An efficient semi-supervised quality control system trained using physics-based MRI-artefact generators and adversarial training.
Large medical imaging data sets are becoming increasingly available. A common challenge in these data sets is to ensure that each sample meets minimum quality requirements devoid of significant artefacts. Despite a wide range of existing automatic methods having been developed to identify imperfections and artefacts in medical imaging, they mostly rely on data-hungry methods. In particular, the scarcity of artefact-containing scans available for training has been a major obstacle in the development and implementation of machine learning in clinical research. To tackle this problem, we propose a novel framework having four main components: (1) a set of artefact generators inspired by magnetic resonance physics to corrupt brain MRI scans and augment a training dataset, (2) a set of abstract and engineered features to represent images compactly, (3) a feature selection process that depends on the class of artefact to improve classification performance, and (4) a set of Support Vector Machine (SVM) classifiers trained to identify artefacts. Our novel contributions are threefold: first, we use the novel physics-based artefact generators to generate synthetic brain MRI scans with controlled artefacts as a data augmentation technique. This will avoid the labour-intensive collection and labelling process of scans with rare artefacts. Second, we propose a large pool of abstract and engineered image features developed to identify 9 different artefacts for structural MRI. Finally, we use an artefact-based feature selection block that, for each class of artefacts, finds the set of features that provide the best classification performance. We performed validation experiments on a large data set of scans with artificially-generated artefacts, and in a multiple sclerosis clinical trial where real artefacts were identified by experts, showing that the proposed pipeline outperforms traditional methods. In particular, our data augmentation increases performance by up to 12.5 percentage points on the accuracy, F1, F2, precision and recall. At the same time, the computation cost of our pipeline remains low - less than a second to process a single scan - with the potential for real-time deployment. Our artefact simulators obtained using adversarial learning enable the training of a quality control system for brain MRI that otherwise would have required a much larger number of scans in both supervised and unsupervised settings. We believe that systems for quality control will enable a wide range of high-throughput clinical applications based on the use of automatic image-processing pipelines.


Differentiation of Muller's chromosomal elements D and E in the obscura group of Drosophila.
Twenty-two markers located on Muller's elements D or E have been mapped by in situ hybridization in six species of the obscura group of Drosophila and in D. melanogaster. The obscura species can be grouped into a Palearctic cluster (D. subobscura, D. madeirensis and D. guanche) and a Nearctic one (D. pseudoobscura, D. persimilis and D. miranda). Eleven of the probes contain known genes: E74, Acp70A, Est5, hsp28/23, hsp83, emc, hsp70, Xdh, Acph-1, Cec and rp49. The remaining probes are recombinant phages isolated from a D. subobscura genomic library. All these markers hybridize to the putative homologous chromosome or chromosomal arm of elements D and E. Thus, these elements have conserved their genic content during species divergence. Chromosomal homologies proposed previously for each element among the species of the same cluster have been compared with the present results. The distribution of markers within each element has changed considerably as inferred from pairwise comparisons of obscura species included in the two different clusters. Only chromosomal segments defined by closely linked markers have been conserved: one such segment has been detected in element D and three in element E between D subobscura and D. pseudoobscura.


High basal metabolic rate does not elevate oxidative stress during reproduction in laboratory mice.
Increased oxidative stress (OS) has been suggested as a physiological cost of reproduction. However, previous studies reported ambiguous results, with some even showing a reduction of oxidative damage during reproduction. We tested whether the link between reproduction and OS is mediated by basal metabolic rate (BMR), which has been hypothesized to affect both the rate of radical oxygen species production and antioxidative capacity. We studied the effect of reproduction on OS in females of laboratory mice divergently selected for high (H-BMR) and low (L-BMR) BMR, previously shown to differ with respect to parental investment. Non-reproducing L-BMR females showed higher oxidative damage to lipids (quantified as the level of malondialdehyde in internal organ tissues) and DNA (quantified as the level of 8-oxodG in blood serum) than H-BMR females. Reproduction did not affect oxidative damage to lipids in either line; however, it reduced damage to DNA in L-BMR females. Reproduction increased catalase activity in liver (significantly stronger in L-BMR females) and decreased it in kidneys. We conclude that the effect of reproduction on OS depends on the initial variation in BMR and varies between studied internal organs and markers of OS.


[Hemicraniectomy for treatment of malignant medial cerebral artery infarction in 3 patients].
In three patients, a 52-year old man, a 54-year old man and a 17-year old woman, sudden neurological signs such as hemiparalysis and hemihypaesthesia developed, with diminished consciousness occurring at a later stage. Imaging revealed total infarction of the area supplied by the right middle cerebral artery with the threat of intracranial hypertension. Once informed consent had been obtained from the patient's representatives, hemicraniectomy with dural augmentation was performed. Although the primary neurological deficit persisted, the three patients assessed their quality of life as valuable with their Barthel scores ranging from 45 to 90. Total infarction of the middle cerebral artery may result in intracranial hypertension and transtentorial herniation owing to the development of cytotoxic oedema, particularly in young patients. The prognosis of this condition is poor partly due to the limited effect of non-surgical treatment. Hemicraniectomy with dural augmentation prevents secondary brain damage caused by the space-occupying effect of the infarct. This operation reduces mortality considerably. The findings in these patients along with the results in the literature warrant a randomised study of the results of hemicraniectomy in patients with malignant middle cerebral artery infarction.


The Role of Repetitive Negative Thoughts in the Vulnerability for Emotional Problems in Non-Clinical Children.
The current study examined the role of repetitive negative thoughts in the vulnerability for emotional problems in non-clinical children aged 8-13 years (N = 158). Children completed self-report questionnaires for assessing (1) neuroticism and behavioral inhibition as indicators of general vulnerability (2) worry and rumination which are two important manifestations of repetitive negative thoughts, and (3) emotional problems (i.e., anxiety, depression, and sleep difficulties). Results demonstrated that there were positive correlations between measures of general vulnerability, repetitive negative thoughts, and emotional problems. Further, support was found for a model in which worry and rumination acted as partial mediators in the relation between neuroticism and symptoms of anxiety and depression. In the case of sleep difficulties, no evidence was obtained for such a mediation model. In fact, data suggested that sleeping difficulties are better conceived as an epiphenomenon of high symptom levels of anxiety and depression or as a risk factor for the development of other types of psychopathology. Finally, besides neuroticism, the temperamental trait of behavioral inhibition appeared to play a unique direct role in the model predicting anxiety symptoms but not in the models predicting depressive symptoms or sleep difficulties. To conclude, the current findings seem to indicate that worry and rumination contribute to children's vulnerability for anxiety and depression.


Estimation of Signal-to-Noise Ratios in Realistic Sound Scenarios.
Both in the design of hearing-device features, such as noise reduction, and in the evaluation measurements of such features, there is a need for more information about the sound scenarios hearing-device users encounter. The limitations of adaptive speech tests as outcome measures in the evaluation of hearing-device features have been discussed. The obvious alternative to adaptive speech testing is to test at a fixed signal-to-noise ratio (SNR). However, the question is which SNRs should be used if the test reflects real-life situations. The purpose of this study was to estimate SNRs in realistic sound environments encountered by hearing aid users. Research design was a descriptive study where recorded sound files were statistically analyzed. A total of 20 experienced, bilaterally fitted hearing aid users, all satisfied with their current hearing aids, made recordings for 3-4 days. The informants were instructed to record different situations in daily life and were told that all situations were of equal importance. The informants ranged in age from 18-81 yr old, and they had various occupations and varying hearing-loss configurations. The total duration of the recorded material for each informant was, on average, 84 min; the number of recordings was, on average, 17 per informant. The sound files were categorized based on the type of background noise and were analyzed with use of a manual noise estimation procedure. Segments of speech with noise present were cut out from the original recordings. Corresponding noise-only segments were also extracted. On the basis of power calculations for these two types of recorded segments, the SNR was estimated. Frequency-specific and overall SNRs, calculated both based on unweighted and A-weighted speech and noise levels, were derived. An estimation uncertainty measure was also developed. The range of SNRs found in the material was large. The most striking finding was that there were very few recorded situations where the SNR was negative or even close to 0 dB. For speech-in-babble noise, the average SNR was approximately 5 dB. The estimation uncertainty was generally low but became higher in highly fluctuating noises and at very low SNRs. The estimated SNRs were higher than previously reported. The results can be used in the design and evaluation of hearing-device features.


