Imaging the lipid-phase-dependent pore formation of equinatoxin II in droplet interface bilayers.

Using phase-separated droplet interface bilayers, we observe membrane binding and pore formation of a eukaryotic cytolysin, Equinatoxin II (EqtII). EqtII activity is known to depend on the presence of sphingomyelin in the target membrane and is enhanced by lipid phase separation. By imaging the ionic flux through individual pores in vitro, we observe that EqtII pores form predominantly within the liquid-disordered phase. We observe preferential binding of labeled EqtII at liquid-ordered/liquid-disordered domain boundaries before it accumulates in the liquid-disordered phase.

Onset of submarine debris flow deposition far from original giant landslide.

Submarine landslides can generate sediment-laden flows whose scale is impressive. Individual flow deposits have been mapped that extend for 1,500 km offshore from northwest Africa. These are the longest run-out sediment density flow deposits yet documented on Earth. This contribution analyses one of these deposits, which contains ten times the mass of sediment transported annually by all of the world's rivers. Understanding how this type of submarine flow evolves is a significant problem, because they are extremely difficult to monitor directly. Previous work has shown how progressive disintegration of landslide blocks can generate debris flow, the deposit of which extends downslope from the original landslide. We provide evidence that submarine flows can produce giant debris flow deposits that start several hundred kilometres from the original landslide, encased within deposits of a more dilute flow type called turbidity current. Very little sediment was deposited across the intervening large expanse of sea floor, where the flow was locally very erosive. Sediment deposition was finally triggered by a remarkably small but abrupt decrease in sea-floor gradient from 0.05 degrees to 0.01 degrees. This debris flow was probably generated by flow transformation from the decelerating turbidity current. The alternative is that non-channelized debris flow left almost no trace of its passage across one hundred kilometres of flat (0.2 degrees to 0.05 degrees) sea floor. Our work shows that initially well-mixed and highly erosive submarine flows can produce extensive debris flow deposits beyond subtle slope breaks located far out in the deep ocean.

Convolutional neural networks for the automatic segmentation of lumbar paraspinal muscles in people with low back pain.

The size, shape, and composition of paraspinal muscles have been widely reported in disorders of the cervical and lumbar spine. Measures of size, shape, and composition have required time-consuming and rater-dependent manual segmentation techniques. Convolutional neural networks (CNNs) provide alternate timesaving, state-of-the-art performance measures, which could realise clinical translation. Here we trained a CNN for the automatic segmentation of lumbar paraspinal muscles and determined the impact of CNN architecture and training choices on segmentation performance. T2-weighted MRI axial images from 76 participants (46 female; age (SD): 45.6 (12.8) years) with low back pain were used to train CNN models to segment the multifidus, erector spinae, and psoas major muscles (left and right segmented separately). Using cross-validation, we compared 2D and 3D CNNs with and without data augmentation. Segmentation accuracy was compared between the models using the Sørensen-Dice index as the primary outcome measure. The effect of increasing network depth on segmentation accuracy was also investigated. Each model showed high segmentation accuracy (Sørensen-Dice index ≥ 0.885) and excellent reliability (ICC2,1 ≥ 0.941). Overall, across all muscles, 2D models performed better than 3D models (p = 0.012), and training without data augmentation outperformed training with data augmentation (p < 0.001). The 2D model trained without data augmentation demonstrated the highest average segmentation accuracy. Increasing network depth did not improve accuracy (p = 0.771). All trained CNN models demonstrated high accuracy and excellent reliability for segmenting lumbar paraspinal muscles. CNNs can be used to efficiently and accurately extract measures of paraspinal muscle health from MRI.

An inconvenient truth about thermoelectrics.

Despite recent advances, thermoelectric energy conversion will never be as efficient as steam engines. That means thermoelectrics will remain limited to applications served poorly or not at all by existing technology. Bad news for thermoelectricians, but the climate crisis requires that we face bad news head on.

Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil.

