Varenicline Interactions at the 5-HT3 Receptor Ligand Binding Site are Revealed by 5-HTBP.
Cys-loop receptors are the site of action of many therapeutic drugs. One of these is the smoking cessation agent varenicline, which has its major therapeutic effects at nicotinic acetylcholine (nACh) receptors but also acts at 5-HT3 receptors. Here, we report the X-ray crystal structure of the 5-HT binding protein (5-HTBP) in complex with varenicline, and test the predicted interactions by probing the potency of varenicline in a range of mutant 5-HT3 receptors expressed in HEK293 cells and Xenopus oocytes. The structure reveals a range of interactions between varenicline and 5-HTBP. We identified residues within 5 Å of varenicline and substituted the equivalent residues in the 5-HT3 receptor with Ala or a residue with similar chemical properties. Functional characterization of these mutant 5-HT3 receptors, using a fluorescent membrane potential dye in HEK cells and voltage clamp in oocytes, supports interactions between varenicline and the receptor that are similar to those in 5-HTBP. The structure also revealed C-loop closure that was less than in the 5-HT-bound 5-HTBP, and hydrogen bonding between varenicline and the complementary face of the binding pocket via a water molecule, which are characteristics consistent with partial agonist behavior of varenicline in the 5-HT3 receptor. Together, these data reveal detailed insights into the molecular interaction of varenicline in the 5-HT3 receptor.


Playing the Clarinet: Influence of Body Posture on Muscle Activity and Sound Quality.
Musculoskeletal complaints are highly prevalent in clarinetists and are related to high arm load while playing. It is hypothesized that postural exercise therapy may be used to adapt muscle activity patterns while playing and thus contribute to better sound quality. The goal of the present study was to investigate the relationship between body posture, muscle activity, and sound quality in clarinetists while playing the instrument in two different postures, their habitual sitting posture (control, CO) vs an experimental sitting posture (EXP) based on Mensendieck postural exercise therapy, method Samama. Twenty healthy professional and student clarinet players, aged 18-60 years, were included in this cross-sectional study. Participants played a 60-second musical excerpt in CO, followed by instruction on the EXP body posture, and then played in the EXP condition. Two-dimensional goniometric analysis was used to calculate body posture; muscle activity was measured bilaterally using surface electromyography. In EXP, a significantly smaller low thoracic angle, smaller high thoracic angle, and larger pelvic tilt angle (all p<0.001) were found. EMG results indicated that the left and right erector spinae L3 and left and right lower trapezius were more active in EXP compared to CO, whereas left upper trapezius and right brachioradialis were less active in EXP than CO. Most participants experienced better sound quality in EXP, whereas blinded experts found no consistent pattern between body posture and sound quality. To conclude, it seems that postural exercise therapy may change muscle activity patterns. By increasing stability, a decrease in activity of the upper extremity muscles can be induced.


Multicolor dye-based flow structure visualization for seal-whisker geometry characterized by computer vision.
Pinniped vibrissae possess a unique and complex three-dimensional topography, which has beneficial fluid flow characteristics such as substantial reductions in drag, lift, and vortex induced vibration. To understand and leverage these effects, the downstream vortex dynamics must be studied. Dye visualization is a traditional qualitative method of capturing these downstream effects, specifically in comparative biological investigations where complex equipment can be prohibitive. High-fidelity numerical simulations or experimental particle image velocimetry are commonplace for quantitative high-resolution flow measurements, but are computationally expensive, require costly equipment, and can have limited measurement windows. This study establishes a method for extracting quantitative data from standard dye visualization experiments on seal whisker geometries by leveraging novel but intuitive computer vision techniques, which maintain simplicity and an advantageous large experimental viewing window while automating the extraction of vortex frequency, position, and advection. Results are compared to direct numerical simulation (DNS) data for comparable geometries. Power spectra and Strouhal numbers show consistent behavior between methods for a Reynolds number of 500, with minima at the canonical geometry wavelength of 3.43 and a peak frequency of 0.2 for a Reynolds number of 250. The vortex tracking reveals a clear increase in velocity from roll-up to 3.5 whisker diameters downstream, with a strong overlap with the DNS data but shows steady results beyond the limited DNS window. This investigation provides insight into a valuable bio-inspired engineering model while advancing an analytical methodology that can readily be applied to a broad range of comparative biological studies.


The middle temporal visual area in the macaque: myeloarchitecture, connections, functional properties and topographic organization.
The location, topographic organization, and function of the middle temporal visual area (MT) in the macaque monkey was studied using anatomical and physiological techniques. MT is a small, elliptically shaped area on the posterior bank of the superior temporal sulcus which can be identified by its direct inputs from striate cortex and by its distinctive pattern of heavy myelination. Its average surface area is 33 mm2, which is less than 3% of the size of striate cortex. It contains a complete, topographically organized representation of the contralateral visual hemifield. There are substantial irregularities in the detailed pattern of topographic organization, however, and the representation is significantly more complex than that found for MT in other primates. Much of MT is devoted to the representation of central visual fields, with the emphasis on central vision being similar to that found in striate cortex. Electrophysiological recordings have confirmed previous reports of a high incidence of direction selective cells in MT. The transition in functional properties, from cells lacking direction selectivity outside MT to direction selective cells within, occurs over a distance of 0.1-0.2 mm or less along the lateral border of MT. Such a transition does not occur along the medial border, however, as the cortex medial to MT contains many cells with strong direction selectivity. Nevertheless, this region differs from MT in its myeloarchitecture, its lack of inputs from striate cortex, and the large size of its receptive fields. These results demonstrate the existence of three distinct visual areas on the posterior bank of the superior temporal sulcus which can be distinguished on the basis of both physiological and anatomical criteria.


IQRray, a new method for Affymetrix microarray quality control, and the homologous organ conservation score, a new benchmark method for quality control metrics.
Microarray results accumulated in public repositories are widely reused in meta-analytical studies and secondary databases. The quality of the data obtained with this technology varies from experiment to experiment, and an efficient method for quality assessment is necessary to ensure their reliability. The lack of a good benchmark has hampered evaluation of existing methods for quality control. In this study, we propose a new independent quality metric that is based on evolutionary conservation of expression profiles. We show, using 11 large organ-specific datasets, that IQRray, a new quality metrics developed by us, exhibits the highest correlation with this reference metric, among 14 metrics tested. IQRray outperforms other methods in identification of poor quality arrays in datasets composed of arrays from many independent experiments. In contrast, the performance of methods designed for detecting outliers in a single experiment like Normalized Unscaled Standard Error and Relative Log Expression was low because of the inability of these methods to detect datasets containing only low-quality arrays and because the scores cannot be directly compared between experiments. The R implementation of IQRray is available at: ftp://lausanne.isb-sib.ch/pub/databases/Bgee/general/IQRray.R. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Farmers' contribution to landscape services in the Netherlands under different rural development scenarios.
Landscape services represent the benefits human populations derive, directly or indirectly, from (agro-)ecosystem functions at the landscape scale. Many of these services are the result of farmers' decision making to allocate resources to other activities than food production and therefore are the result of farm the adoption of on-farm rural activities. With changing agricultural and rural policies, the future provision of landscape services to fulfill societal demands is not guaranteed. This study aims at mapping the spatial distribution of the adoption of on-farm rural activities under different explorative scenarios. For a Dutch landscape, storylines at the landscape scale were developed by combining global storylines, resulting from the Global Environmental Outlook, with local storylines resulting from key informant interviews. Subsequently these storylines were translated into quantitative scenarios that were implemented into a simulation procedure based on spatially explicit econometric models of farmer's decision making. Results show that further market liberalization leads to a decrease of landscape services in the study area. In our study, only increased cooperation between government, farmers and citizens appears to result in a general increase of all landscape services across the entire landscape.


Sex Differences of Human Cardiac Progenitor Cells in the Biological Response to TNF-α Treatment.
Adult cardiac progenitor cells (CPCs), isolated as cardiosphere-derived cells (CDCs), represent promising candidates for cardiac regenerative therapy. CDCs can be expanded in vitro manyfolds without losing their differentiation potential, reaching numbers that are appropriate for clinical applications. Since mechanisms of successful CDC survival and engraftment in the damaged myocardium are still critical and unresolved issues, we aimed at deciphering possible key factors capable of bolstering CDC function. In particular, the response and the phenotype of CDCs exposed to low concentrations of the multifunctional cytokine tumor necrosis factor α (TNF-α), known to be capable of activating cell survival pathways, have been investigated. Furthermore, differential biological responses of CDCs from male and female donors, in terms of cell cycle progression and cell spreading, have also been assessed. The results obtained indicate that (i) the intracellular signaling activated in our experimental conditions is most likely due to the prosurvival and proliferative signaling of TNF-α receptor 2 and that (ii) cells from female patients appear more responsive to TNF-α treatment in terms of cell cycle progression and migration ability. In conclusion, the present report highlights the hypothesis that TNF-stimulated CDCs isolated from females may represent a promising candidate for cardiac regenerative therapy applications.


[Tissue microarrays, or the advent of chips in pathology].
Tissue microarray technology is a new method used to analyze several hundred tumor samples on a single slide allowing high throughput analysis of genes and proteins on a large cohort. The method consists to core tissues from paraffin-embedded tissue donor blocks and placing them into a single paraffin block. Despite the low amount of tissue analyzed by tissue microarray, different studies have demonstrated a high concordance of protein expression between this technique and the conventional tissue sections.


Citrate anticoagulation for CRRT in children: comparison with heparin.
Regional anticoagulation with citrate is an alternative to heparin in continuous renal replacement therapies, which may prolong circuit lifetime and decrease hemorrhagic complications. A retrospective comparative cohort study based on a prospective observational registry was conducted including critically ill children undergoing CRRT. Efficacy, measured as circuit survival, and secondary effects of heparin and citrate were compared. 12 patients on CRRT with citrate anticoagulation and 24 patients with heparin anticoagulation were analyzed. Median citrate dose was 2.6 mmol/L. Median calcium dose was 0.16 mEq/kg/h. Median heparin dose was 15 UI/kg/h. Median circuit survival was 48 hours with citrate and 31 hours with heparin (P = 0.028). 66.6% of patients treated with citrate developed mild metabolic alkalosis, which was directly related to citrate dose. There were no cases of citrate intoxication: median total calcium/ionic calcium index (CaT/I) of 2.16 and a maximum CaT/I of 2.33, without metabolic acidosis. In the citrate group, 45.5% of patients developed hypochloremia and 27.3% hypomagnesemia. In the heparin group, 27.8% developed hypophosphatemia. Three patients were moved from heparin to citrate to control postoperatory bleeding. In conclusion citrate is a safe and effective anticoagulation method for CRRT in children and it achieves longer circuit survival than heparin.