Tetranuclear iron complexes bearing benzenetetrathiolate bridges as four-electron transformation templates and their electrocatalytic properties for proton reduction.
Two tetranuclear iron-sulfur complexes, (μ,μ-pbtt)[Fe(2)(CO)(6)](2) (pbtt = benzene-1,2,4,5-tetrathiolato, 3) and (μ,μ-obtt)[Fe(2)(CO)(6)](2) (obtt = benzene-1,2,3,4-tetrathiolato, 4), were prepared from reaction of Fe(3)(CO)(12) and the corresponding tetramercaptobenzene in THF, respectively. Complexes 5 and 6, (μ,μ-pbtt)[Fe(2)(CO)(5)L(1)][Fe(2)(CO)(5)L(2)] (L(1) = CO, L(2) = PPyr(3) (Pyr = N-pyrrolyl), 5; L(1) = L(2) = PPyr(3), 6) were obtained by controlling CO displacement of 3 with PPyr(3). Molecular structures of 3-6 were determined by spectroscopic and single-crystal X-ray analyses. All-CO Fe(4)S(4) complexes 3 and 4 each display four-electron reduction processes in consecutive chemically reversible two-electron reduction events with relatively narrow potential spans in the cyclic voltammograms. Phosphine-substituted Fe(4)S(4) complexes 5 and 6 exhibit two consecutive two-electron reduction events, which are not fully reversible. The electrocatalytic properties of 3 and 4 for proton reduction were studied using a series of carboxylic acids of increasing strength (CH(3)COOH, CH(2)ClCOOH, CHCl(2)COOH, CCl(3)COOH, and CF(3)COOH). The mechanisms for electrochemical proton reduction to hydrogen catalyzed by complex 3 as a function of acid strength are discussed.


Neuro-functional differences associated with arithmetic processing in Turner syndrome.
Turner syndrome (TS) is a neurogenetic disorder characterized by the absence of one X chromosome in a phenotypic female. Individuals with TS are at risk for impairments in mathematics. We investigated the neural mechanisms underlying arithmetic processing in TS. Fifteen subjects with TS and 15 age-matched typically developing controls were scanned using functional MRI while they performed easy (two-operand) and difficult (three-operand) versions of an arithmetic processing task. Both groups activated fronto-parietal regions involved in arithmetic processing during the math tasks. Compared with controls, the TS group recruited additional neural resources in frontal and parietal regions during the easier, two-operand math task. During the more difficult three-operand task, individuals with TS demonstrated significantly less activation in frontal, parietal and subcortical regions than controls. However, the TS group's performance on both math tasks was comparable to controls. Individuals with TS demonstrate activation differences in fronto-parietal areas during arithmetic tasks compared with controls. They must recruit additional brain regions during a relatively easy task and demonstrate a potentially inefficient response to increased task difficulty compared with controls.


Allosteric Modulation Mechanism of the mGluR5 Transmembrane Domain.
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor type 5 (mGluR5), a prototypical class C G protein-coupled receptor (GPCR), have shown therapeutic potential for various neurological disorders. Understanding the allosteric activation mechanism is essential for the rational design of mGluR5 PAMs. We studied the actions of positive and negative allosteric modulators within the transmembrane domain of mGluR5, using enhance-sampling all-atom molecular dynamics simulations. We found dual binding modes of the PAM, associated with distinct shapes of the allosteric pocket. The negative allosteric modulators, in contrast, showed only one binding mode. The simulations revealed the mechanism by which the PAM activated the receptor, in the absence of the orthosteric agonist (the so-called allosteric agonism). The mechanism relied on dynamic communications between amino-acid motifs that are highly conserved across class C GPCRs. The findings may guide structure-based design and virtual screening of allosteric modulators for mGluR5 as well as for other class C GPCRs.


Effects of bovine somatotropin administration on growth, physiological, and reproductive responses of replacement beef heifers.
This experiment compared growth, body composition, plasma IGF-I and leptin, and reproductive development of beef heifers receiving or not recombinant bovine ST (BST) beginning after weaning until the first breeding season. Fifty Angus × Hereford heifers (initial BW = 219 ± 2 kg; initial age = 208 ± 2 d), weaned at approximately 6 mo of age, were assigned to the experiment (d 0 to 210). On d 0, heifers were ranked by initial BW and age and assigned to 1) treatment with BST or 2) saline control. Heifers assigned to the BST treatment received subcutaneous (s.c.) injections containing 250 mg of sometribove zinc whereas control heifers received a 5-mL s.c. injection of 0.9% saline every 14 d. Treatments were initiated on d 14 and last administered on d 196. Heifers were maintained on separate pastures harvested for hay the previous summer according to treatment and received grass and alfalfa hay at a rate to provide a daily amount of 7.0 and 1.0 kg of DM per heifer, respectively. Heifer shrunk BW was collected on d 1 and 211 for heifer ADG calculation. Blood samples were collected weekly from d 0 to 210 for determination of plasma progesterone to estimate puberty attainment as well as plasma concentrations of IGF-I and leptin in selected samples. On d 0, 63, 133, and 189, heifers were evaluated for intramuscular marbling, LM depth, and backfat thickness via real-time ultrasonography. No treatment effects were detected (P = 0.27) for heifer ADG (0.49 vs. 0.51 kg/d for control and BST heifers, respectively; SEM = 0.02). Mean backfat thickness was lesser (P < 0.01) in BST heifers compared with control cohorts (3.56 vs. 3.92 mm, respectively; SEM = 0.08). Heifers receiving BST had greater plasma IGF-I concentrations compared with control cohorts 7 d after treatment administration (treatment × day interaction; P < 0.01). Mean plasma leptin concentrations were lesser (P = 0.05) in BST heifers compared with control cohorts (1.82 vs. 2.03 ng/mL, respectively; SEM = 0.07). Onset of puberty was hastened in BST heifers compared with control cohorts (treatment × day interaction; P = 0.04). In summary, a greater proportion of BST heifers reached puberty during the experiment compared with control cohorts, despite lesser plasma leptin concentrations, backfat thickness, and similar ADG. Hence, circulating IGF-I was positively associated with hastened puberty attainment independently of growth rate, circulating leptin concentrations, and body fat content of replacement beef heifers.


Bioabsorbable polymeric material coils for embolization of intracranial aneurysms: a preliminary experimental study.
A new embolic agent, bioabsorbable polymeric material (BPM), was incorporated into Guglielmi detachable coils (GDCs) to improve long-term anatomical results in the endovascular treatment of intracranial aneurysms. The authors investigated whether BPM-mounted GDCs (BPM/GDCs) accelerated the histopathological transformation of unorganized blood clot into fibrous connective tissue in experimental aneurysms created in swine. Twenty-four experimental aneurysms were created in 12 swine. In each animal, one aneurysm was embolized using BPM/GDCs and the other aneurysm was embolized using standard GDCs. Comparative angiographic and histopathological data were analyzed at 2 weeks and 3 months postembolization. At 14 days postembolization, angiograms revealed evidence of neck neointima in six of eight aneurysms treated with BPM/GDCs compared with zero of eight aneurysms treated with standard GDCs (p < 0.05). At 3 months postembolization, angiograms demonstrated that four of four aneurysms treated with BPM/GDC were smaller and had neck neointima compared with zero of four aneurysms treated with standard GDCs (p = 0.05). At 14 days, histological analysis of aneurysm healing favored BPM/GDC treatment (all p < 0.05): the grade of cellular reaction around the coils was 3 +/- 0.9 (mean +/- standard deviation) for aneurysms treated using BPM/GDCs compared with 1.6 +/- 0.7 for aneurysms treated using GDCs alone; the percentage of unorganized thrombus was 16 +/- 12% compared with 37 +/- 15%, and the neck neointima thickness was 0.65 +/- 0.26 mm compared with 0.24 +/- 0.21 mm, respectively. At 3 months postembolization, only neck neointima thickness was significantly different (p < 0.05): 0.73 +/- 0.37 mm in aneurysms filled with BPM/GDCs compared with 0.16 +/- 0.14 mm in aneurysms filled with standard GDCs. In experimental aneurysms in swine, BPM/GDCs accelerated aneurysm fibrosis and intensified neck neointima formation without causing parent artery stenosis or thrombosis. The use of BPM/GDCs may improve long-term anatomical outcomes by decreasing aneurysm recanalization due to stronger in situ anchoring of coils by organized fibrous tissue. The retraction of this scar tissue may also decrease the size of aneurysms and clinical manifestations of mass effect observed in large or giant aneurysms.


Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism.
1. Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS. 2. The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. 3. The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p = 0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p = 0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud's syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p = 0.037, p = 0.042, p = 0.039 and p = 0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p = 0.017). 4. The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.


Exosomes derived from platelet-rich plasma administration in site mediate cartilage protection in subtalar osteoarthritis.
Subtalar osteoarthritis (STOA) is often secondary to chronic ankle sprains, which seriously affects the quality of life of patients. Due to its etiology and pathogenesis was not studied equivocally yet, there is currently a lack of effective conservative treatments. Although they have been used for tissue repair, platelet-rich plasma-derived exosomes (PRP-Exo) have the disadvantage of low retention and short-lived therapeutic effects. This study aimed to determine whether incorporation of PRP-Exo in thermosensitive hydrogel (Gel) increased their retention in the joint and thereby playing a therapeutic role on STOA due to chronic mechanical instability established by transecting lateral ligaments (anterior talofibular ligament (ATFL)/calcaneal fibular ligament (CFL)). PRP-Exo incorporated Gel (Exo-Gel) system, composed of Poloxamer-407 and 188 mixture-based thermoresponsive hydrogel matrix in an optimal ratio, was determined by its release ability of Exo and rheology of Gel response to different temperature. The biological activity of Exo-Gel was evaluated in vitro, and the therapeutic effect of Exo-Gel on STOA was evaluated in vivo. Exo released from Exo-Gel continuously for 28 days could promote the proliferation and migration of mouse bone mesenchymal stem cells (mBMSCs) and chondrocytes, at the same time enhance the chondrogenic differentiation of mBMSCs, and inhibit inflammation-induced chondrocyte degeneration. In vivo experiments confirmed that Exo-Gel increased the local retention of Exo, inhibited the apoptosis and hypertrophy of chondrocytes, enhanced their proliferation, and potentially played the role in stem cell recruitment to delay the development of STOA. Thus, Delivery of PRP-Exo incorporated in thermosensitive Gel provides a novel approach of cell-free therapy and has therapeutic effect on STOA.


Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination.
The 18 kDa translocator protein (TSPO) is a target for development of diagnostic imaging agents for glioblastoma and neuroinflammation. Clinical translation of TSPO imaging agents has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Disclosed brain-permeant second-generation TSPO ligands bind TSPO A147T with reduced affinity compared to the wild type protein (TSPO WT). Efforts to develop a TSPO ligand that binds TSPO WT and TSPO A147T with similarly high affinity have been hampered by a lack of knowledge about how ligand structure differentially influences interaction with the two forms of TSPO. To gain insight, we have established human embryonic kidney cell lines stably over-expressing human TSPO WT and TSPO A147T, and tested how modifications of a novel N-alkylated carbazole scaffold influence affinity to both TSPO isoforms. Most of the new analogues developed in this study showed high affinity to TSPO WT and a 5-6-fold lower affinity to TSPO A147T. Addition of electron-withdrawing substituents yielded analogues with highest affinity for TSPO A147T without decreasing affinity for TSPO WT. This knowledge can be used to inform further development of non-discriminating TSPO ligands for use as diagnostic markers for glioblastoma and neuroinflammation irrespective of rs6971.


Characteristics and gel properties of gelatin from goat skin as affected by pretreatments using sodium sulfate and hydrogen peroxide.
Goat skin can be used as an alternative raw material for gelatin production, in which pretreatment conditions can determine the characteristics or properties of the resulting gelatin. The present study aimed to investigate the effect of pretreatment using sodium sulfate (Na2SO4) and hydrogen peroxide (H2O2) on properties of goat skin gelatin. Pretreatment of skin using Na2SO4 (0-1 mol L(-1)) increased the yield of gelatin in a concentration-dependent manner. When skins with prior Na2SO4 treatment were bleached using H2O2 (0-2 mol L(-1)), the resulting gelatin showed higher yield and gel strength than those without prior Na2SO4 treatment. All gelatins had α-chain as a major component, followed by β-chain. The degradation induced by H2O2 was lower in gelatin with prior Na2SO4 treatment. L* values increased with increasing H2O2 concentrations (P < 0.05) due to the bleaching effect of H2O2. With Na2SO4 and H2O2 pretreatments, gelatin gel had a finer and more ordered microstructure. Gelatin had an imino acid content of 217 residues/1000 residues with gelling and melting temperature of 22.49 and 32.28 °C, respectively. The optimal pretreatment conditions for gelatin extraction from goat skin included soaking the skin in 0.75 mol L(-1) NaOH, followed by treatment using 0.75 mol L(-1) Na2SO4 and subsequent bleaching with 2 mol L(-1) H2O2. This resulted in gelatin with superior quality to the untreated counterpart.


Paralemmin-3 contributes to lipopolysaccharide-induced inflammatory response and is involved in lipopolysaccharide-Toll-like receptor-4 signaling in alveolar macrophages.
Alveolar macrophages (AMs) are the first line of defense against foreign stimulation in alveoli, and they participate in inflammatory responses during acute lung injury (ALI). Previous studies indicated that paralemmin-3 (PALM3) expression is induced by lipopolysaccharides (LPS) and may be involved in LPS-Toll-like receptor 4 (TLR4) signaling in alveolar epithelial cells. The aim of the present study was to investigate the effect of PALM3 on LPS-induced inflammation and its underlying mechanisms in rat AMs. For this purpose, the authors detected the expression of PALM3 in AMs by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting following LPS stimulation. Following this, a recombinant adenovirus expressing short hairpin RNA (shRNA) for PALM3 was constructed, as well as a recombinant adenovirus carrying the rat PALM3 gene to modulate the expression of PALM3 in rat AMs. At 48 h after transfection, the PALM3 expression in AMs was detected by RT-qPCR and western blotting. The levels of several cytokines and the activity of nuclear factor-κB and interferon regulatory factor 3 in AMs were measured after LPS stimulation. The localization of PALM3 and LPS-TLR4 signaling adaptor molecules in AMs was analyzed by confocal microscopy, and the physical interactions of PALM3 with these adaptors were assessed by co-immunoprecipitation assays. LPS induced PALM3 expression in AMs and that PALM3 expression promoted the LPS-induced inflammatory response, while PALM3 downregulation suppressed the LPS-induced inflammatory response in AMs. In addition, the results demonstrated that PALM3 could interact with TLR4, myeloid differentiation factor 88, interleukin (IL)-1 receptor associated kinase-1, tumor necrosis factor receptor associated factor-6, and Toll-IL-1 receptor containing adapter molecule-2 in AMs after LPS stimulation. These results suggested that PALM3 contributes to the LPS-induced inflammatory response and participates in LPS-TLR4 signaling in AMs. These data may provide the basis for the development of novel targeted therapeutic strategies of treating ALI.


Retinal detachment secondary to branch vein occlusion: Part I.
Eight patients with retinal detachment secondary to branch vein occlusion were studied. Retinal detachment secondary to branch vein occlusion occurs when the vein occlusion is severe and there is marked capillary nonperfusion and leakage. The detachment is limited to the area of the occluded vein and does not extend beyond the equator. Usually the detachment is shallow; however, it can be bullous as demonstrated in 3 of our patients. Fluorescein angiography revealed the typical findings associated with branch vein occlusion, in addition to late pooling of the dye into the fluid in the subretinal space. In each of the 6 cases treated by laser photocoagulation, reattachment of the retina occurred. The disease is discussed from the standpoint of ocular findings, fluorescein angiography, diagnosis and differential diagnosis, course, treatment, and prognosis.