PURPOSE: To investigate and measure the metabolism of colorectal cancer liver metastases using 18F-fluorodeoxyglucose positron emission tomography (FDG PET), before and during the first month of chemotherapy. The findings were compared with tumor outcome conventionally assessed using changes in tumor size. PATIENTS AND METHODS: Patients with colorectal cancer liver metastases were treated with fluorouracil (5FU) as a protracted venous infusion (300 mg/m2/d), with or without interferon-alpha 2b for two 10-week blocks separated by a 2-week break. Before and at 1 to 2 and 4 to 5 weeks on treatment, FDG PET scans were performed. Patients fasted, were injected intravenously with FDG (50 to 100 MBq), and scanned using a large-area positron camera; the image data was processed such that regions of interest could be identified. The results were expressed as a ratio of FDG uptake in the tumor and normal liver (T:L) or as a semiquantitative standardized uptake value (SUV). These measures were compared with the tumor dimensions measured on a computed tomographic (CT) scan performed at 12 weeks from commencement of chemotherapy. RESULTS: Twenty patients were studied; however, two did not have assessable liver metastases. Objective partial responses were observed in 11 of 18 patients. A total of 27 metastatic lesions were assessable. Pretreatment T:L ratios and SUVs did not correlate with tumor response, although response was associated with lower 1- to 2-week (1.84 v 2.17; t=2.667; P < .02) and 4- to 5-week (1.36 v 2.28; t=5.02; P < .001) T:L ratios, and 4- to 5-week (3.57 v 4.95; t=2.492; P < .05) SUVs. Expressed as a percent of the baseline values of the T:L ratio, responding lesions had a greater reduction in metabolism (67% v 99%; t=7.53; P < .001). The 4- to 5-week T:L ratio was able to discriminate response from nonresponse both in a lesion-by-lesion and overall patient response assessment (sensitivity 100%; specificity 90% and 75%, respectively). CONCLUSION: Positron emission tomography used to evaluate the uptake of FDG in tumors yields data that correlate with the antitumor effect of chemotherapy in patients with liver metastases from colorectal cancer.

Quantification of skeletal kinetic indices in Paget's disease using dynamic 18F-fluoride positron emission tomography.

The purpose of this study was to quantify indices of regional bone metabolism in Paget's disease and to compare these indices with normal bone using dynamic 18F-fluoride positron emission tomography (PET). Seven patients with vertebral Paget's disease had 1 h dynamic 18F-fluoride PET scans performed. The scans included a diseased vertebra and an adjacent normal vertebra. Arterial plasma input functions were also measured. A three-compartment, four-parameter model was used with nonlinear regression analysis to estimate bone kinetic variables. Compared with normal bone, pagetic bone demonstrated higher values of plasma clearance to bone mineral (Ki; 1.03 x 10(-1) vs. 0.36 x 10(-1) ml/min per milliliter; p = 0.018) and clearance to total bone tissue (K1; 2.38 x 10(-1) vs. 1.25 x 10(-1) ml/min per milliliter; p = 0.018), reflecting increased mineralization and blood flow, respectively. Release of 18F-fluoride from bone mineral (k4) was lower in pagetic bone (p = 0.022), suggesting tighter binding of 18F-fluoride to bone mineral. The notional volume of the extravascular bone compartment (K1/k2) was greater in pagetic bone (p = 0.018). Although the unidirectional extraction efficiency from the extravascular space to bone mineral (Ki/K1) was greater in pagetic bone (p = 0.018), a lower pagetic value of k2 (p = 0.028), describing the rate of transfer from the bone extravascular compartment to plasma, suggests that the 18F-fluoride that enters the relatively fibrotic marrow space of pagetic bone may be less accessible for return to plasma. These findings confirm some of the known pathophysiology of Paget's disease, introduce some new observations, and show how dynamic 18F-fluoride PET may be of value in the measurement of regional metabolic parameters in focal bone disorders.

Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.

Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.

Speech-related visualization of laryngeal muscles with fluorine-18-FDG.

UNLABELLED: This study describes the physiological uptake of 18F-fluoro-2-deoxyglucose (FDG) by the laryngeal muscles secondary to activation of the patient's vocal folds and related laryngeal muscles during speech. METHODS: Twenty-four patients undergoing routine PET scans were randomized into two groups to ascertain the relationship between FDG uptake in the laryngeal region and speech. One group was assigned to talk and the other group remained silent during the injection and uptake period of FDG. RESULTS: FDG uptake in the laryngeal muscles in the scans was correlated with speech. Patients who spoke continually during the uptake period had high-grade FDG uptake, those who spoke intermittently had low-grade uptake and those who remained silent had no detectable increase in FDG uptake in the region of the larynx. CONCLUSION: The relationship between the degree of laryngeal muscle uptake and speech provides useful information to allow differentiation of physiological from pathological uptake in the neck.