Extended transoral approaches: surgical technique and analysis.
The transoral approach provides the most direct exposure to extradural lesions of the ventral craniovertebral junction. Lesions that extend beyond the exposure provided by the standard transoral approach require an extended transoral modification. The exposure can be expanded in the sagittal and axial planes by adding mandibulotomy, mandibuloglossotomy, palatotomy, and transmaxillary approaches to the standard transoral approach. Extended transoral approaches increase the surgical complexity and the risk of cosmetic and functional complications. Until recently, selection of an extended approach has been arbitrary and dependent on the surgeon's familiarity with the surgical approach. We review the literature of extended transoral approaches and analyze the different modifications in terms of the technical aspects, added exposure, and complications. Classic approaches and recently published morphometric studies that objectively document the gain in exposure provided by several modifications were analyzed and tabulated to outline the limits of exposure and risk of complications associated with the various modifications. Transmaxillary approaches expand the exposure to include the sphenoid sinus and upper lateral clivus. To expand the exposure more inferiorly to C4-C5, mandibulotomy or mandibuloglossotomy can be applied. Mandibuloglossotomy increases the rostral exposure as well to the upper third of the clivus. Palatotomy increases rostral exposure without requiring a facial incision or perioperative tracheostomy, but is associated with a significant risk of velopharyngeal insufficiency. Surgical decisions can be based on comprehensive preoperative evaluation of anatomy, pathology, and radiographic studies to maximize exposure while minimizing complications.


Nutrient profile and energy cost of food sold by informal food vendors to learners in primary and secondary schools in the Eastern Cape, South Africa.
To assess type, nutrient profile and cost of food items sold by informal vendors to learners; and to determine nutrient content of corn-based processed snacks frequently sold. Cross-sectional survey. Quintile 1 to 3 schools (n 36) randomly selected from six education districts; Eastern Cape, South Africa. Informal food vendors (n 92) selling inside or immediately outside the school premises. Food items sold at most schools were corn-based processed snacks (94 % of schools), sweets (89 %), lollipops (72 %) and biscuits (62 %). Based on the South African Nutrient Profiling model, none of these foods were profiled as healthy. Foods less commonly sold were fruits (28 % of schools) and animal-source foods; these foods were profiled as healthy. Mean (sd) energy cost (per 418 kJ (100 kcal)) was highest for animal-source foods (R2·95 (1·16)) and lowest for bread and vetkoek (R0·76 (0·21)), snacks (R0·76 (0·30)) and confectionery products (R0·70 (0·28)). The nutrient profiling score was inversely related to the energy cost of the food item (r = -0·562, P = 0·010). Compared with brand-name corn-based processed snacks, non-branded snacks had lower energy (2177 v. 2061 kJ; P = 0·031) content per 100 g. None of the brand-name samples contained sucrose; six of the nine non-branded samples contained sucrose, ranging from 4·4 to 6·2 g/100 g. Foods mostly sold were unhealthy options, with the healthier food items being more expensive sources of energy.


Magnetic resonance imaging of the liver: New imaging strategies for evaluating focal liver lesions.
The early detection of focal liver lesions, particularly those which are malignant, is of utmost importance. The resection of liver metastases of some malignancies (including colorectal cancer) has been shown to improve the survival of patients. Exact knowledge of the number, size, and regional distribution of liver metastases is essential to determine their resectability. Almost all focal liver lesions larger than 10 mm are demonstrated with current imaging techniques but the detection of smaller focal liver lesions is still relatively poor. One of the advantages of magnetic resonance imaging (MRI) of the liver is better soft tissue contrast (compared to other radiologic modalities), which allows better detection and characterization of the focal liver lesions in question. Developments in MRI hardware and software and the availability of novel MRI contrast agents have further improved the diagnostic yield of MRI in lesion detection and characterization. Although the primary modalities for liver imaging are ultrasound and computed tomography, recent studies have suggested that MRI is the most sensitive method for detecting small liver metastatic lesions, and MRI is now considered the pre-operative standard method for diagnosis. Two recent developments in MRI sequences for the upper abdomen comprise unenhanced diffusion-weighted imaging (DWI), and keyhole-based dynamic contrast-enhanced (DCE) MRI (4D THRIVE). DWI allows improved detection (b = 10 s/mm(2)) of small (< 10 mm) focal liver lesions in particular, and is useful as a road map sequence. Also, using higher b-values, the calculation of the apparent diffusion coefficient value, true diffusion coefficient, D, and the perfusion fraction, f, has been used for the characterization of focal liver lesions. DCE 4D THRIVE enables MRI of the liver with high temporal and spatial resolution and full liver coverage. 4D THRIVE improves evaluation of focal liver lesions, providing multiple arterial and venous phases, and allows the calculation of perfusion parameters using pharmacokinetic models. 4D THRIVE has potential benefits in terms of detection, characterization and staging of focal liver lesions and in monitoring therapy.


Histopathological features of canine spontaneous non-neoplastic gastric polyps - a retrospective study of 15 cases.
Fifteen cases of canine gastric polyps, collected over a 4-year period, were investigated using gross inspection, histological procedures and immunohistochemical techniques for Helicobacter infection. No breed or sex predisposition was found for gastric polyps, although they occurred mainly in elderly animals. There were 9 pedunculated and 6 sessile polypoid growths, between 5 to 30 mm in diameter developed mainly in the pyloric region of the stomach. The most common type of gastric polyps was the hyperplastic one. The inflammatory type was identified in three cases. Foci of AB/PAS Goblet positive cells resembling intestinal metaplasia, mild dysplasia of gastric epithelium, well delimited calcified areas, islands of osteoid matrix and nematodes were present in some of these lesions. Histological examination of the adjacent gastric polyp (surrounding gastric mucosa) revealed a severe chronic inflammation in 13 cases and a high grade of Helicobacter species colonization in all cases, but Kendall test analysis showed no correlation between Helicobacter spp. colonization degree and gastritis scores (τ = 0289; p = 0.204). A significant correlation was found between Helicobacter spp. location and gastritis scores (τ = 0.497; p = 0.035). Immunohistochemistry performed with a polyclonal antibody confirmed Helicobacter spp. infection in all cases. Based on their morphology, Helicobacter pylori - like organisms were described in 3 of 15 cases. No high degree of dysplasia nor neoplasia were identified in these lesions. The etiology and pathogenesis of gastric polyps in dogs are still unknown, although a severe chronic antral gastritis may be a predisposing condition for development of gastric polyps in dogs.


Assessing the impact of obesity on full endoscopic spine surgery: surgical site infections, surgery durations, early complications, and short-term functional outcomes.
An increasing number of obese patients undergoing elective spine surgery has been reported. Obesity has been associated with a substantially higher number of surgical site infections and a longer surgery duration. However, there is a lack of research investigating the intersection of obesity and full endoscopic spine surgery (FESS) in terms of functional outcomes and complications. The aim of this study was to evaluate wound site infections and functional outcomes following FESS in obese patients. Patients undergoing lumbar FESS at the participating institutions from March 2020 to March 2023 for degenerative pathologies were included in the analysis. Patients were divided into obese (BMI > 30 kg/m2) and nonobese (BMI 18-30 kg/m2) groups. Data were collected prospectively using an approved smartphone application for 3 months postsurgery. Parameters included demographics, surgical details, a virtual wound checkup, the visual analog scale for back and leg pain, and the Oswestry Disability Index (ODI) as a functional outcome measure. A total of 118 patients were included in the analysis, with 53 patients in the obese group and 65 in the nonobese group. Group homogeneity was satisfactory regarding patient age (obese vs nonobese: 55.5 ± 14.7 years vs 59.1 ± 17.1 years, p = 0.25) and sex (p = 0.85). No surgical site infection requiring operative revision was reported for either group. No significant differences for blood loss per level (obese vs nonobese: 9.7 ± 16.8 ml vs 8.0 ± 13.3 ml, p = 0.49) or duration of surgery per level (obese vs nonobese: 91.2 ± 57.7 minutes vs 76.8 ± 39.2 minutes, p = 0.44) were reported between groups. Obese patients showed significantly faster improvement regarding ODI (-3.0 ± 9.8 vs 0.7 ± 11.3, p = 0.01) and leg pain (-4.4 ± 3.2 vs -2.9 ± 3.7, p = 0.03) 7 days postsurgery. This effect was no longer significant 90 days postsurgery for either ODI (obese vs nonobese: -11.4 ± 11.4 vs -9.1 ± 9.6, p = 0.24) or leg pain (obese vs nonobese: -4.3 ± 3.9 vs -3.5 ± 3.8, p = 0.28). The results highlight the effectiveness and safety of lumbar FESS in obese patients. Unlike with open spine surgery, obese patients did not experience significant increases in surgery time or postoperative complications. Interestingly, obese patients demonstrated faster early recovery, as indicated by significantly greater improvements in ODI and leg pain at 7 days after surgery. However, there was no difference in improvement between the groups at 90 days after surgery.


Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress.
Amyloid beta-peptide (Abeta), the central constituent of senile plaques in Alzheimer's disease (AD) brain, has been shown to be a source of free radical oxidative stress that may lead to neurodegeneration. In the current study Abeta(1-40), found in AD brain, and the amyloid fragment Abeta(25-35) were used in conjunction with electron paramagnetic resonance spin trapping techniques to demonstrate that these peptides mediate free radical production. The methionine residue in these peptides is believed to play an important role in their neurotoxicity. Substitution of methionine by structurally similar norleucine in both Abeta(1-40) and Abeta(25-35), and the substitution of methionine by valine, or the removal of the methionine in Abeta(25-35), abrogates free radical production and protein oxidation of and toxicity to hippocampal neurons. These results are discussed with relevance to the hypothesis that neurodegeneration in Alzheimer's disease may be due in part to Abeta-associated free radical oxidative stress that involves methionine, and to the use of spin trapping methods to infer mechanistic information about Abeta.