Narrative review: tetanus-a health threat after natural disasters in developing countries.
Tetanus is an expected complication when disasters strike in developing countries, where tetanus immunization coverage is often low or nonexistent. Collapsing structures and swirling debris inflict numerous crush injuries, fractures, and serious wounds. Clostridium tetani infects wounds contaminated with dirt, feces, or saliva and releases neurotoxins that may cause fatal disease. Clusters of infections have recently occurred after tsunamis and earthquakes in Indonesia, Kashmir, and Haiti. The emergency response to clusters of tetanus infections in developing countries after a natural disaster requires a multidisciplinary approach in the absence of an intensive care unit, readily available resources, and a functioning cold-chain system. It is essential that injured people receive immediate surgical and medical care of contaminated, open wounds with immunization and immunoglobulin therapy. Successful treatment of tetanus depends on prompt diagnosis of clinical tetanus, treatment to ensure neutralization of circulating toxin and elimination of C. tetani infection, control of spasms and convulsions, maintenance of the airway, and management of respiratory failure and autonomic dysfunction.


Sex Differences in Adolescent Anorexia and Bulimia Nervosa: Beyond the Signs and Symptoms.
We review research related to sex differences in eating disorders (EDs) in adolescents. Prior work has explored clinical differences; thus, we examine literature in areas identified as playing an etiological or maintenance role in EDs including: genetics, hormones, neurocognitive inefficiencies, and reward circuitry. Sex steroids appear to a play role in the unmasking of genetic risk for development of EDs and puberty may be a heightened period of risk for females. While neurocognitive differences have been well studied in adults with ED, research with adolescents has been less conclusive. Recent work suggests that neural circuitry involved in reward and punishment may play role in development and maintenance of EDs in females. Males are underrepresented in these areas of research. Given known sex differences in healthy adolescents, it is likely there are sex differences in the putative biological etiology/maintenance of EDs. Males should be included in future research.


[Clones of the lymphoblastoid line RPMI-6410t requiring an exogenous growth factor].
It was earlier established that the RPMI-6410t cells, obtained from a patient with acute myeloblastemia, synthesized a growth factor which maintains their proliferation and had a specific receptor for this factor on their surface. The use of a medium conditioned by the 6410t cells made it possible to define conditions in which practically 100% efficiency cloning of these cells is attained by the method of limiting dilutions. In the present work, this method of cloning was applied to obtain from the 6410t strain clones which are characterized by a requirement for an exogenous growth factor. These clones, like the 6410t cells, have on their surface specific receptors but, unlike the parental cells, do not synthesize the growth factor and do not form colonies in soft agar, i. e. lose one of the features of malignancy. These facts agree with the published data according to which the proliferation of normal cells is regulated by exogenous growth factors and confirm a suggestion put forward in our previous work that the endocrine regulation of cell growth is one of the mechanisms of malignancy.


Patient race/ethnicity and quality of patient-physician communication during medical visits.
We examined the association between patient race/ethnicity and patient-physician communication during medical visits. We used audiotape and questionnaire data collected in 1998 and 2002 to determine whether the quality of medical-visit communication differs among African American versus White patients. We analyzed data from 458 African American and White patients who visited 61 physicians in the Baltimore, Md-Washington, DC-Northern Virginia metropolitan area. Outcome measures that assessed the communication process, patient-centeredness, and emotional tone (affect) of the medical visit were derived from audiotapes coded by independent raters. Physicians were 23% more verbally dominant and engaged in 33% less patient-centered communication with African American patients than with White patients. Furthermore, both African American patients and their physicians exhibited lower levels of positive affect than White patients and their physicians did. Patient-physician communication during medical visits differs among African American versus White patients. Interventions that increase physicians' patient-centeredness and awareness of affective cues with African Americans patients and that activate African American patients to participate in their health care are important strategies for addressing racial/ethnic disparities in health care.


A comparison of three systems for performing single-photon emission tomography.
A comparison is made between the performance of three transverse axial single-photon emission tomographic machines, namely a rotating gamma-camera and two different scanning systems. Each system has been evaluation in terms of the spatial resolution, sensitivity and efficiency. The functional dependence of the volume sensitivity on the size of the emitting object has been derived using a theoretical model of the photon emission, attenuation and detection. The model is shown to predict this size dependence well and is consistent with the experimental observations.


Electromyographic activity in the immobilized shoulder girdle musculature during contralateral upper limb movements.
The purpose of this study was to quantify electromyographic (EMG) activity in the immobilized shoulder girdle musculature at rest and during a battery of contralateral upper limb activities. Six asymptomatic men, aged 22 to 33 years, volunteered to participate. Fine-wire (supraspinatus, infraspinatus) and surface (deltoids, trapezii, biceps, serratus anterior) electrodes recorded the mean peak normalized (percent maximal voluntary contraction [%MVC]) EMG activity from each immobilized muscle at rest and during slow, fast, and incrementally resisted contralateral upper limb motions (5, 15, and 25 lb). EMG activity in all muscles was low during quiet immobilized standing (<1.5% maximal voluntary contraction [MVC]). During slow contralateral upper limb motions, activity ranged from 0.7% to 51.6% MVC (highest in trapezii) and was less than 15% MVC in the supraspinatus, infraspinatus, and anterior deltoid. Bimanual jar opening increased biceps activity from 7.8% to 16.1% MVC. During fast contralateral upper limb motions, peak infraspinatus activity increased to 56.7% during a fast straightforward reach. Supraspinatus activity was relatively high during all resisted backward-pulling motions (25.2%-32.1% MVC), whereas resisted forward reaching produced relatively little activity in the anterior deltoid, supraspinatus, infraspinatus, or biceps. Several slow and fast motions produced high trapezius activity (>45% MVC) with low supraspinatus, biceps, and anterior deltoid activities (<10% MVC). Our findings suggest that (1) immobilized shoulder girdle muscle EMG activity during quiet standing is negligible in asymptomatic individuals; (2) contralateral upper limb motions at self-selected speeds are not likely to be harmful to healing tissues; (3) during early healing periods, patients with biceps-labral injury should minimize bimanual activities, those with supraspinatus injury should avoid backward-pulling motions, and those with infraspinatus injury should avoid fast straightforward reaches; and (4) cross-body, straightforward, or downward reaches at either a slow or fast speed may be appropriately prescribed as rehabilitative exercises that can be initiated while the shoulder remains immobilized.


Selective and hyperactive uptake of foreign DNA by adaptive immune systems of an archaeon via two distinct mechanisms.
Central to the disparate adaptive immune systems of archaea and bacteria are clustered regularly interspaced short palindromic repeats (CRISPR). The spacer regions derive from invading genetic elements and, via RNA intermediates and associated proteins, target and cleave nucleic acids of the invader. Here we demonstrate the hyperactive uptake of hundreds of unique spacers within CRISPR loci associated with type I and IIIB immune systems of a hyperthermophilic archaeon. Infection with an environmental virus mixture resulted in the exclusive uptake of protospacers from a co-infecting putative conjugative plasmid. Spacer uptake occurred by two distinct mechanisms in only one of two CRISPR loci subfamilies present. In two loci, insertions, often multiple, occurred adjacent to the leader while in a third locus single spacers were incorporated throughout the array. Protospacer DNAs were excised from the invading genetic element immediately after CCN motifs, on either strand, with the secondary cut apparently produced by a ruler mechanism. Over a 10-week period, there was a gradual decrease in the number of wild-type cells present in the culture but the virus and putative conjugative plasmid were still propagating. The results underline the complex dynamics of CRISPR-based immune systems within a population infected with genetic elements.


Oestrous cycles, oestrus and ovulation of the zebu in the Mexican tropics.
The length of the oestrous cycle, oestrus and the time of ovulation were assessed in 20 adult, non-lactating zebu cows over 53 consecutive days of observation. Oestrus was detected at 30-minute observation periods daily. Peripheral blood samples were collected twice weekly for progesterone determination. To measure the length of the synchronised oestrous period, 10 cows with a palpable corpus luteum were injected with prostaglandin F2 alpha and continuously observed for 96 hours. Two cows at a time were exposed to a bull with a deviated penis for five minutes every three hours during this period. To measure the length of the natural oestrus, eight of the 10 cows from the previous experiment were continuously observed from day 21 after prostaglandin injection. They were kept during the daytime in a field with two teaser bulls and at night in a cattle pen where they were exposed to a teaser bull every three hours. Oestrus was considered to occur when the cow stood to be mounted. Ovulation was detected by rectal palpation every three hours in five cows starting six hours after receptivity commenced until ovulation took place. The length of the oestrous cycle was 20.1 +/- 1.9 days; 20 per cent of the animals did not show oestrus although their progesterone levels demonstrated that they were cycling. Two cows showed oestrus following prostaglandin F2 alpha injection although they were cycling as revealed by serum progesterone. Five animals showed behavioural oestrus around 118 hours after injection and following their release. Oestrus duration was 15.3 +/- 6.0 hours and ovulation occurred 28.2 +/- 5.0 hours after the start of the period of sexual receptivity.