The effects of single dose oral hydralazine on blood flow through human lung tumours.

Hydralazine has been shown to reduce tumour blood flow and to potentiate the cytotoxicity of melphalan and bioreductive agents in mice. In order to determine whether such a strategy might have clinical potential, a study was undertaken to investigate the effects of hydralazine on blood flow through human tumours. Twenty-two patients with carcinoma of the bronchus received a single oral dose of hydralazine in the range 25 to 150 mg (0.37-2.86 mg/kg) according to age and acetylator status. Tumour blood flow was assessed by single photon emission computed tomography (SPECT) performed 10 min following intravenous 99Tcm-HMPAO on two occasions 2-8 days apart, the second being performed 60 min after hydralazine administration. In 20 evaluable patients, hydralazine caused a 38% increase in blood flow through the whole tumour (p = 0.007) and a 28% increase in flow through the tumour centre (p = 0.03) with greater increases occurring in patients sustaining greater falls in peripheral resistance. Tumour vascular resistance fell indicating active vasodilation in arterioles supplying tumours. Side-effects due to hydralazine were reported by eight patients.

Evaluation of the cytotoxicity of the indoloquinone eo9 in a human colon adenocarcinoma model.

The development of anti-cancer drugs that are active in regions of low oxygen tension within solid tumours is an important goal for the chemotherapist. Equally as important is the utilization of appropriate model systems for their selection. This study describes morphological characteristics of multicellular spheroids derived from the human carcinoma cell line, DLD-1 and the evaluation of an investigational bioreductive alkylating agent (EO9) in monolayers, spheroids and xenografts. Histological examination of the cell line in vitro revealed typical features of glandular epithelium with microvilli on free surfaces and cell junction formation. Spheroids had acina formation, extensive necrosis and hypoxia at the time of treatment suggesting the spheroid model to be more representative of solid tumour geometry than more conventional in vitro test systems. EO9 is active against this cell line grown as a monolayer (IC50=0.76 mug ml-1) but is inactive against spheroids or established solid tumours in vivo. The suitability of this system for evaluating bioreductive drugs is discussed.

Optimization of noise-equivalent count rates in 3D PET.

We have used noise-equivalent count (NEC) rates to optimize count rate performance for 3D acquisition in PET in a wide range of situations, with particular reference to imaging of the torso. We have also compared NEC performance for 2D and 3D acquisition in order to establish the conditions under which 3D mode offers an improvement over 2D mode. Measurements were performed on four tissue-equivalent phantoms ranging in size from that of an infant's head (13 cm diameter) to that of an obese adult's chest (37 cm x 48 cm). Count rate data were acquired as a function of phantom size, activity in the field of view, lower energy discriminator level (LLD) and acquisition mode, and NEC rates were derived as a function of these variables. The LLD at which the highest NEC rate is obtained shows a dependence both on phantom size and on the activity in the field of view both for 2D and for 3D acquisition. The relative advantage of 3D mode over 2D mode, at the optimum LLD setting, is also strongly dependent both on activity in the field of view (FOV) and on the phantom size. The main limiting factors for 3D NEC rates are detector dead-time for small phantoms and random coincidences for large phantoms. The 3D NEC rate is more than twice as great as the 2D NEC rate when less than 60 MBq is present in the FOV for all phantoms except the largest, in which case a ratio of two is only achieved for activities less than 25 MBq. For the smallest phantom, 3D/2D NEC ratios of greater than 3.5 are obtained when the activity in the FOV falls below 10 MBq.

99Tcm-labelled meso-HMPAO and glutathione content of human lung tumours.