Multicolor protein FRET with tryptophan, selective coumarin-cysteine labeling, and genetic acridonylalanine encoding.
Site-specific fluorescence probes can be used to measure distances within proteins when used as part of a Förster resonance energy transfer (FRET) pair. Here we report the synthesis of a coumarin maleimide (Mcm-Mal) that is fluorogenic upon reaction with cysteine. We demonstrate that cysteine, acridonylalanine (Acd) double mutant proteins can be produced by unnatural amino acid mutagenesis and reacted with Mcm-Mal to generate Mcm/Acd labeled proteins for FRET studies. The Mcm/Acd FRET pair is minimally-perturbing, easy to install, and well-suited to studying protein distances in the 15-40 Å range. Furthermore, Mcm/Acd labeling can be combined with tryptophan fluorescence in three color FRET to monitor multiple interactions in one experiment.


Ethnobotanical Documentation of Medicinal Plants Used by the Indigenous Panay Bukidnon in Lambunao, Iloilo, Philippines.
The Panay Bukidnon is a group of indigenous peoples living in the interior highlands of Panay Island in Western Visayas, Philippines. Little is known about their ethnobotanical knowledge due to limited written records, and no recent research has been conducted on the medicinal plants they used in ethnomedicine. This study aims to document the medicinal plants used by the indigenous Panay Bukidnon in Lambunao, Iloilo, Panay Island. Semi-structured interviews were conducted with 75 key informants from June 2020 to September 2021 to determine the therapeutic use of medicinal plants in traditional medicine. A total of 131 medicinal plant species distributed in 121 genera and 57 families were used to address 91 diseases in 16 different uses or disease categories. The family Fabaceae was best represented with 13 species, followed by Lamiaceae with nine species and Poaceae with eight species. The leaf was the most frequently used plant part and decoction was the most preferred form of preparation. To evaluate the plant importance, use value (UV), relative frequency citation (RFC), relative important index (RI), informant consensus factor (ICF), and fidelity level (FL) were used. Curcuma longa L. had the highest UV (0.79), Artemisia vulgaris L. had the highest RFC value (0.57), and Annona muricata L. had the highest RI value (0.88). Diseases and symptoms or signs involving the respiratory system and injury, poisoning, and certain other consequences of external causes recorded the highest ICF value (0.80). Blumea balsamifera (L.) DC. and Chromolaena odorata (L.) R.M. King & H. Rob were the most relevant and agreed species for the former and latter disease categories, respectively. C. odorata had the highest FL value (100%) and was the most preferred medicinal plant used for cuts and wounds. The results of this study serve as a medium for preserving cultural heritage, ethnopharmacological bases for further drug research and discovery, and preserving biological diversity.


Cellular interactions in the rat somatosensory thalamocortical system during normal and epileptic 5-9 Hz oscillations.
In Genetic Absence Epilepsy Rats from Strasbourg (GAERS), generalized spike-and-wave (SW) discharges (5-9 SW s(-1)) develop during quiet immobile wakefulness from a natural, medium-voltage, 5-9 Hz rhythm. This study examines the spatio-temporal dynamics of cellular interactions in the somatosensory thalamocortical system underlying the generation of normal and epileptic 5-9 Hz oscillations. Paired single-unit and multi-unit recordings between the principal elements of this circuit and intracellular recordings of thalamic, relay and reticular, neurones were conducted in neuroleptanalgesied GAERS and control, non-epileptic, rats. The identity of the recorded neurones was established following juxtacellular or intracellular marking. At least six major findings have emerged from this study. (1) In GAERS, generalized spike-and-wave discharges were correlated with synchronous rhythmic firings in related thalamic relay and reticular neurones. (2) Usually, corticothalamic discharges phase-led related relay and reticular firings. (3) A depolarizing wave emerging from a barrage of EPSPs was the cause of both relay and reticular discharges. (4) In some relay cells, which had a relatively high membrane input resistance, the depolarizing wave had the shape of a ramp, which could trigger a low-threshold Ca2+ spike. (5) In reticular cells, the EPSP barrage could further trigger voltage-dependent depolarizations. (6) The epilepsy-related thalamic, relay and reticular, intracellular activities were similar to the normal-related thalamic activities. Overall, these findings strongly suggest that, during absence seizures, corticothalamic neurones play a primary role in the synchronized excitation of thalamic relay and reticular neurones. The present study further suggests that absence-related spike-and-wave discharges correspond to hypersynchronous wake-related physiological oscillations.


Tyler asbestos workers: mortality experience in a cohort exposed to amosite.
To examine the causes of death among 1130 former workers of a plant in Tyler, Texas dedicated to the manufacture of asbestos pipe insulation materials. This cohort is important and unusual because it used amosite as the only asbestiform mineral in the production process. High level exposure of such a specific type was documented through industrial hygiene surveys in the plant. Deaths were ascertained through various sources including data tapes from the Texas Department of Health and the national death index files. As many death certificates as possible were secured (304/315) and cause of death assigned. After select exclusions, 222 death certificates were used in the analysis. Causes of death were compared with age, race, and sex specific mortalities for the United States population with a commercial software package (OCMAP Version 2.0). There was an excess of deaths from respiratory cancer including the bronchus, trachea, and lung (standardised mortality ratio (SMR) 277 with 95% confidence interval (95% CI) 193 to 385). Four pleural mesotheliomas and two peritoneal mesotheliomas were identified. The analysis also showed an increasing risk of respiratory malignancy with increased duration of exposure including a significant excess of total deaths from respiratory cancer with less than six months of work at the plant (SMR 268 with 95% CI 172 to 399). The importance of the cohort lies with the pure amosite exposure which took place in the plant and the extended period of latency which has followed. The death certificate analysis indicates the pathogenicity of amosite, the predominant commercial amphibole used in the United States. These data confirm a link between amosite asbestos and respiratory malignancy as well as mesothelioma.


Thyrotropin secretion in mild and severe primary hypothyroidism is distinguished by amplified burst mass and Basal secretion with increased spikiness and approximate entropy.
Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods no longer in use. The insights afforded by earlier methods are limited. We studied TSH secretion in patients with primary hypothyroidism (eight patients with severe and eight patients with mild hypothyroidism) with up-to-date analytical tools and compared the results with outcomes in 38 healthy controls. Patients and controls underwent a 24-h study with 10-min blood sampling. TSH data were analyzed with a newly developed automated deconvolution program, approximate entropy, spikiness assessment, and cosinor regression. Both basal and pulsatile TSH secretion rates were increased in hypothyroid patients, the latter by increased burst mass with unchanged frequency. Secretory regularity (approximate entropy) was diminished, and spikiness was increased only in patients with severe hypothyroidism. A diurnal TSH rhythm was present in all but two patients, although with an earlier acrophase in severe hypothyroidism. The estimated slow component of the TSH half-life was shortened in all patients. Increased TSH concentrations in hypothyroidism are mediated by amplification of basal secretion and burst size. Secretory abnormalities quantitated by approximate entropy and spikiness were only present in patients with severe disease and thus are possibly related to the increased thyrotrope cell mass.


[Pneumatosis cystoides intestinalis].
AIR-FILLED CYSTS: Pneumatosis cystoides intestinalis (PCI) is a benign air-filled cystic formation lying in submucosal or subserous digestive tissue. PCI has been reported all along the digestive tract. Manifestations of PCI vary greatly. Some cases are asymptomatic, while others are revealed by abdominal pain or pneumoperitoneum. Outcome is usually favorable. The plain radiogram of the abdomen shows gaseous cysts of various forms lying between the liver and the diaphragm. Pneumoperitoneum may be present. Computed tomography is the ideal diagnostic test. Endoscopy may be useful for colonic localizations. Many causes have been suggested and debated. Fifteen percent of all cases of PCI are idiopathic. In the other cases, digestive tract or respiratory tract diseases, are usually the underlying cause. Exceptionally systemic disease may be associated with PCI, particularly systemic sclerosis. Surgery should be reserved for particularly severe cases.


Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex.
Ethanol administration to rats by ethanol vapor inhalation (14 days) results in a 40-50% reduction in the level of gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit mRNAs [4.4 and 4.8 kilobases (kb)] in the cerebral cortex. The level of alpha 2 subunit mRNA (8.0 kb) was also reduced by 29%, whereas there was no effect of prolonged ethanol exposure on the level of alpha 3 subunit mRNA (3.1 kb). Ethanol exposure did not alter the steady state levels of cerebral cortical glutamic acid decarboxylase or beta-actin mRNAs. Moreover, no alterations in the levels of total RNA, poly(A)+ RNA, or rRNA were observed, suggesting that the ethanol-induced reductions in GABAA receptor alpha 1 and alpha 2 subunit mRNAs were not the result of a generalized effect of ethanol administration on transcription or mRNA turnover. These ethanol-induced reductions in GABAA receptor alpha subunit mRNAs may underlie alterations in GABAA receptor function or number observed following prolonged ethanol exposure in rats.