Neonatal tetanus in Turkey; what has changed in the last decade?
Neonatal tetanus (NT) is still considered as one of the major causes of neonatal death in many developing countries. The aim of the present study was to assess the characteristics of sixty-seven infants with the diagnosis of neonatal tetanus followed-up in the Pediatric Infectious Diseases Ward of Dicle University Hospital, Diyarbakir, between 1991 and 2006, and to draw attention to factors that may contribute (or may have contributed) to the elimination of the disease in Diyarbakir. The data of sixty-seven infants whose epidemiological and clinical findings were compatible with neonatal tetanus were reviewed. Patients were stratified into two groups according to whether they survived or not to assess the effect of certain factors in the prognosis. Factors having a contribution to the higher rate of tetanus among newborn infants were discussed. A total of 55 cases of NT had been hospitalized between 1991 and 1996 whereas only 12 patients admitted in the last decade. All of the infants had been delivered at home by untrained traditional birth attendants (TBA), and none of the mothers had been immunized with tetanus toxoid during her pregnancy. Twenty-eight (41.8%) of the infants died during their follow-up. Lower birth weight, younger age at onset of symptoms and at the time admission, the presence of opisthotonus, risus sardonicus and were associated with a higher mortality rate. Although the number of neonatal tetanus cases admitted to our clinic in recent years is lower than in the last decade efforts including appropriate health education of the masses, ensurement of access to antenatal sevices and increasing the rate of tetanus immunization among mothers still should be made in our region to achieve the goal of neonatal tetanus elimination.


A Review of Adsorbents for Heavy Metal Decontamination: Growing Approach to Wastewater Treatment.
Heavy metal is released from many industries into water. Before the industrial wastewater is discharged, the contamination level should be reduced to meet the recommended level as prescribed by the local laws of a country. They may be poisonous or cancerous in origin. Their presence does not only damage people, but also animals and vegetation because of their mobility, toxicity, and non-biodegradability into aquatic ecosystems. The review comprehensively discusses the progress made by various adsorbents such as natural materials, synthetic, agricultural, biopolymers, and commercial for extraction of the metal ions such as Ni2+, Cu2+, Pb2+, Cd2+, As2+ and Zn2+ along with their adsorption mechanisms. The adsorption isotherm indicates the relation between the amount adsorbed by the adsorbent and the concentration. The Freundlich isotherm explains the effective physical adsorption of the solute particle from the solution on the adsorbent and Langmuir isotherm gives an idea about the effect of various factors on the adsorption process. The adsorption kinetics data provide valuable insights into the reaction pathways, the mechanism of the sorption reaction, and solute uptake. The pseudo-first-order and pseudo-second-order models were applied to describe the sorption kinetics. The presented information can be used for the development of bio-based water treatment strategies.


Impact of patients' preexisting metabolic risk factors on the choice of antipsychotics by office-based physicians.
This study examined the association between patients' preexisting metabolic risk factors and the physician's choice of antipsychotic agent based on its propensity to cause metabolic side effects. Data were from the 2005-2007 National Ambulatory Medical Care Survey (NAMCS); 1,898 office-based visits were identified during which prescriptions of antipsychotics were mentioned. Antipsychotics were classified as having high, medium, or low risk based on their propensity to cause metabolic abnormalities; a separate category for antipsychotic polypharmacy was specified for visits during which multiple antipsychotics were mentioned. Patients' preexisting metabolic risk was assessed by the presence of diabetes, hyperlipidemia, obesity, or hypertension. With controls for other patient and physician characteristics, multinomial logit regression models were applied to examine the association between the level of metabolic risk of the prescribed antipsychotic agents and the patient's baseline metabolic risk. Compared with patients of normal weight or who were underweight according to body mass index, obese patients were less likely to receive antipsychotics with high risk (relative risk ratio [RRR]=.14, 95% confidence interval [CI]=.05-.37) or medium risk (RRR=.39, CI=.19-.78) of causing metabolic abnormalities. However, having preexisting metabolic conditions, such as diabetes, hyperlipidemia, or hypertension, had little effect on physicians' choice of antipsychotics with regard to metabolic risk properties. Patients' weight appeared to be the key consideration in providers' decision to order or continue antipsychotics according to the associated metabolic risk. Further studies are warranted to understand the factors that determine the choice of antipsychotics for patients with preexisting metabolic conditions, such as diabetes, hyperlipidemia, or hypertension.


Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model.
Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.


Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia.
Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1 (+/-), Nrg1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.


Myeloma cells suppress osteoblasts through sclerostin secretion.
Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co-cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of β-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor κ-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM.


[An optimum dose-finding study of HR810 (CPR) in chronic respiratory tract infections].
In order to determine the optimal dose of cefpirome sulfate (HR810, CPR) against respiratory tract infections (RTI), an optimal dose-finding study was conducted on cases of chronic RTI, and the clinical properties of the drug were compared with those of ceftazidime (CAZ). Inpatients with chronic RTI were randomly assigned to 3 groups: an HR 0.5 g group, receiving 0.5 g X 2/day of CPR an HR 1.0 g group, receiving 1.0 X 2/day of CPR and a CAZ group, receiving 1.0 g X 2/day of CAZ. As a rule, the drugs were administered by intravenous drip infusion for 14 days, after which period clinical efficacy, bacteriological response, safety, and utility were investigated. Of the total 121 cases, 106 were subject to analysis of clinical efficacy, including 38 cases in the HR 0.5 g group, 32 in the HR 1.0 g group, and 36 in the CAZ group. Efficacy rates in the assessment by the committee were 84.2% for the HR 0.5 g group, 75.0% for the HR 1.0 g group, and 86.1% for the CAZ group, without any significant difference between the 3 groups. The bacterial elimination rates were 73.9%, 75.0% m and 88.5%, respectively, without any significant difference between the 3 groups. Associated reactions were noted in 2 of 36 cases in the HR 1.0 g group (eruption and diarrhea), but not in the other 2 groups. The incidence of abnormal clinical laboratory findings was 23.1% in the HR 0.5 g group, 22.2% in the HR 1.0 g group, and 22.5% in the CAZ group, without any significant difference between the 3 groups. Utility rates were 84.2% for the HR 0.5 g group, 74.2% for the HR 1.0 g group, and 86.1% for the CAZ group, without any significant difference between the 3 groups. The HR 0.5 g and 1.0 groups showed no difference in clinical efficacy, bacteriological response, safety, and utility against RTI, and the results of both groups were about equal to those of the CAZ group.


The Comprehensive Cancer Care Network of Romagna: the opportunities generated by the OECI accreditation program.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS is a public-private partnership among 3 public sector bodies and 6 private nonprofit organizations and represents the hub of the Oncology Network of Romagna, which provides a wide range of services for the population ranging from primary prevention to palliative care. In 2012, IRST took part in the ministerial research project of the Organisation of European Cancer Institutes (OECI) accreditation program for Comprehensive Cancer Centers. The self-assessment period lasted 6 months and was coordinated by a multidisciplinary project team headed by a project leader. Each project team member coordinated a subgroup whose task was to analyze specific standards from qualitative and quantitative questionnaires. During the self-assessment period for the areas in which IRST did not meet OECI requirements, the project team outlined several improvement plans. At the end of the self-assessment period, the OECI Accreditation & Designation Board approved the documentation presented by IRST and a peer review visit was scheduled. The OECI report suggested establishing a more specific and stronger centralized management and leadership of all the oncologic activities carried out in other centers. In accordance with these suggestions, IRST and the Local Health Authority of Romagna laid the foundations for a new management model for the Oncology Network of Romagna: the Comprehensive Cancer Care Network (CCCN). The CCCN is a territory-oriented model (population approach) based on a principle of cooperation and collaboration among the network nodes.