Levels of reduced glutathione (GSH) are increased in some types of malignant tumours and are known to influence the response to radio- and chemotherapy. In vitro studies suggest a correlation between cellular GSH concentration and retention of the meso form of hexamethyl propyleneamineoxime (HMPAO). This study investigates the relationship between in vivo tissue retention of 99Tcm-labelled HMPAO and GSH concentration in ten patients referred for thoracotomy for possible lung cancer. Retention of 99Tcm-HMPAO was measured using single photon emission computed tomography (SPECT). The tumour and normal lung concentration of reduced glutathione (GSH) was measured in tissue specimens collected peroperatively. Malignancy was confirmed in eight patients. Of seven patients undergoing curative resection for carcinoma, tumour GSH concentration was higher (mean 2.76 mM) than normal lung (mean 1.04 mM). In one neurofibroma, the GSH concentration was 1.80 mM. No correlation was found between 99Tcm meso-HMPAO retention and either the tumour GSH concentration or the tumour:lung GSH ratio. The results from this small series demonstrate that the intracellular GSH concentration of malignant lung tumours is generally higher than that in normal lung but that meso-HMPAO retention could not be used to predict these levels.

Ending neglect: providing effective childhood tuberculosis training for health care workers in Tanzania.

SETTING: Health care facilities in Dar es Salaam, Pwani, and Arusha, Tanzania. OBJECTIVE: To assess health care worker (HCW) knowledge and practices 1 year after specialized training in childhood tuberculosis (TB). DESIGN: Using a standardized survey, we interviewed a convenience sample of HCWs providing both general and specialized care to children. RESULTS: We interviewed 117 HCWs in TB clinics, maternal and child health clinics, human immunodeficiency virus (HIV) clinics, out-patient departments, and pediatric in-patient wards at 12 facilities. A total of 81 HCWs (62% of nurses, 74% of clinicians) reported having attended the national childhood TB training course. Most HCWs responded correctly to questions on childhood TB diagnosis, treatment, and TB-HIV co-management, regardless of training history. Most HCWs reported that they routinely obtain chest radiographs, HIV testing, and a TB contact history when evaluating children for TB. Less than half of HCWs reported routinely obtaining sputum for mycobacterial culture or performing a tuberculin skin test. Three times as many trained as untrained HCWs reported having ever prescribed isoniazid preventive therapy (IPT) to a child (P < 0.05). CONCLUSION: In general, levels of childhood TB knowledge were high and practices were in accordance with national guidance. Specific gaps in diagnosis, treatment and use of IPT were identified for future focused training.

Contexte : Structures de soins de santé à Dar es Salam, Pwani et Arusha, Tanzanie.Objectif : Evaluer les connaissances et pratiques du personnel de santé (HCW) un an après une formation spécifique à la tuberculose de l'enfant (TB).Schéma : Grâce à une enquête standardisée, nous avons interviewé un échantillon de complaisance de HCW offrant des soins à la fois généraux et spécialisés à des enfants.Résultats : Nous avons interviewé 117 HCW dans des dispensaires de TB, des centres de santé maternelle et infantile, des dispensaires pour le virus de l'immunodéficience humaine (VIH), des consultations externes et des services de pédiatrie dans 12 établissements. Un total de 81 HCW (62% d'infirmières, 74% de cliniciens) a affirmé avoir bénéficié de la formation nationale relative à la TB de l'enfant. La majorité a répondu correctement aux questions relatives au diagnostic de la TB de l'enfant, à son traitement et à la prise en charge conjointe de la TB et du VIH, quels que soient les antécédents de formation. La plupart ont dit demander en routine des radiographies pulmonaires, un test VIH et une recherche de contacts tuberculeux lors de l'évaluation des enfants. Moins de la moitié des HCW a affirmé recueillir des crachats en routine pour une culture mycobactérienne ou réaliser un test cutané à la tuberculine. La prescription de thérapie préventive par isoniazide (IPT) a été faite trois fois plus souvent par des HCW formés que par ceux qui ne l'avaient pas été (P < 0,05).Conclusion : En général, les connaissances en matière de TB de l'enfant étaient élevées et les pratiques conformes aux directives nationales. L'étude a identifié des lacunes spécifiques en matière de diagnostic, de traitement et d'utilisation de l'IPT afin de mieux cibler les futures formations.