Ultrasound-Assisted Technology Versus the Conventional Landmark Location Method in Spinal Anesthesia for Cesarean Delivery in Obese Parturients: A Randomized Controlled Trial.
Spinal anesthesia, which is commonly used in cesarean deliveries, is often difficult to perform in obese parturients because of poorly palpable surface landmarks and positioning challenges. This study aimed to evaluate the benefits of ultrasound-assisted technology for performing spinal anesthesia in obese parturients. Parturients with a body mass index (BMI) ≥30 kg/m scheduled for elective cesarean delivery were randomized to undergo spinal anesthesia using the conventional landmark location technique (landmark group, n = 40) or prepuncture ultrasound examination (ultrasound group, n = 40). All participants underwent spinal anesthesia in the lateral position. The primary outcome was the first-attempt success rate. Secondary outcomes were the number of skin punctures and needle passes, procedure times, patient satisfaction, changes in the intended interspace, and incidence of complications. The ultrasound group had a significantly higher first-attempt success rate (87.5% vs 52.5%; P = .001), fewer cases requiring >10 needle passes (1 vs 17; P < .001), and fewer skin punctures and needle passes (P < .001 for both). There was no statistically significant difference in the time taken to identify the needle insertion site between the 2 groups (202.5 vs 272.0 seconds; P = .580). Both the spinal injection time and total procedure time were significantly longer in the landmark group (P < .001). Patient satisfaction scores were significantly higher in the ultrasound group (P = .001). Among patients with BMI between 30 and 34.9 kg/m, there was no statistically significant difference in the first-attempt success rate (P = .407), number of cases with >10 needle passes (P = .231), spinal injection time (P = .081), or total procedure time (P = .729); however, more time was required to identify the needle insertion site in the ultrasound group (P < .001). For patients with BMI between 35 and 43 kg/m, the ultrasound group had a significantly higher first-attempt success rate (P ≤ .041), fewer cases with >10 needle passes (P ≤ .01), and shorter procedure times, including the time required to identify the needle insertion site (P < .001). Prepuncture ultrasound examination can facilitate spinal anesthesia in the lateral position in obese parturients (35 kg/m ≤ BMI ≤ 43 kg/m) by improving the first-attempt success rate, reducing the number of needle passes and puncture attempts, shortening the total procedure time, and improving patient satisfaction.


The shell matters: one step synthesis of core-shell silicon nanoparticles with room temperature ultranarrow emission linewidth.
Here we present a one-step synthesis that provides silicon nanocrystals with a thin shell composed of a ceramic-like carbonyl based compound, embedded in a porous organosilicon film. The silicon nanocrystals were synthesised from hydrogen silsesquioxane molecules, modified with organic molecules containing carbonyl groups, which were annealed at 1000 °C in a slightly reducing 5% H2 : 95% Ar atmosphere. The organic character of the shell was preserved after annealing due to trapping of organic molecules inside the HSQ-derived oxide matrix that forms during the annealing. The individual silicon nanocrystals, studied by single dot spectroscopy, exhibited a significantly narrower emission peak at room temperature (lowest linewidth ∼ 17 meV) compared to silicon nanocrystals embedded in a silicon oxide shell (150 meV). Their emission linewidths are even significantly narrower than those of single CdSe quantum dots (>50 meV). It is hypothesized that the Si-core-thin shell structure of the nanoparticle is responsible for the unique optical properties. Its formation within one synthesis step opens new opportunities for silicon-based quantum dots. The luminescence from the produced nanocrystals covers a broad spectral range from 530-720 nm (1.7-2.3 eV) suggesting strong application potential for solar cells and LEDs, following the development of a suitable mass-fabrication protocol.


Bacterial biofilms predominate in both acute and chronic human lung infections.
A basic paradigm of human infection is that acute bacterial disease is caused by fast growing planktonic bacteria while chronic infections are caused by slow-growing, aggregated bacteria, a phenomenon known as a biofilm. For lung infections, this paradigm has been thought to be supported by observations of how bacteria proliferate in well-established growth media in the laboratory-the gold standard of microbiology. To investigate the bacterial architecture in sputum from patients with acute and chronic lung infections. Advanced imaging technology was used for quantification and direct comparison of infection types on fresh sputum samples, thereby directly testing the acute versus chronic paradigm. In this study, we compared the bacterial lifestyle (planktonic or biofilm), growth rate and inflammatory response of bacteria in freshly collected sputum (n=43) from patient groups presenting with acute or chronic lung infections. We found that both acute and chronic lung infections are dominated by biofilms (aggregates of bacteria within an extracellular matrix), although planktonic cells were observed in both sample types. Bacteria grew faster in sputum from acute infections, but these fast-growing bacteria were enriched in biofilms similar to the architecture thought to be reserved for chronic infections. Cellular inflammation in the lungs was also similar across patient groups, but systemic inflammatory markers were only elevated in acute infections. Our findings indicate that the current paradigm of equating planktonic with acute and biofilm with chronic infection needs to be revisited as the difference lies primarily in metabolic rates, not bacterial architecture.


Acute viral hepatitis (C - genotype 6a and B) acquired during kidney transplantation by two patients and review of the literature.
Two patients were contaminated by hepatitis during kidney transplantation from unrelated living donors, performed abroad in 2006. One patient died from fulminant hepatitis C (the first case of virus genotype 6a diagnosed in Israel) 2 months after transplantation and the other developed acute hepatitis B with YMDD to YVDD mutation necessitating life-long antiviral therapy. The dilemma of antiviral therapy in transplant recipients is discussed in this paper. Patients awaiting kidney transplantation by far outnumber the kidneys available for cadaver transplantation. International trade with living non-related kidneys has therefore become common. Comorbid conditions, although significant, are often ignored. After transplantation, the first patient presented with a picture of fulminant hepatitis C; immunosuppressive medication was tapered rapidly. This patient subsequently died from hepatic failure. The patient with active hepatitis B with YVDD mutation is receiving ongoing treatment by lamivudine and adefovir.


Differential proteomic analysis of cancer stem cell properties in hepatocellular carcinomas by isobaric tag labeling and mass spectrometry.
Malignant tumors are relatively resistant to treatment due to their heterogeneous nature, drug resistance, and tendency for metastasis. Recent studies suggest that a subpopulation of cancer cells is responsible for the malignant outcomes. These cells are considered as cancer stem cells (CSC). Although a number of molecules have been identified in different cancer cells as markers for cancer stem cells, no promising markers are currently available for hepatocellular carcinoma cells. In this study, two clones of Hep3B cell lines were functionally characterized as control or CSC-like cells, based on properties including spheroid formation, drug resistance, and tumor initiation. Furthermore, their protein expression profiles were investigated by isobaric tags for relative and absolute quantitation (iTRAQ), and a total of 1,127 proteins were identified and quantified from the combined fractions; 50 proteins exhibited at least 2-fold differences between these two clones. These 50 proteins were analyzed by GeneGo and were found to be associated with liver neoplasms, hepatocellular carcinoma (HCC), and liver diseases. They were also components of metabolic pathways, immune responses, and cytoskeleton remodeling. Among these proteins, the expressions of S100P, S100A14, and vimentin were verified in several HCC cell lines, and their expressions were correlated with tumorigenicity in HCC cell lines. The functional significance of vimentin and S100A14 were also investigated and verified.


Efficacy of Dipeptide-Coated Magnetic Nanoparticles in Lung Cancer Models Under Pulsed Electromagnetic Field.
Lung cancer is the leading cause of cancer deaths and the overall 5-year survival rate is less than 17%. Hyperthermia is an alternative approach for the treatment of lung cancer and is associated with fewer side effects. We employed ironoxide nanoparticles in inducing localized hyperthermia in lung cancer cells using a pulsed electromagnetic field (PEMF). We synthesized, characterized and determined the uptake of dipeptide-coated iron oxide nanoparticles. Further, their ability in inducing localized hyperthermia in PEMF on lung cancer cells was assessed. Results showed nanoparticles are non-cytotoxic and showed enhanced cellular uptake in lung cancer cells. In vivo studies in nude mice lung tumor xenografts confirmed the presence in the tumors. Lung cancer cells pretreated with dipeptide-coated magnetic nanoparticles upon PEMF exposure induced cell death.


Depression and glycemic control in elderly ethnically diverse patients with diabetes: the IDEATel project.
The purpose of the study was to investigate the effect of comorbid depression on glycemic control and on response to a telemedicine case management intervention for elderly, ethnically diverse diabetic patients. Medicare beneficiaries in underserved areas were participants (n = 1,665) in the Informatics for Diabetes Education and Telemedicine (IDEATel) project and randomized to a telemedicine case management intervention or usual care. The data analyzed include baseline demographics (age, sex, race/ethnicity, marital status, insulin use, years of education, years of diabetes, and pack-years smoked) and measures of glycemic control (HbA(1c) [A1C]), comorbidity, diabetes symptom severity, functional disability and depression, and 1-year (n = 1,578) A1C. The association between depression and glycemic control was analyzed cross-sectionally and prospectively. At baseline, there was a significant correlation between depression and A1C and a trend for depression to predict A1C when other factors were controlled. However, in prospective analyses, depression did not predict change in A1C, either in the control or intervention group. In this large sample of elderly diabetic patients, a weak relationship between depression and A1C was found, but depression did not prospectively predict change in glycemic control. Thus, there is no evidence that depression should be used to exclude patients from interventions. Also, we should evaluate the impact of depression on outcomes other than glycemic control.


Plant drought tolerance provided through genome editing of the trehalase gene.
Drought is one of the main abiotic factors that affect agricultural productivity, jeopardizing food security. Modern biotechnology is a useful tool for the generation of stress-tolerant crops, but its release and field-testing involves complex regulatory frameworks. However, gene editing technology mediated by the CRISPR/Cas9 system is a suitable strategy for plant breeding, which can lead to precise and specific modifications in the plant genome. The aim of the present work is to produce drought-tolerant plant varieties by modifying the trehalase gene. Furthermore, a new vector platform was developed to edit monocot and dicot genomes, by modifying vectors adding a streptomycin resistance marker for use with the hypervirulent Agrobacterium tumefaciens AGL1 strain. The gRNA design was based on the trehalase sequence in several species of the genus Selaginella that show drought tolerance. Arabidopsis thaliana carrying editions in the trehalase substrate-binding domain showed a higher tolerance to drought stress. In addition, a transient transformation system for gene editing in maize leaves was characterized.