Lipoprotein modification and atherosclerosis in aging.
The development of extensive atherosclerosis of major arteries of the heart, brain, and lower extremities is a particularly frequent problem in elderly individuals and is responsible for the majority of the cardiovascular morbidity and mortality in this population. Although the frequency and severity of this problem is well recognized, there has been relatively little investigation of the effects of aging on the development of atherosclerosis. Work by a number of investigators over the last 10-15 years has demonstrated that modifications of lipoproteins, resulting from oxidative stress, glycoxidation, formation of AGE, or other processes may play an important role in atherosclerosis. As described in this review, the aging process may enhance lipoprotein modification and atherosclerosis in several ways. Conditions such as hypertension, diabetes, and menopause all increase in frequency with advancing age and may contribute both directly and indirectly to lipoprotein modification and vascular injury.Additionally, in some studies of older animals and humans, there seems to be evidence for greater in vivo oxidative stress. Whether this is a specific consequence of aging and associated medical conditions, or related to differences in dietary fatty acid or antioxidant content or other lifestyle differences is currently unknown. One important consequence of this may be enhanced susceptibility of lipoproteins to oxidation. Additional study of lipoprotein modifications associated with aging is clearly needed, and may provide new insight and solutions to the common problem of atherosclerosis in the elderly.


Advance care planning in chronic obstructive pulmonary disease: barriers and opportunities.
Experts in palliative care have increasingly recognized the global epidemic of chronic obstructive pulmonary disease (COPD), its astonishing rise in prevalence, and its profound impact on patients' quality of life and functional capacity. Unfortunately, patients with COPD receive less advance care planning (ACP) and palliative care as compared with patients with other diseases with similar prognoses. This review highlights recent advances in identifying barriers to ACP and opportunities for providing more effective and timely palliative care. Patients with COPD identify dyspnea as their most disabling symptom. Disease-directed care provides only partial relief from dyspnea, which eventually becomes refractory and requires transition to palliative care. Throughout all stages of COPD, however, integrating palliative care with disease-directed treatments improves patients' well being and functional capacities. Observational studies have identified multiple barriers to effective ACP. Because of the unique disease trajectory of COPD, professional groups have proposed new models for palliative care specifically tailored to COPD. Patients with COPD benefit from better integration of palliative and disease-specific care throughout the course of their disease from diagnosis to death. Pulmonary rehabilitation may provide a platform for coordinating integrated care. Health agencies will increasingly expect better coordination of services for patients with this progressive, disabling, and eventually terminal disease.


Leishmania antigens activated CD4+ T cells expressing CD200R receptors are the prime IL-10 producing phenotype and an important determinant of visceral leishmaniasis pathogenesis.
The excessive production of IL-10, an anti-inflammatory cytokine, by Leishmania antigen-activated T cells is supposed to be a key player in the onset and progression of visceral leishmaniasis (VL). The IL-10-producing sources in VL remain unidentified and uncharacterized. In this study, we reveal that antigen-activated CD4+ T cells, i.e., CD44+CD4+ T cells expressing CD200R receptors, are the prime IL-10-producing phenotypes in Leishmania donovani infection-induced pathogenesis. These phenotypes are separate from CD25+Foxp3+CD4+ T regulatory cells, which are classical IL-10-producing phenotypes. In order to ascertain the role of CD200R and CD25 receptors in IL-10 overexpression-associated VL pathogenesis, we abrogated CD200R and CD25 receptor-mediated signaling in the infected mice. The splenic load of parasites and the size of the liver and spleen were significantly reduced in CD200-blocked mice as compared to CD25-blocked mice. Further, the CD200 blocking polarized CD4+ T cells to pro-inflammatory cytokines-producing phenotypes, as we observed a higher frequency of IFN-γ, TNF-α, and IL-12 positive cells as compared to controls including the CD25 blocking. Our findings suggest that in L. donovani infection-induced pathogenesis the expression of CD200R on antigen-activated T cells helps them to acquire IL-10-producing abilities as part of its one of the survival strategies. However, more studies would be warranted to better understand CD200R receptors role in VL pathogenesis and to develop the next generation of therapeutic and prophylactic control measures.


Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases.
Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathologic functions; they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis, and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs-particularly the triad ANGPTL3, 4, and 8-have an established role in lipid metabolism through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTL expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed, and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the current review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTL family in the cardiovascular system, their contribution to CVD, and the therapeutic potential of manipulating some of them.


Origin and tailoring of the antiferromagnetic domain structure in α-Fe2O3 thin films unraveled by statistical analysis of dichroic spectromicroscopy (x-ray photoemission electron microscopy) images.
The magnetic microstructure and domain wall distribution of antiferromagnetic α-Fe2O3 epitaxial layers is determined by statistical image analyses. Using dichroic spectromicroscopy images, we demonstrate that the domain structure is statistically invariant with thickness and that the antiferromagnetic domain structure of the thin films is inherited from the ferrimagnetic precursor layer one, even after complete transformation into antiferromagnetic α-Fe2O3. We show that modifying the magnetic domain structure of the precursor layer is a genuine way to tune the magnetic domain structure and domain walls of the antiferromagnetic layers.


Better Visual Outcome by Intraocular Lens Ejection in Geriatric Patients with Ruptured Ocular Injuries.
Ocular trauma is one of the leading causes of visual impairment worldwide. Because of the popularity of cataract surgeries, aged individuals with ocular trauma commonly have a surgical wound in their eyes. The purpose of this study was to evaluate the visual outcome of cases that were coincident with intraocular lens (IOL) ejection in the eyes with ruptured open-globe ocular injuries. Consecutive patients with open-globe ocular injuries were first reviewed. Patients' characteristics, corrected distance visual acuities (CDVAs) over 3 years after the trauma, causes of injuries, traumatic wound patterns, and coexistence of retinal detachment were examined. The relationships between poor CDVA and the other factors, including the complications of crystalline lens and IOL ejection, were examined. A total of 105 eyes/patients [43 eyes with rupture, 33 with penetrating, 28 with intraocular foreign body (IOFB), and 1 with perforating injuries] were included. Rupture injuries were common in aged patients and were mostly caused by falls, whereas penetrating and IOFB injuries were common in young male patients. CDVAs of the eyes with rupture injuries were significantly worse than those of the eyes with penetrating or IOFB injuries. CDVA from more than 50% of the ruptured eyes resulted in no light perception or light perception to 20/500. CDVA of the ruptured eyes complicated by crystalline lens ejection was significantly worse than that of those complicated by IOL ejection. The wounds of the ruptured eyes complicated by IOL ejection were mainly located at the superior corneoscleral limbus, whereas those of the eyes complicated by crystalline lens ejection were located at the posterior sclera. There were significant correlations between poor CDVA and retinal detachment and crystalline lens ejection. These results proposed a new trend in the ocular injuries that commonly occur in aged patients; history of cataract surgery might affect the final visual outcome after open-globe ocular injuries.


Vaginal flora in women undergoing hysterectomy with antibiotic prophylaxis.
One objection occasionally raised against the use of routine antibiotic prophylaxis for pelvic surgery is the concern that the flora of treated patients will be altered, thus favoring the emergence of different, potentially more resistant organisms. This report summarizes experience with 100 women undergoing elective hysterectomy who were subjected to short-term cefazolin, penicillin, or placebo prophylaxis. The changes in preoperative versus postoperative flora were similar among antibiotic-treated and placebo-treated groups. In general, postoperative isolation of gram-negative aerobes and Bacteroides sp increased, and isolation of gram-positive aerobes (except group D streptococci) decreased in antibiotic-treated and placebo-treated groups. The clinical implications of these findings are discussed.