Marco de referencia: Los establecimientos de atención de salud de Dar es-Salaam, Pwani y Arusha en Tanzania.Objetivo: Evaluar los conocimientos y las prácticas de los profesionales de salud (HCW) un año después de haber recibido una capacitación especializada sobre la tuberculosis (TB) de la infancia.Método: Se administró una encuesta normalizada a una muestra de conveniencia de los HCW que prestan atención general y especializada a los niños.Resultados: Se entrevistaron 117 HCW de los consultorios de TB, salud maternoinfantil, atención de la infección por el virus de la inmunodeficiencia humana (VIH) y de los servicios de atención ambulatoria y hospitalización pediátrica en 12 establecimientos. Ochenta y un HCW refirieron haber asistido al programa nacional de capacitación sobre la TB en la infancia (62% del personal de enfermería y 74% del personal médico). La mayoría de los HCW respondió de manera correcta a las preguntas sobre el diagnóstico y el tratamiento de la TB y la atención integrada de la TB-VIH, independientemente de las capacitaciones recibidas. La mayoría de los interrogados refirió la solicitud sistemática de radiografías de tórax, pruebas diagnósticas del VIH y el interrogatorio sobre los antecedentes de contacto con casos de TB cuando examinaba niños con presunción clínica de TB. Menos de la mitad de los HCW declaró la obtención corriente de muestras de esputo para cultivo de micobacterias o la práctica de la prueba cutánea de la tuberculina. Fue tres veces más frecuente que los HCW que habían recibido una capacitación, hubiesen recetado en alguna ocasión el tratamiento preventivo con isoniazida (IPT) a un niño en comparación con HCW sin antecedentes de capacitación (P < 0,05).Conclusión: En general, se observó un buen conocimiento de la TB de la infancia y las prácticas fueron conformes con las directrices nacionales. Se pusieron en evidencia algunas deficiencias en materia de diagnóstico, tratamiento y aplicación del IPT, sobre las cuales se centrará la atención en los futuros programas de capacitación.

A comparison of induced astigmatism in 20- vs 25-gauge vitrectomy procedures.

INTRODUCTION: Surgically induced astigmatism is an unwanted variable that can lead to poorer visual and refractive outcomes in patients undergoing vitrectomy even when a technically precise procedure has been performed. This study assesses the difference in surgically induced astigmatism (SIA) between the traditional 20-gauge vitrectomy and the newer 25-gauge sutureless technique by comparing pre- and post-procedure keratometry readings. METHOD: The study is a retrospective consecutive case series of vitrectomies performed by a single surgeon. There were a total of 47 patients, eight with bilateral procedures, 24 who underwent the 20 gauge, and 31 who had the 25-gauge procedure. Patients were excluded for corneal altering pathology or scleral buckling procedures. Vector analysis of pre- and post-vitrectomy readings was performed using Alpin's method, facilitated by the ASSORT program version 4.1. RESULTS: Mean time at which post-operative keratometry readings were taken was 3.9 months (1-36). Mean astigmatism at presentation was 0.63 D and 0.92 D and at post-surgically follow-up 1.14 D and 0.91 D (20 and 25 gauge, respectively). Mean SIA was 0.66 D (SD=0.8 D) for the 20-gauge group and 0.27 D (SD=0.23 D) for the 25 gauge (P=0.037). The calculated figure of SIA variability representing the 95% CI for the maximum amount of SIA for each procedure was 2.26 D and 0.73 D for the 20- and 25-gauge procedure, respectively. CONCLUSIONS: The study shows that the 25-gauge technique involves a statistically significant reduction in the amount of SIA. This can ultimately lead to a better visual and refractive outcome for the patient.

Photofragment slice imaging studies of pyrrole and the Xe...pyrrole cluster.

The photolysis of pyrrole has been studied in a molecular beam at wavelengths of 250, 240, and 193.3 nm, using two different carrier gases, He and Xe. A broad bimodal distribution of H-atom fragment velocities has been observed at all wavelengths. Near threshold at both 240 and 250 nm, sharp features have been observed in the fast part of the H-atom distribution. Under appropriate molecular beam conditions, the entire H-atom loss signal from the photolysis of pyrrole at both 240 and 250 nm (including the sharp features) disappear when using Xe as opposed to He as the carrier gas. We attribute this phenomenon to cluster formation between Xe and pyrrole, and this assumption is supported by the observation of resonance enhanced multiphoton ionization spectra for the (Xe...pyrrole) cluster followed by photofragmentation of the nascent cation cluster. Ab initio calculations are presented for the ground states of the neutral and cationic (Xe...pyrrole) clusters as a means of understanding their structural and energetic properties.