A randomized, controlled trial of vitamin D supplementation upon musculoskeletal health in postmenarchal females.
There has been a resurgence of vitamin D deficiency rickets throughout the developed world, with infants and adolescents being primarily affected. Adolescence is a crucial period for muscle and bone mineral accumulation. The aim was to determine the effect of vitamin D supplementation on the adolescent musculoskeletal system. We conducted a community-based, double-blind, randomized controlled trial in a secondary school. Postmenarchal 12- to 14-yr-old females participated in the trial. Ninety-nine were screened, 73 were included in randomized controlled trial, and 69 completed the trial. There were no adverse events. Four doses of 150,000 IU vitamin D(2) (ergocalciferol) were given over 1 yr. Dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and jumping mechanography were used. At follow-up, 25-hydroxyvitamin D [25(OH)D] status was 56.0 ± 8.9 nmol/liter in the intervention group and 15.8 ± 6.6 nmol/liter in controls. There were no effects of supplementation on bone; however, for muscle function, efficiency of movement improved in the vitamin D-treated group. There was an interaction between baseline 25(OH)D concentration and response to vitamin D supplementation for muscle jump velocity. Despite improvements in 25(OH)D status, treatment with vitamin D(2) was not shown to increase mineral accretion, bone geometry or strength, muscle force, or power. There were greater increases in jump velocity in girls with the lowest baseline 25(OH)D concentrations. Lack of effect of intervention after the period of peak mineral and muscle mass accretion suggests that earlier action is required.


Higher-Order Chromatin Structures of Chromosomally Integrated HHV-6A Predict Integration Sites.
Human herpesvirus -6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes. Viral integration can occur in several cell types, including germinal cells, resulting in individuals that harbor the viral genome in every cell of their body. The integrated genome is efficiently silenced but can sporadically reactivate resulting in various clinical symptoms. To date, the integration mechanism and the subsequent silencing of HHV-6A/B genes remains poorly understood. Here we investigate the genome-wide chromatin contacts of the integrated HHV-6A in latently-infected cells. We show that HHV-6A becomes transcriptionally silent upon infection of these cells over the course of seven days. In addition, we established an HHV-6-specific 4C-seq approach, revealing that the HHV-6A 3D interactome is associated with quiescent chromatin states in cells harboring integrated virus. Furthermore, we observed that the majority of virus chromatin interactions occur toward the distal ends of specific human chromosomes. Exploiting this finding, we established a 4C-seq method that accurately detects the chromosomal integration sites. We further implement long-read minION sequencing in the 4C-seq assay and developed a method to identify HHV-6A/B integration sites in clinical samples.


Stoichiometry of STAT3 and mitochondrial proteins: Implications for the regulation of oxidative phosphorylation by protein-protein interactions.
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor and downstream product of cytokine and growth factor pathways. Among members of the STAT family, STAT3 has garnered particular interest due to its role in cancer and development. Recently, it was proposed that STAT3 regulates cardiac ATP generation in vivo through protein interaction with the mitochondrial complexes of oxidative phosphorylation, specifically Complexes I/II. For this mechanism to work effectively, the cellular ratio of Complexes I/II and STAT3 must approach one. However, using three different proteomic approaches in cardiac tissue, we determined the ratio of Complexes I/II and STAT3 to be approximately 10(5). This finding suggests that direct protein interaction between Complexes I/II and STAT3 cannot be required for optimal ATP production, nor can it dramatically modulate oxidative phosphorylation in vivo. Thus, STAT3 is likely altering mitochondrial function via transcriptional regulation or indirect signaling pathways that warrant further investigation.


Substituent effects on the ring-opening mechanism of lithium bromocyclopropylidenoids to allenes.
The ring-opening reactions of lithium bromocyclopropylidenoids to allenes have been investigated computationally at the B3LYP/6-31G(d) level of theory. Formally, two pathways can be considered: the reaction may either proceed in a concerted fashion or stepwise with the intermediacy of a free cyclopropylidene. In both cases, the loss of the bromide ion determines the kinetic of the reaction. The stability of the reactive intermediate, i.e., the carbene, is dependent on the substituent. Cyclopropylidenes bearing an electron-donating group (+M) are extremely unstable and ring-open readily to the allene. In contrast, bromocyclopropylidenoids with electron-withdrawing groups are particularly stable species. Here, a high energy barrier needs to be overcome in order to split off bromide and to generate the corresponding carbene or allene. Still, for most of the monosubstituted cyclopropylidenes investigated during this study, the activation energy for the cyclopropylidene to allene rearrangement is lower than the energy required for parent compound (X = H) except for X = -SiH3 and -CF3.


Extrafascial hysterectomy after concurrent chemoradiotherapy in locally advanced cervical adenocarcinoma.
To evaluate whether adjuvant simple hysterectomy after concurrent chemoradiotherapy (CCRT) improves progression-free survival (PFS) compared with current standard care in locally advanced cervical adenocarcinoma (LACAC). We reviewed a cohort of 55 patients with LACAC (International Federation of Gynecology and Obstetrics [FIGO] stage IB2, IIA2, IIB, III without distant metastasis) diagnosed and treated with radical CCRT at Peking Union Medical College Hospital between January 2004 and October 2014. We compared 34 patients who underwent adjuvant extrafascial hysterectomy with 21 patients with standard care after CCRT. The primary outcome was PFS. Overall survivals (OS) between the two groups were also compared. Surgery feasibility, operative complications, and pathologic features after radiation therapy were also analyzed. PFS was significantly improved in surgery group (log-rank p=0.0097; hazard ratio [HR], 0.3431; 95% CI, 0.152 to 0.772), as were OS (log-rank p=0.0419; HR, 0.3667; 95% CI, 0.139 to 0.964). Analysis of stage IIB demonstrates a similar result. There were no severe complications related to postradiation surgery in this series. The mean blood loss was less in laparoscopic group than those in the open group (87 mL vs. 208 mL, p=0.036, Mann-Whitney U-test). Approximately 47% patients (16/34) had pathologic residue tumor on hysterectomy specimens. About 94% patients (32/34) got complete remission after adjuvant surgery. Adjuvant hysterectomy after CCRT improves survival outcome for patients with LACAC compared with current standard care. Extrafascial hysterectomy is sufficient in tumor reduction and laparoscopic procedure may be more promising with lower blood loss and expedite recovery.


A Nanocavitation Approach to Understanding Water Capture, Water Release, and Framework Physical Stability in Hierarchically Porous MOFs.
Chemically stable metal-organic frameworks (MOFs) featuring interconnected hierarchical pores have proven to be promising for a remarkable variety of applications. Nevertheless, the framework's susceptibility to capillary-force-induced pore collapse, especially during water evacuation, has often limited practical applications. Methodologies capable of predicting the relative magnitudes of these forces as functions of the pore size, chemical composition of the pore walls, and fluid loading would be valuable for resolution of the pore collapse problem. Here, we report that a molecular simulation approach centered on evacuation-induced nanocavitation within fluids occupying MOF pores can yield the desired physical-force information. The computations can spatially pinpoint evacuation elements responsible for collapse and the chemical basis for mitigation of the collapse of modified pores. Experimental isotherms and difference-electron density measurements of the MOF NU-1000 and four chemical variants validate the computational approach and corroborate predictions regarding relative stability, anomalous sequence of pore-filling, and chemical basis for mitigation of destructive forces.


Disease volume and distribution as drivers of treatment decisions in metastatic prostate cancer: From chemohormonal therapy to stereotactic ablative radiotherapy of oligometastases.
The prognosis of men with metastatic, castration-sensitive prostate cancer (CSPC) depends on both the distribution and extent of metastases, among other things. Patients with low-volume or oligometastatic disease have improved survival compared with those with high-volume metastases. While chemohormonal therapy is the new standard of care for men with high-volume metastatic CSPC, stereotactic ablative radiotherapy (SABR) is emerging as a promising treatment option with low toxicity for the management of oligometastatic CSPC. Our review summarizes the current evidence on the role of SABR in oligometastatic prostate cancer. SABR shows control rates of metastases ranging from 88% to 100% at 6 months to 3 years, and progression-free survival commonly reported as >50% for the first 12 months. In addition, SABR may allow androgen-deprivation therapy to be delayed by more than 2 years in selected patients, minimizing the chronic side effects associated with such therapy. However, much still needs to be learned before SABR can be implemented as standard treatment for oligometastatic prostate cancer.


Mixed-methods approach for measuring the impact of video telehealth on outpatient clinic triage nurse workflow.
Nurse-delivered telephone triage is a common component of outpatient clinic settings. Adding new communication technology to clinic triage has the potential to not only transform the triage process but also alter triage workflow. Evaluating the impact of new technology on an existing workflow is paramount to maximizing the efficiency of the delivery system. This study investigated triage nurse workflow before and after the implementation of video telehealth using a sequential mixed-methods protocol that combined ethnography and time-motion study to provide a robust analysis of the implementation environment. Outpatient clinic triage using video telehealth required significantly more time than telephone triage did, indicating a reduction in nurse efficiency. Despite the increased time needed to conduct video telehealth, nurses consistently rated it useful in providing triage. Interpretive analysis of the qualitative and quantitative data suggests that the increased depth and breadth of data available during video triage alter the assessment that triage nurses provide physicians. This in turn could affect the time physicians spend formulating a diagnosis and treatment plan. While the immediate impact of video telehealth is a reduction in triage nurse efficiency, what is unknown is the impact of video telehealth on physician and overall clinic efficiency. Future studies should address this area.


Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism.
We investigated the effect of the angiotensin type 1 (AT-1) receptor antagonist, irbesartan, on matrix metalloproteinase (MMP) activity and cardiac cytokines in an animal model of diabetic cardiomyopathy. Diabetes was induced in 20 C57/bl6 mice by injection of streptozotocin (STZ). These animals were treated with irbesartan or placebo and were compared with nondiabetic controls. Left ventricular (LV) function was measured by pressure-volume loops with parameters for systolic function (end systolic elastance [Ees]) and diastolic function (cardiac stiffness) 8 weeks after STZ treatment. The cardiac protein content of interleukin (IL)1beta and transforming growth factor (TGF)beta1 were measured by enzyme-linked immunosorbent assay. The total cardiac collagen content and collagen type 1 and 3 were measured by histochemistry, and MMP-2 activity was measured by gelatin zymography. LV dysfunction was documented by impaired Ees and diastolic stiffness in STZ mice compared with controls. This was accompanied by increased TGFbeta, IL1beta, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1beta, TGFbeta, and cardiac fibrosis compared with untreated diabetic animals and normalized MMP activity. These findings present evidence that AT-1 receptor antagonists attenuate cardiac failure by decreasing cardiac inflammation and normalizing MMP activity, leading to normalized cardiac fibrosis in STZ-induced diabetic cardiomyopathy.