Heat Conduction Performance over a Poly(ethylene glycol) Self-Assembled Monolayer/Water Interface: A Molecular Dynamics Study.
This study examined the interfacial heat condition between a poly(ethylene glycol) (PEG) self-assembled monolayer (SAM) and water using molecular dynamics simulation. It was found that the PEG SAM has higher thermal boundary conductance (TBC) than the traditionally used alkane-based SAM. The TBC conditionally varied with the length of the PEG molecules, where interfacial thermal resistance was a key factor. Our results reveal that the TBC of the PEG SAM/water interface is greatly influenced by its structural properties rather than the matching of vibrational properties between the SAM terminal and water. The structural analysis shows that the water structure around the terminal oxygen atom of the SAM plays a vital role in controlling the TBC. In this study, the concept of free volume has also been exploited, and the result suggests that the reduction of the free volume fraction accommodates a higher TBC. The model was precisely validated against experimental data by calculating the tilt angle and dihedral angle of the PEG SAM, the persistence length of the PEG chain in the water medium, and the sulfur position of the PEG SAM headgroup on the gold surface using quantitative scanning transmission electron microscopy image simulation.


Ethics and society review: Ethics reflection as a precondition to research funding.
Researchers in areas as diverse as computer science and political science must increasingly navigate the possible risks of their research to society. However, the history of medical experiments on vulnerable individuals influenced many research ethics reviews to focus exclusively on risks to human subjects rather than risks to human society. We describe an Ethics and Society Review board (ESR), which fills this moral gap by facilitating ethical and societal reflection as a requirement to access grant funding: Researchers cannot receive grant funding from participating programs until the researchers complete the ESR process for their proposal. Researchers author an initial statement describing their proposed research's risks to society, subgroups within society, and globally and commit to mitigation strategies for these risks. An interdisciplinary faculty panel iterates with the researchers to refine these risks and mitigation strategies. We describe a mixed-method evaluation of the ESR over 1 y, in partnership with a large artificial intelligence grant program at our university. Surveys and interviews of researchers who interacted with the ESR found 100% (95% CI: 87 to 100%) were willing to continue submitting future projects to the ESR, and 58% (95% CI: 37 to 77%) felt that it had influenced the design of their research project. The ESR panel most commonly identified issues of harms to minority groups, inclusion of diverse stakeholders in the research plan, dual use, and representation in datasets. These principles, paired with possible mitigation strategies, offer scaffolding for future research designs.


[Prevention of stress injury to the heart and its hypoxic contracture by using the natural antioxidant alpha-tocopherol].
Experiments on the isolated hearts of rats, subjected to emotional and painful stress have shown it to potentiate the ischaemic and hypoxic damage of the heart, evaluated by the loss of CPK enzyme by the myocardium and the degree of hypoxic contracture. Preliminary administration to animals of alpha-tocopherol prevents contractility disorders of the heart provoked by stress and the potentiating effect of stress on the ischaemic damage and the development of hypoxic contracture. alpha-Tocopherol also limits the damaging action of hypoxia on the heart and that of reoxygenation. The data obtained suggest the possibility of alpha-tocopherol use in the treatment of myocardial infarction.


Visual mismatch negativity: the detection of stimulus change.
Mismatch negativity is an event related potential generated by a mechanism which detects stimulus change. Such a mechanism is important to enable attention to be switched to important changes in the environment. The effect has been extensively studied in the auditory modality. The present investigation was designed to establish whether the enhanced negativity in the visual event related potential evoked by deviant stimuli presented infrequently among a sequence of repeated standard stimuli is really associated with the detection of stimulus change. The experiment set out to distinguish effects associated with stimulus change from those related to the physical attributes of the stimuli or to differences in the refractory state of receptors or neurons. The findings support the hypothesis that deviance-related negativity reflects the operation of a change detection mechanism and not the refractory state of elements of the visual system.


Elementary processes of the magnesium ion-dependent adenosine triphosphatase activity of heavy meromyosin. A transient kinetic approach to the study of kinases and adenosine triphosphatases and a colorimetric inorganic phosphate assay in situ.
Transient kinetic studies of Mg(2+)-dependent heavy-meromyosin ATPase (adenosine triphosphatase) were done by monitoring the release of both ADP and P(i) into the reaction medium by using linked assay systems. The release of P(i) was monitored by its quantitative transfer to ADP, with concomitant reduction of NAD(+) in the presence of d-glyceraldehyde 3-phosphate, d-glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase. The dissociation rates of the products, ADP and P(i), from heavy meromyosin were shown to be faster than the rate-controlling process, which occurs after the initial bond cleavage of ATP. The chromophoric ATP analogue, 6-mercapto-9-beta-d-ribofuranosylpurine 5'-triphosphate (thioATP) was used as a substrate and spectral changes associated with a single turnover of heavy meromyosin could be assigned to elementary processes of the mechanism. It was shown that the dissociation rate of thioADP was not the rate-controlling process of the thioATPase, whose catalytic-centre activity was 7.6 times that of the ATPase at pH8. The dissociation rate of ADP from heavy meromyosin was measured by using thioATP as displacing agent and was found to be 2.3s(-1), which is about 50 times the catalytic-centre activity of the ATPase at pH8. Transient kinetic studies with chromophoric adenosine phosphate analogues have general application for kinases and ATPases both in characterizing the chemical states of the intermediates and in delineating the elementary processes of the enzyme mechanism.


Mild cognitive impairment in the general population: occurrence and progression to Alzheimer disease.
Our aims were to 1) detect the occurrence of three mild cognitive impairment (MCI) subtypes in the general population; 2) identify cases of cognitive impairment which are not detected by current operational criteria for MCI and; 3) determine the predictive value of the subtypes for identifying future Alzheimer disease (AD). Three-year prospective study. Population-based Swedish study, the Kungsholmen Project. Three hundred seventy-nine nondemented older adults aged 75-95. Standard plus modified MCI criteria were applied at baseline. In the modified definitions, the requirement for normal general cognition was removed. A category for persons without MCI who had only global cognitive deficits was added. Three-year progression to AD was assessed (DSM-III-R criteria). Occurrence per 100 nondemented persons of MCI-amnestic, MCI-multidomains, and MCI-single-nonmemory was 2.1%, 1.8%, and 7.2%, respectively. When applying modified definitions for MCI-amnestic and MCI-multidomains, the occurrence almost doubled. Seven percent of the sample had impairment on a global cognitive task but performed at normal levels on all other domain-specific tasks. MCI-multidomains showed the highest progression to AD (hazard ratio [HR]: 23.6, 9.3-60.1). MCI-amnestic reached similar predictivity only when using the modified definition (HR: 17.9, 6.8-46.9). Even participants without MCI who had only global deficits had a ninefold risk of AD (HR: 9.1, 2.8-29.4). Two-thirds of MCI-multidomains, but only half of MCI-amnestic progress to AD. The standard MCI criteria failed to identify those people with global cognitive deficits who have, however, a high risk of progressing to AD.


In situ expression of interleukin-10 and interleukin-12 in active human cutaneous leishmaniasis.
Th1-type cellular immune responses (interferon-gamma) play a critical role in protection against Leishmania spp. infection, whereas Th2-type cytokines (interleukin (IL)-4, IL-10) have a counter-protective effect. IL-12, a potent inducer of Th1-type cellular immune responses, may play a pivotal role in the development of a protective response. We found that IL-10 and IL-12 mRNAs were expressed in most lesions of individuals with active cutaneous leishmaniasis. The quantity of IL-12 mRNA was highly variable but correlated strongly with the level of interferon-gamma expression. IL-12 expression also paralleled the expression of IL-10, a potent in vitro suppressor of IL-12 and interferon-gamma production. The more chronic, non-healing lesions generally had higher levels of IL-12 mRNA indicating that the expression of this cytokine alone was not sufficient to induce healing. Although the in situ production of IL-10 did not appear to block IL-12 expression, IL-10 may still promote disease by direct suppression of macrophage activation.


