: Larger tidal volume and more thoracic contribution to respiration were found to increase the RIIV peak-to-peak value (p < 0.0005). In the supine position, the tidal volume influence was stronger than that of thoraco-abdominal separation, and in the sitting position, the opposite was seen. CONCLUSIONS: The effects on the RIIV signal following changes in thoraco-abdominal separation and tidal volume are of the same order of magnitude. In the supine position, the influence of thoracic versus abdominal contribution to the tidal volume is not as significant as in the sitting position. Photoplethysmography is a promising technique for combined monitoring of several respiratory parameters, including tidal volume. In situations where the relative thoracic and abdominal contributions are likely to vary, the tidal volume information becomes less reliable.

Neurophysiological findings in vibration-exposed male workers.

Fractionated nerve conduction, vibrotactile sense, and temperature thresholds were studied in 73 symptomatic vibration-exposed male workers. Three symptomatic groups were distinguished: patients with isolated sensorineural symptoms; with isolated vasospastic problems; and with both. Clinical carpal tunnel syndrome occurred in 14 patients and abnormal cold intolerance (without blanching of the fingers) in 23. In the group as a whole, nerve conduction studies were abnormal in the median nerve but not in the ulnar nerve and vibration perception and temperature thresholds were impaired. Of the three symptomatic groups, patients with isolated sensorineural symptoms differed from controls. No differences were seen between patients with and without clinical carpal tunnel syndrome. With severe sensorineural symptoms the vibration perception thresholds, but not the values of the nerve conduction studies, were further impaired. The results indicated two injuries that are easily confused: one at receptor level in the fingertips and one in the carpal tunnel. Careful clinical assessment, neurophysiological testing, and examination of vibrotactile sense are required before carpal tunnel release should be considered in these patients.

Outcomes of periradicular surgery in cases with apical pathosis and untreated canals.

OBJECTIVE: Surgical management is intended to eliminate or block infection originating in the root canals. The root end is customarily sealed to prevent pathogenic products remaining in the root canal from reaching the periradicular tissues. The purpose of this study was to evaluate the microbiologic and radiographic outcomes of surgical treatment of periradicular pathosis associated with teeth with necrotic pulps. STUDY DESIGN: One tooth from each of 10 patients was root-end resected and root-end filled without prior root canal treatment. One year postoperatively, the outcomes were assessed radiographically and the root canals were sampled for bacteria. RESULTS: Radiographic examination showed complete or incomplete (scar tissue) healing in 5 teeth and uncertain healing in the other 5 teeth. Bacteriologic samples from the root canals were positive in 9 of the 10 cases. CONCLUSIONS: In teeth with necrotic pulps, treatment of periradicular pathosis by surgery and root-end filling may show radiographic evidence of satisfactory healing 1 year postoperatively. However, viable bacteria may persist in the canals, constituting a potential risk factor for recurrence of periradicular pathosis.

The somatostatin analog octreotide inhibits growth of interleukin-6 (IL-6)-dependent and IL-6-independent human multiple myeloma cell lines.

Somatostatin and its analogs can inhibit growth in several cell types, in part by interfering with insulin-like growth factor-I (IGF-I) signaling. Our previous studies point to the importance of paracrine and autocrine IGF-I in the support of growth and survival of human multiple myeloma (MM) cell lines. In this report, we have investigated the potential role of a somatostatin analog, octreotide, in regulating growth and/or survival in MM. The results show that all MM cell lines express functional somatostatin receptors (sst). The MM cell lines express the subtypes sst2, sst3, and predominantly sst5 as determined by reverse-transcriptase polymerase chain reaction and fluorescence-activated cell sorter analysis. Octreotide inhibited the growth of both the interleukin-6 (IL-6)-dependent and the IL-6-independent MM cell lines. The effect is mainly cytostatic, resulting in 25% to 45% growth inhibition, and in three of eight of the MM cell lines a weak induction of apoptosis was recorded. Our results also show that octreotide may act as an inducer of apoptosis in primary B-B4(+) plasma cells isolated from bone marrow of MM patients. In conclusion, the results show a novel pathway for growth inhibition of MM cells: the activation of somatostatin receptor signaling.