Expression profiles of the MXD3 gene and association of sequence variants with growth traits in Xianan and Qinchuan cattle.
Max dimerization protein 3 (MXD3) belongs to the MYC superfamily of basic helix-loop-helix leucine zipper transcription factors, and MXD3-MAX heterodimers can bind to promoters of target genes to modulate their expression. The aim of this study was to determine the MXD3 mRNA expression levels in various cattle tissues comprising heart, liver, spleen, lung, kidney, Longissimus dorsi muscle and subcutaneous fat in Chinese Qinchuan and Xianan cattle breeds. The RT-qPCR data showed that the MXD3 gene was variably expressed between all tissues and at levels that were significantly different between two breeds (p < .05). We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to investigate the possible association between single-nucleotide polymorphisms (SNP) within the MXD3 gene and five different growth traits in cattle. We found two intronic SNPs (g.2694 C>T and g.3801 T>C) and one SNP in 3'untranslated region (3'UTR) (g.6263 G>A) of MXD3 gene. Association analysis revealed strong associations between pairwise and triple SNP combinations and the growth traits. Based on these results, we suggest that MXD3 polymorphisms could be useful as molecular markers in the Chinese beef cattle breeding program.


[Monoclonal antibody HMB-45 in diagnosis of intra-ocular melanoma].
69 eyes, which had to be enucleated because of an uveal melanoma, were investigated immunohistologically. HMB-45-antigen, which is supposed to be highly specific for melanocytic tumours, was found in 68 cases (sensitivity 99%) with a monoclonal antibody. S 100-antigen was positive in 63 cases (sensitivity 91%) using a polyclonal antibody. The addition of HMB-45-immunohistochemistry to routine histological diagnostic procedures is valuable, when a non-melanocytic uveal tumour cannot be ruled out or when the degree of melanoma-invasion has to be determined with greater accuracy. At the site of melanoma-invasion changes of cellular reactivity seem to occur, as 11 of the 69 studied tumours (16%) showed an increased HMB-45-expression in this area. HMB-45-antigen was detectable even in paraffin embedded material obtained from eyes enucleated 30 years ago.


Neuroimaging of the dopamine/reward system in adolescent drug use.
Adolescence is characterized by heightened risk-taking, including substance misuse. These behavioral patterns are influenced by ontogenic changes in neurotransmitter systems, particularly the dopamine system, which is fundamentally involved in the neural coding of reward and motivated approach behavior. During adolescence, this system evidences a peak in activity. At the same time, the dopamine (DA) system is neuroplastically altered by substance abuse, impacting subsequent function. Here, we describe properties of the dopamine system that change with typical adolescent development and that are altered with substance abuse. Much of this work has been gleaned from animal models due to limitations in measuring dopamine in pediatric samples. Structural and functional neuroimaging techniques have been used to examine structures that are heavily DA-innervated; they measure morphological and functional changes with age and with drug exposure. Presenting marijuana abuse as an exemplar, we consider recent findings that support an adolescent peak in DA-driven reward-seeking behavior and related deviations in motivational systems that are associated with marijuana abuse/dependence. Clinicians are advised that (1) chronic adolescent marijuana use may lead to deficiencies in incentive motivation, (2) that this state is due to marijuana's interactions with the developing DA system, and (3) that treatment strategies should be directed to remediating resultant deficiencies in goal-directed activity.


Endogenous lectin from terminally differentiated epidermal cells.
We isolated a concanavalin A (Con-A)-binding glycoprotein from human stratum corneum by nonionic detergent extraction, lectin affinity chromatography, and preparative gel electrophoresis. This glycoprotein migrates as a single band at 40 kilodaltons at sodium-dodecyl-sulfate gel electrophoresis with or without the presence of 2-mercaptoethanol. It was shown to have a heterogeneous distribution between pH 5.6 and 7.6 by isoelectric focusing. The glycoprotein is histidine rich (10.4%) but is distinct from other histidine-rich proteins (epidermal filaggrin and the histidine-rich glycoprotein from serum). It does not bind to lectins specific for L-fucose or alpha-D-galactose. We prepared a monospecific polyclonal antibody to the 40-kilodalton glycoprotein; at the ultrastructural level, it cytoimmunolocalizes exclusively to the membranes of the stratum corneum. A unique feature of the glycoprotein is that it is an endogenous lectin: it hemagglutinates trypsinized and gluteraldehyde-fixed rabbit erythrocytes. The inhibition of its hemagglutination was found to be greatest with amino sugars, down to a saccharide concentration of 10(-5) mM. Such a high affinity of binding at the cell surface suggests that this glycoprotein is a major carbohydrate-binding, cross-linking molecule that holds adjacent corneocytes together in the stratum corneum. We hypothesize that this lectin plays a role in the adhesion and desquamation of the stratum corneum.


Midterm results of percutaneous endovascular treatment for acute and chronic deep venous thrombosis.
Treatment of deep venous thrombosis (DVT) with therapeutic anticoagulation has been increasingly challenged by aggressive percutaneous treatment using ultrasound-accelerated catheter-directed thrombolysis (US-CDT) or percutaneous pharmacomechanical thrombectomy (PMT). These techniques have been promoted to improve thrombus removal, prolong venous patency, prevent venous insufficiency, and reduce postthrombotic syndrome. This study reviews midterm results using these endovascular techniques for both acute and chronic DVT. A retrospective chart review was performed on patients treated for acute or chronic DVT with US-CDT and/or PMT. Charts were reviewed for patient demographics, medical history and treatment, operative details, and postoperative outcomes. Intraoperative venography and intravascular ultrasound quantified clot response to therapy. Duplex ultrasound defined the pre- and postoperative extent of venous thrombosis, venous patency, and valvular function. Between October 1, 2002 and September 30, 2010, 80 patients were treated for iliofemoral (n = 48), iliofemoropopliteal (n = 15), or femoropopliteal (n = 17) venous thrombosis. Mean age was 45.8 years (range, 15-78 years), and 24 patients (30%) had a documented history of hypercoagulable state. Intravascular ultrasound confirmed May-Thurner syndrome in 34 patients (42.5%). Fifty-two patients (65%) were treated for acute DVT; the mean time to intervention from symptom onset was 8.7 ± 4.5 days (range, 1-14 days). The remaining 28 patients (35%) had chronic symptoms and were treated at a mean of 8.6 ± 10.9 months (range, 1.5-36 months) after DVT diagnosis was made. Patients were treated with PMT (n = 43, 53.8%), US-CDT (n = 14, 17.5%), or both (n = 32, 28.7%). Clot lysis (>90%) was achieved in 72 of 80 patients (90%). Tenecteplase was used for all cases, and the mean dose was 8.6 ± 4.3 mg. Adjunctive procedures, including angioplasty with or without stent placement, were required in 90% (n = 47) of acute patients and in 96% (n = 27) of chronic patients (P = .33). Three patients (3.8%) had postoperative bleeding events requiring blood transfusion; there were no occurrences of intracranial hemorrhage or clinically significant pulmonary embolism. At a mean follow-up of 3.8 years (range, 1-8.9 years), venous patency was present in 49 of 52 acute patients (94%) and in 23 of 28 chronic patients (82%) (P = .12). Valve function was preserved in 41 of 52 (79%) acute patients vs 11 of 28 (39%) chronic patients (P < .001). US-CDT and PMT can effectively remove acute and chronic thrombus in the lower extremity deep venous system. Vein patency and valvular function is better preserved at midterm follow-up after treatment for acute DVT, however intervention should be considered in patients with chronic DVT as well.


Neurobiology and neuroanatomy of psychiatric symptoms in parkinsonism.
The present article aims to review state-of-the-art evidence of altered neurobiology and neuroanatomy underlyingpsychiatric symptoms in parkinsonism. This issue covers a wide range of symptoms encompassing anxiety, mooddisorders, psychosis as well as substance abuse and specific compulsive behaviors. Such a complex nosographymakes it impossible to deal with the neurobiology and neuroanatomy of each psychopathological condition perse, unless offering a trivial list of symptoms joined with brief explanations reporting potential causal mechanisms.This approach would only provide a rough synthesis of what previously reported without adding neither novelconcepts nor evidence to improve our insight into the neurobiology of parkinsonism as a psychiatric condition.Therefore, the analytical description of each psychiatric symptom associated with parkinsonism will be avoided butit will be referenced instead. In contrast, the present article will focus on the mechanisms why such a class of nonmotorsymptoms clusters in parkinsonian patients. In addition, we will seek to establish the relationship betweenthe occurrence of a given psychiatric condition and specific parkinsonian phenotypes. Again, an emphasis will begiven to the occurrence of behavioral fluctuations in parkinsonism where both motor and psychiatric symptomsmay possess a specific timing. The timing of these fluctuations will be related to the timing of dopamine substitutiontherapy and involvement of multiple neurotransmitters and brain regions as well. We provide evidence showingthat specific parkinsonian phenotypes (and genotypes) possess a widespread neuropathology, which in turn associatesto a fairly specific psychopathology. In contrast, other phenotypes (and genotypes) bring to very selectiveneuronal degeneration where the occurrence of psychiatric symptoms is rare if not absent at all. These clinicalpathological phenotypes associate with specific molecular mechanisms in the dynamics of neurobiology of disease.


Human cardiac-specific cDNA array for idiopathic dilated cardiomyopathy: sex-related differences.
Idiopathic dilated cardiomyopathy (IDCM) constitutes a large portion of patients with heart failure of unknown etiology. Up to 50% of all transplant recipients carry this clinical diagnosis. Female-specific gene expression in IDCM has not been explored. We report sex-related differences in the gene expression profile of ventricular myocardium from patients undergoing cardiac transplantation. We produced and sequenced subtractive cDNA libraries, using human left ventricular myocardium obtained from male transplant recipients with IDCM and nonfailing human heart donors. With the resulting sequence data, we generated a custom human heart failure microarray for IDCM containing 1,145 cardiac-specific oligonucleotide probes. This array was used to characterize RNA samples from female IDCM transplant recipients. We identified a female gene expression pattern that consists of 37 upregulated genes and 18 downregulated genes associated with IDCM. Upon functional analysis of the gene expression pattern, deregulated genes unique to female IDCM were those that are involved in energy metabolism and regulation of transcription and translation. For male patients we found deregulation of genes related to muscular contraction. These data suggest that 1) the gene expression pattern we have detected for IDCM may be specific for this disease and 2) there is a sex-specific profile to IDCM. Our observations further suggest for the first time ever novel targets for treatment of IDCM in women and men.


Human-like compliant locomotion: state of the art of robotic implementations.
This review paper provides a synthetic yet critical overview of the key biomechanical principles of human bipedal walking and their current implementation in robotic platforms. We describe the functional role of human joints, addressing in particular the relevance of the compliant properties of the different degrees of freedom throughout the gait cycle. We focused on three basic functional units involved in locomotion, i.e. the ankle-foot complex, the knee, and the hip-pelvis complex, and their relevance to whole-body performance. We present an extensive review of the current implementations of these mechanisms into robotic platforms, discussing their potentialities and limitations from the functional and energetic perspectives. We specifically targeted humanoid robots, but also revised evidence from the field of lower-limb prosthetics, which presents innovative solutions still unexploited in the current humanoids. Finally, we identified the main critical aspects of the process of translating human principles into actual machines, providing a number of relevant challenges that should be addressed in future research.


Associations of mortality and cardiovascular disease risks with diabetes and albuminuria in urban Indigenous Australians: the DRUID follow-up study.
To assess the relationships of diabetes and albuminuria with all-cause mortality and cardiovascular disease outcomes in a population without prior cardiovascular disease using data from the Darwin Region Urban Indigenous Diabetes (DRUID) study. We conducted a prospective cohort study of 706 participants (aged 15-81 years, 68% women) without prior cardiovascular disease who underwent a 75-g oral glucose tolerance test. Deaths and fatal or non-fatal cardiovascular disease were determined over 7 years, and hazard ratios with 95% CIs and population attributable risks were estimated for baseline glycaemia and albuminuria. Compared with normoglycaemia and after adjustment for age, sex, hypertension, dyslipidaemia and smoking, known diabetes was associated with an adjusted hazard ratio of 4.8 (95% CI 1.5-14.7) for all-cause mortality and 5.6 (95% CI 2.1-15.2) for cardiovascular disease. Compared with normoalbuminuria, the respective adjusted risks for macroalbuminuria were 10.9 (95% CI 3.7-32.1) and 3.9 (95% CI 1.4-10.8). The Adjusted all-cause mortality and cardiovascular disease estimated population attributable risks for diabetes were 27% and 32%, and for albuminuria they were 32% and 21%, respectively. In our study population, the burden of mortality and cardiovascular disease was largely driven by diabetes and albuminuria. This finding on the influence of diabetes and albuminuria is consistent with reports in other high-risk Indigenous populations and should be better reflected in risk scores and intervention programmes.


[A historical analysis of "insight" category in psychiatry].
This work presents a historical analysis of the formation and development of "insight" category (awareness of illness) in the process of interdisciplinary collaboration between psychiatry, psychology and social sciences. Different meanings of the term "insight" and their impact on the modern perception of the awareness of illness phenomenon are analyzed. The differences in particular aspects of the clinical reality described by insight and other concepts used in the studies of awareness of illness are highlighted. The need for introduction of a new conventional category "insight" for studying the problem of awareness of a mental illness and perspectives of their empirical investigation.


Hidden genetic variation in the germline genome of Tetrahymena thermophila.
Genome architecture varies greatly among eukaryotes. This diversity may profoundly affect the origin and maintenance of genetic variation within a population. Ciliates are microbial eukaryotes with unusual genome features, such as the separation of germline and somatic genomes within a single cell and amitotic division. These features have previously been proposed to increase the rate of molecular evolution in these species. Here, we assessed the fitness effects of genetic variation in the two genomes of natural isolates of the ciliate Tetrahymena thermophila. We find more extensive genetic variation in fitness in the transcriptionally silent germline genome than in the expressed somatic genome. Surprisingly, this variation is not primarily deleterious, but has both beneficial and deleterious effects. We conclude that Tetrahymena genome architecture allows for the maintenance of genetic variation that would otherwise be eliminated by selection. We consider the effect of selection on the two genomes and the impacts of reproductive strategies and the mechanism of sex determination on the structure of this variation.


Quantitative high-throughput determination of endogenous retinoids in human plasma using triple-stage liquid chromatography/tandem mass spectrometry.
A high-throughput ultrasensitive analytical method based on liquid chromatography with positive ion atmospheric pressure chemical ionization (APCI) coupled to tandem mass spectrometric detection (LC/MS/MS) was developed for the determination of all-trans-4-oxo-retinoic acid (at4oxoRA), 13-cis-4-oxo-retinoic acid (13c4oxoRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (atRA) and all-trans-retinol (atROH) in human plasma. A stable isotope of atRA was used as internal standard (IS). The analytes and IS were isolated from 100 microL plasma by acetonitrile mono-phase extraction (MPE) performed in black 96-well microtiterplates. A 100 microL injection was focused on-column and chromatographed on an Agilent ZORBAX SB-C18 rapid-resolution high-throughput (RRHT) column with 1.8-microm particles (4.6 mmx50 mm) maintained at 60 degrees C. The initial mobile phase composition was acetonitrile/water/formic acid (10:90:0.1, v/v/v) delivered at 1.8 mL/min. Elution was accomplished by a fast gradient to acetonitrile/methanol/formic acid (90:10:0.1, v/v/v). The method had a chromatographic total run time of 7 min. An Applied Biosystems 4000 Q TRAP linear tandem mass spectrometer equipped with a heated nebulizer (APCI) ionization source was operated in multiple reaction monitoring (MRM) mode with the precursor-to-product ion transitions m/z 315.4-->297 (4-oxo-retinoic acids), 301.2-->205 (retinoic acids), 305.0-->209 (IS) and 269.2-->93 (retinol) used for quantification. The assay was fully validated and found to have acceptable accuracy, precision, linearity, sensitivity and selectivity. The mean extraction recoveries from spiked plasma samples were 80-105% for the various retinoids at three different levels. The intra-day accuracy of the assay was within 8% of nominal and intra-day precision was better than 8% coefficient of variance (CV) for retinoic acids. Inter-day precision results for quality control samples run over a 12-day period alongside clinical samples showed mean precision better than 12.5% CV. The limit of quantification was in the range of 0.1-0.2 ng/mL and the mass limit of detection (mLOD) was in the range 1-4 pg on column for the retinoic acids. The assay has been successfully applied to the analysis of 1700 plasma samples.


Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron.
Hypertension is among the most prevalent and catastrophic chronic diseases worldwide. While the efficacy of renin angiotensin system (RAS) blockade in lowering blood pressure illustrates that the RAS is broadly activated in human hypertension, the frequent failure of RAS inhibition to prevent or reverse hypertensive organ damage highlights the need for novel therapies to combat RAS-dependent hypertension. We previously discovered elevated levels of the macrophage cytokine IL-1 in the kidney in a murine model of RAS-mediated hypertension. Here we report that IL-1 receptor (IL-1R1) deficiency or blockade limits blood pressure elevation in this model by mitigating sodium reabsorption via the NKCC2 co-transporter in the nephron. In this setting, IL-1R1 activation prevents intra-renal myeloid cells from maturing into Ly6C(+)Ly6G(-) macrophages that elaborate nitric oxide, a natriuretic hormone that suppresses NKCC2 activity. By revealing how the innate immune system regulates tubular sodium transport, these experiments should lead to new immunomodulatory anti-hypertensive therapies.


Chicken vitellogenin gene-binding protein, a leucine zipper transcription factor that binds to an important control element in the chicken vitellogenin II promoter, is related to rat DBP.
We screened a chicken liver cDNA expression library with a probe spanning the distal region of the chicken vitellogenin II (VTGII) gene promoter and isolated clones for a transcription factor that we have named VBP (for vitellogenin gene-binding protein). VBP binds to one of the most important positive elements in the VTGII promoter and appears to play a pivotal role in the estrogen-dependent regulation of this gene. The protein sequence of VBP was deduced from a nearly full length cDNA copy and was found to contain a basic/zipper (bZIP) motif. As expected for a bZIP factor, VBP binds to its target DNA site as a dimer. Moreover, VBP is a stable dimer free in solution. A data base search revealed that VBP is related to rat DBP. However, despite the fact that the basic/hinge regions of VBP and DBP differ at only three amino acid positions, the DBP binding site in the rat albumin promoter is a relatively poor binding site for VBP. Thus, the optimal binding sites for VBP and DBP may be distinct. Similarities between the VBP and DBP leucine zippers are largely confined to only four of the seven helical spokes. Nevertheless, these leucine zippers are functionally compatible and appear to define a novel subfamily. In contrast to the bZIP regions, other portions of VBP and DBP are markedly different, as are the expression profiles for these two genes. In particular, expression of the VBP gene commences early in liver ontogeny and is not subject to circadian control.