Midclavicular catheters in the antepartum population. A continuous quality improvement review.

After a catheter-induced subclavian thrombosis, a continuous quality improvement (CQI) study was undertaken to answer the question: Are midclavicular lines appropriate in high-risk obstetric patients? This article reports the findings of a retrospective chart audit that described 32 consecutively placed midclavicular lines in a high-risk obstetric population. Study variables included maternal and catheter characteristics, as well as dwell time and rationales for line discontinuance. Therapy was completed in 68%. There were no episodes of noncompliance, catheter malfunction, or bleeding. Episodes of phlebitis and occlusion were relatively uncommon; positive cultures occurred in six catheter tips but were unaccompanied by any clinical evidence indicative of bacteremia or catheter sepsis. However, given the growing recognition of the risks of subclinical and clinical thrombosis endemic to the midclavicular position, increasing reports of malposition that are logistically unable to address, and the growing number of osmotically active solutions being used that are not suited to anything other than superior vena cava dilution, the authors have stopped placing midclavicular catheters in the high-risk obstetric population.

Vibrotactile sense in the hand-arm vibration syndrome.

OBJECTIVES: The purpose of this study was to investigate disturbances of the vibrotactile sense and their relation to clinical symptoms and findings among male symptomatic workers suffering from the hand-arm vibration syndrome. METHODS: Ninety-six such patients were interviewed and given a clinical and tactilometric examination. The symptoms were classified according to the Stockholm Workshop Scale. A sensibility index was used to quantify vibrotactile sense in the tactilogram. RESULTS: An abnormal sensibility index (<0.8) was recorded for 57.3% of the patients (mean of 4 fingers), at least 1 finger being abnormal in 72.9% of the patients. The sensibility index did not statistically differ between the patients suffering from sensorineural symptoms and those with vibration white finger. The stages of sensorineural symptoms, according to the Stockholm Workshop Scale, corresponded with the sensibility index, whereas the stages of vibration white finger did not. There were significant differences in the sensibility index between the fingers, between the right and left hands, and between the fingers innervated by the ulnar and median nerves. Bilateral symptoms and cold intolerance were associated with considerable impairment of the vibrotactile sense. Clinical median nerve involvement in the carpal tunnel was not reflected by the sensibility index. CONCLUSIONS: There is a considerable degree of neural involvement in all symptomatic vibration-exposed patients irrespective of symptoms. As symptoms progress, the severity of sensorineural symptoms, but not of vibration white finger, is reflected by the sensibility index. Cold intolerance is strongly related to nervous involvement and should be noted in the patient history. Tactilometry should be performed on 1 median and 1 ulnar nerve-innervated finger of both hands, as an examination of 1 finger alone may be misleading.

Structural nerve changes at wrist level in workers exposed to vibration.

OBJECTIVES: To analyse the character of morphological changes occurring in a well defined peripheral nerve in humans exposed to vibration from hand held tools. METHODS: Biopsies of the dorsal interosseus nerve just proximal to the wrist were taken from 10 men exposed to vibration and from 12 male age matched necropsy controls. The nerve was resected for pain relief either as the sole procedure or in conjunction with carpal tunnel release. All specimens were sectioned and examined by light microscopy in standard sections, thin epon sections, and teasing preparations. RESULTS: The combined results of the analyses showed pathological changes in all 10 patients dominated by breakdown of myelin and by interstitial and perineurial fibrosis. All but one of the 12 controls were normal. CONCLUSION: These findings often show severe nerve injury previously not described at this level. They indicate that demyelination may be the primary lesion in neuropathy induced by vibration followed by fibrosis associated with incomplete regeneration or with organisation of oedema. Vibration can induce structural changes in peripheral nerves just proximal to the wrist and such changes may constitute a structural component in carpal tunnel syndrome among people exposed to vibration. This may help to explain the poor results achieved by carpal tunnel release in these patients.