Value of inhibin staining in gynecological pathology.
Recent years have seen the publication of many articles investigating the value of antibodies against inhibin in diagnostic surgical pathology. This review concentrates on the uses of inhibin staining in gynecological pathology. alpha-inhibin is diagnostically the most useful antibody and is a sensitive immunohistochemical marker of most ovarian sex cord-stromal tumors and, as such, is of value in the diagnosis of this heterogeneous group of neoplasms that can be confused morphologically with a wide range of other tumors. Because the antibody is not entirely specific for ovarian sex cord-stromal tumors, it should always be used as part of a larger panel. alpha-inhibin staining may also be of value in confirming late recurrence or metastasis of an ovarian sex cord-stromal tumor, especially a granulosa cell tumor. Sex cord-like elements within uterine tumors resembling ovarian sex cord tumors are also commonly immunoreactive with alpha-inhibin, perhaps indicating true sex cord differentiation. alpha-inhibin staining may also be of value in cytological preparations in confirming a functional cyst and excluding a cyst or cystadenoma of epithelial origin. Syncytiotrophoblastic cells are also immunoreactive, as are most trophoblastic tumors. Thus, positive staining may be of value in confirming an intrauterine gestation or in the diagnosis of a trophoblastic neoplasm. Another gynecological neoplasm that is commonly positive with alpha-inhibin is the so-called female adnexal tumor of probable wolffian origin, and, therefore, the antibody is of no value in the distinction of this neoplasm from a sex cord-stromal tumor, tumors that are often in the differential diagnosis.


The Role of Autophagy in Rheumatic Disease.
Autophagy is an evolutionarily conserved degradation process in triggered by metabolic stress or environmental changes. Autophagy involves formation of autophagosomes, which fuse with lysosomes and degrade encapsulated intracellular components, such as long-lived and misfolded proteins, as well as intracellular organelles. Autophagy has been implicated in a wide variety of physiological and pathological conditions, and was recently implicated in the regulation of immunity and inflammation. Rheumatic diseases are a group of disorders characterized by immune system malfunctions in which the body attacks its own tissues. These diseases can seriously threaten human health if untreated. Although the underlying pathophysiology of autoimmune diseases has not yet been fully elucidated, autophagy has been implicated in their progression. In this article, we review the basics of autophagy, and the functional role of autophagy in the pathogenesis of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease and ankylosing spondylitis (AS). Moreover, we reviewed the role of autophagy and autophagy-related genes (Atgs) in innate and adaptive immunity, as well as the pathogenic crosstalk between autophagy and apoptosis. Our findings should provide valuable insights into the role of autophagy in the pathogenesis of rheumatic diseases. In addition, identification of novel autophagy-associated target proteins may offer a promising target for drugs treating human rheumatic disorders.


[Smoking in schools of nursing].
A study was made among students and instructors of three schools of nursing at São Paulo City, Brazil, on number of smokers, non smokers and previous smokers and the causes that led them to start smoking as well as to withdraw from the habit. In a population of 636 studients the authors found 24.1% smokers, 68.5% non smokers, 7.4% previous smokers. The percentage of 117 instructors were 23.1%, 62.4% and 14.5% respectively. The reason for start smoking most frequently mentioned by both groups was curiosity (35.2% and 28.2% respectively). For leaving the habit was conscience of damage to health (72.5% and 65.2%). For the non smokers this was the main reason for never starting the habit. The authors studied also the age of start smoking, number of cigarettes smoked per day. The outside influences for smoking or not orientation of others about the damages of smoking to health were also considered.


Infectious mutants of HTLV-III with changes in the 3' region and markedly reduced cytopathic effects.
A variant of human T-lymphotropic virus type III (HTLV-III) is described that replicates but does not kill normal human T cells in vitro. This variant, designated X10-1, was derived from the genome of a cytopathic HTLV-III clone (pHXB2D) by excision of a 200-base pair segment in the 3' region of the virus, spanning the env and 3'-orf genes. Comparable variants with 55 to 109 base pairs deleted exclusively in 3'-orf produced, in contrast, virus that was extremely cytopathic. On the basis of these findings it is concluded that the 3'-orf gene is not required for cytopathogenicity or replication of HTLV-III. In addition, the results suggest that virus replication and cytotoxicity are not intrinsically coupled. Furthermore, since clone X10-1 retains the ability to trans-activate genes linked to the viral long terminal repeats, trans-activation per se is not responsible for T-cell killing by HTLV-III. These results also raise the possibility that the carboxyl terminus of the envelope gene of HTLV-III has a direct role in T-cell killing by this virus.


[Vitamin K2 therapy for myelodysplastic syndrome].
Vitamin K2 is reported to induce apoptosis or differentiation of leukemic cell lines in vitro. We administered a vitamin K2 analog, menatetrenone, at 45 mg daily to 23 patients with myelodysplastic syndrome (MDS): 13 patients with RA, 2 with RARS, 6 with RAEB and 2 with RAEB-T. Good response (GR) and partial response (PR) were defined as an increase of hemoglobin concentration exceeding 2 g/dl and 1-2 g/dl without transfusion, respectively. Six of the RA patients showed improvement of anemia (GR, 3 patients; PR, 3 patients). RA patients who did not have a hypocellular bone marrow and were transfusion-independent tended to be responsive to vitamin K2 therapy in combination with vitamin D3 or anabolic steroids. No adverse effect of vitamin K2 was observed, and the time required to obtain the hematological response was short, being 3 months on average. We believe that vitamin K2 therapy has potential as a treatment for patients with MDS.


Pathology of chronic A-V Block.
Study of 177 cases of permanent A-V block shows idiopathic bilateral bundle branch fibrosis to be the commonest single cause (33%). This entity covers a spectrum of localised loss of conduction fibres in the proximal left bundle branch and bifurcating main bundle (Lev's disease) to moore periphery loss of conduction fibres in the bundle branches alone (Lenègre's disease). The aetiological factors in idiopathic bundle branch fibrosis are still obscure. Ischaemic damage is responsible for 17% of cases and are usually patients who have survived destruction of the bundle branches in septal infarction. Calcific A-V block is the term applied to destruction of the main bundle by large masses of calcification in the mitral or aortic valve rings and is responsible for 10% of cases of chronic A-V block. The mass of calcium is visible to the naked eye at autopsy or by X ray in life. Cardiomyopathies of all types (except hypertrophic obstructive cardiomyopathy) involve the conduction system and produce 14% of cases of A-V block. The remaining numerous causes of chronic A-V block are individually very rare ranging through tumour involvement, congenital defects, collagen diseases and surgical or traumatic damage.


Macrophage IL-1β-positive microvesicles exhibit thrombo-inflammatory properties and are detectable in patients with active juvenile idiopathic arthritis.
IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1β secretion. The first objective of our study was to characterize IL-1β-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions in vitro and in vivo. The second objective was to detect circulating IL-1β-positive MVs in JIA patients. MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1β, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied in vitro by measuring VCAM-1, ICAM-1, and E-selectin expression after HUVEC co-culture and factor-Xa generation test was realized. In vivo, MVs' ability to recruit leukocytes in a murine model of peritonitis was evaluated. Plasmatic IL-1β-positive MVs were studied ex vivo in 10 active JIA patients using flow cytometry. THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1β and bioactive TF. IL-1β-positive MVs expressed P2X7 receptor and released soluble IL-1β in response to ATP stimulation in vitro. In mice, MVs induced a leukocyte peritoneal infiltrate, which was reduced by treatment with the IL-1 receptor antagonist. Finally, IL-1β-positive MVs were detectable in plasma from 10 active JIA patients. MVs shed from activated macrophages contain IL-1β, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients.


Ultrasound examination of the postpartum uterus: what is normal?
To establish normal ultrasonographic findings for the postpartum uterus after vaginal delivery, and to characterize associated bleeding patterns. Postpartum women were scanned by transabdominal ultrasound within 48 h after normal vaginal delivery. Uterine length, uterine width, endometrial stripe thickness and endometrial contents were evaluated by a single sonographer. Patients maintained a daily symptom diary for 6 weeks and were interviewed by telephone at 2 weeks. Statistical analysis was performed using chi2, Fisher's exact test, Student's t test and Pearson correlation. Mean endometrial stripe thickness was 1.1 +/- 0.6 cm, mean uterine length was 16.1 +/- 1.7 cm and mean uterine width was 8.7 +/- 1.0 cm. Postpartum bleeding requiring more than four protective pads per day for > or =10 days was associated with a thicker endometrial stripe (1.5 +/- 0.7 cm vs. 0.9 +/- 0.4 cm, p = 0.006). However, no patients experienced postpartum bleeding complications requiring intervention. Of the 40 women evaluated, 16 had echogenic material in the uterine cavity (mean size 12.7 +/- 6.9 cm2). The presence of echogenic material was not associated with the amount or duration of bleeding. Frequent postpartum ultrasonographic findings include a thickened endometrial stripe and echogenic material in the uterine cavity. The echogenic material commonly seen in the endometrial cavity of asymptomatic patients was not associated with the development of bleeding complications.


Optical Coherence Tomographic Patterns as Predictors of Structural Outcome After Intravitreal Ranibizumab in Diabetic Macula Edema.
The purpose of this study was to present an association between the treatment response of diabetic macular edema (DME) to intravitreal ranibizumab (IVR) injections and different morphology patterns using spectral domain optical coherence tomography (SD-OCT). This retrospective study included 216 eyes of 142 subjects who received IVR for DME and were observed for at least 2 years. Medical charts and SD-OCT images of consecutive patients were reviewed at baseline, 1, 3, 6, 12, and 24 months after first IVR treatment. The OCT patterns were characterized as diffuse retinal thickening (DRT), cystoid macular edema (CME), serous retinal detachment (SRD), and vitreomacular interface abnormalities (VMIAs). All patients were classified into four groups based on the OCT findings. For a total of 216 eyes, 36 eyes were classified into the DRT group, 76 in the CME group, 42 in the SRD group, and 62 in the VMIA group. There were significant central macula thickness (CMT) improvements in all groups at the 1st month and the 2nd year, except for the DRT group at the 2nd year. Patients with OCT findings of hyperreflective dots (HRDs), metabolic parameters of hyperlipidemia, and coronary artery disease (CAD) had significantly less improvements in CMT at 2-year follow-up (P=0.029, 0.007, <0.001, respectively). A trend toward decreased effectiveness after long-term IVR treatment was observed in the DRT group. Consistent IVR treatment could still achieve favorable improvement in the reduction of CMT in 2-year follow-up in the VMIA group. Different OCT patterns in DME may affect the therapeutic role of anti-VEGF agents and predict the structure outcome.


Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats.
Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; "Ecstasy"). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance, suggesting that 5-HT re-uptake inhibitors such as fluoxetine may be less effective at treating depression in chronic abusers of MDMA.