The relationship between prevalent medial meniscal intrasubstance signal changes and incident medial meniscal tears in women over a 1-year period assessed with 3.0 T MRI.
Intrasubstance meniscal signal changes not reaching the articular surface on fast spin echo (FSE) sequences are considered to represent mucoid degeneration on MRI. The aim of this study was to evaluate the association of prevalent intrasubstance signal changes with incident tears of the medial meniscus detected on 3.0 T MRI over a 1-year period. A total of 161 women aged ≥ 40 years participated in a longitudinal 1-year observational study of knee osteoarthritis. MRI (3.0 T) was performed at baseline and 12-month follow-up. The anterior horn, body, and posterior horn of the medial meniscus were scored by two experienced musculoskeletal radiologists using the Boston-Leeds Osteoarthritis Knee Score (BLOKS) system. Four grades were used to describe the meniscal morphology: grade 0 (normal), grade 1 (intrasubstance signal changes not reaching the articular surface), grade 2 (single tears), and grade 3 (complex tears and maceration). Fisher's exact test and the Cochran-Armitage trend test were performed to evaluate whether baseline intrasubstance signal changes (grade 1) predict incident meniscal tears/maceration (grades 2 and/or 3) in the same subregion of the medial meniscus, when compared to subregions without pathology as the reference group (grade 0). Medial meniscal intrasubstance signal changes at baseline did not predict tears at follow-up when evaluating the anterior and posterior horns (left-sided p-values 0.06 and 0.59, respectively). No incident tears were detected in the body. We could not demonstrate an association between prevalent medial meniscal intrasubstance signal changes with incident tears over a 1-year period.


Factors influencing outcome following mild traumatic brain injury in adults.
This study aimed to investigate outcome in adults with mild traumatic brain injury (TBI) at 1 week and 3 months postinjury and to identify factors associated with persisting problems. A total of 84 adults with mild TBI were compared with 53 adults with other minor injuries as controls in terms of postconcussional symptomatology, behavior, and cognitive performance at 1 week and 3 months postinjury. At 1 week postinjury, adults with mild TBI were reporting symptoms, particularly headaches, dizziness, fatigue, visual disturbance, and memory difficulties. They exhibited slowing of information processing on neuropsychological measures, namely the WAIS-R Digit Symbol subtest and the Speed of Comprehension Test. By 3 months postinjury, the symptoms reported at 1 week had largely resolved, and no impairments were evident on neuropsychological measures. However, there was a subgroup of 24% of participants who were still suffering many symptoms, who were highly distressed, and whose lives were still significantly disrupted. These individuals did not have longer posttraumatic amnesia (PTA) duration. They were more likely to have a history of previous head injury, neurological or psychiatric problems, to be students, females, and to have been injured in a motor vehicle accident. The majority were showing significant levels of psychopathology. A range of factors, other than those directly reflecting the severity of injury, appear to be associated with outcome following mild TBI.


Effects of biochar layer position on treatment performance and microbial community in subsurface flow constructed wetlands for removal of cadmium and lead.
Levels of cadmium (Cd) and lead (Pb) correspond to common composition in acid mine wastewater of Hunan Province of China. The removal path of Cd and Pb and the structure of microbial community were investigated by developing constructed wetlands (CWs) with different layer positions of biochar. The biochar as a layer at the bottom of CW (BCW) system exhibited maximum Cd and Pb removal efficiencies of 96.6-98.6% and 97.2-98.9%, respectively. Compared with original soil, BCW increased the relative proportions of Proteobacteria, Firmicutes, Acidobacteriota, Verrucomicrobiota, Desulfobacterota, Armatimonadota, Bacteroidota, Patescibacteria, Basidiomycota (phylum level) and Burkholderia-Caballeronia-Paraburkholderia, Citrifermentans, Chthonomonadales, Cellulomonas, Geothrix, Terracidiphilus, Gallionellaceae, Microbacterium, Vanrija, Apiotrichum, Saitozyma, Fusarium (genus level). The concentrations of Cd and Pb were positively correlated with Verrucomicrobiota, Basidiomycota (phylum level), and Methylacidiphilaceae, Meyerozyma, Vanrija (genus level). This study demonstrates that BCW system can improve removal performance toward Cd and Pb, as well as alter microbial community.


Inflammation and Epilepsy: Preclinical Findings and Potential Clinical Translation.
The lack of treatments which can prevent epilepsy development or improve disease prognosis represents an unmet and urgent clinical need. The development of such drugs requires a deep understanding of the mechanisms underlying disease pathogenesis. In the last decade, preclinical studies in models of acute seizures and of chronic epilepsy highlighted that neuroinflammation arising in brain areas of seizure onset and generalization is a key contributor to neuronal hyper-excitability underlying seizure generation. Microglia and astrocytes are pivotal cells involved in both the induction and perpetuation of the inflammatory response to epileptogenic injuries or seizures; other cell contributors are neurons, cell components of the blood brain barrier and leukocytes. From the clinical standpoint, neuroinflammation is now considered an hallmark of epileptogenic foci in various forms of focal onset pharmacoresistant epilepsies. Moreover, pharmacological studies in animal model with drugs targeting specific inflammatory molecules, and changes in intrinsic seizure susceptibility of transgenic mice with perturbed neuroinflammatory mechanisms, have demonstrated that neuroinflammation is not a bystander phenomenon but has a pathogenic role in seizures, cell loss and neurological co-morbidities. Understanding the role of neuroinflammation in seizure pathogenesis is instrumental for a mechanism-based discovery of selective therapies targeting the epilepsy causes rather than its symptoms, thereby allowing the development of novel disease-modifying treatments. Notably, clinical translation of laboratory findings may take advantage of anti-inflammatory drugs already in medical use for peripheral autoinflammatory or autoimmune disorders. This review reports key preclinical and clinical findings supporting a role for brain inflammation in the pathogenesis of seizures. It also highlights the emerging proof-of-concept studies showing signs of clinical efficacy of target-specific anti-inflammatory interventions in epilepsies of differing etiologies. We will discuss the need for biomarkers and novel clinical trial designs for anti-inflammatory therapies that have a mechanism of action very different than standard antiepileptic drugs.


Irreversible inhibition of TRF2TRFH recruiting functions by a covalent cyclic peptide induces telomeric replication stress in cancer cells.
The TRF2 shelterin component is an essential regulator of telomere homeostasis and genomic stability. Mutations in the TRF2TRFH domain physically impair t-loop formation and prevent the recruitment of several factors that promote efficient telomere replication, causing telomeric DNA damage. Here, we design, synthesize, and biologically test covalent cyclic peptides that irreversibly target the TRF2TRFH domain. We identify APOD53 as our most promising compound, as it consistently induces a telomeric DNA damage response in cancer cell lines. APOD53 forms a covalent adduct with a reactive cysteine residue present in the TRF2TRFH domain and induces phenotypes consistent with TRF2TRFH domain mutants. These include induction of a telomeric DNA damage response, increased telomeric replication stress, and impaired recruitment of RTEL1 and SLX4 to telomeres. We demonstrate that APOD53 impairs cancer cell growth and find that co-treatment with APOD53 can exacerbate telomere replication stress caused by the G4 stabilizer RHPS4 and low dose aphidicolin (APH).


Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety.
A series of 3-methylidene-1H-indol-2(3H)-ones substituted with a 5- or 6-pentafluorosulfanyl group has been synthesized by a Knoevenagel condensation reaction of SF5-substituted oxindoles with a range of aldehydes. The resulting products were characterized by X-ray crystallography studies and were tested for biological activity versus a panel of cell lines and protein kinases. Some exhibited single digit nM activity.


Impact of baseline lipoprotein and C-reactive protein levels on coronary atheroma regression following high-intensity statin therapy.
Guidelines now recommend high-intensity statin therapy in all patients with proven atherosclerotic disease. Yet the impact of baseline lipoprotein and C-reactive protein (CRP) levels on measures of disease regression to this therapy are unknown. The aim of this study was to test the hypothesis that high-intensity statin therapy causes equivalent degrees of coronary atheroma regression irrespective of baseline lipoprotein and CRP levels. In 8 prospective randomized trials using serial coronary intravascular ultrasound, 1,881 patients who maintained or switched to 18- to 24 months of high-intensity statin therapy (rosuvastatin 40 mg or atorvastatin 80 mg) were stratified according to baseline lipoprotein and CRP levels. Changes in coronary percentage atheroma volume (PAV) and total atheroma volume (TAV) were evaluated. High-intensity statin therapy produced significant reductions from baseline in low-density lipoprotein cholesterol by 38.4%, non-high-density lipoprotein (HDL) cholesterol by 33.6%, triglycerides by 13.1%, and CRP by 33.3%, while increasing HDL cholesterol by 11.7% (p <0.001 for all). This was associated with regression of PAV by 0.7% and of TAV by 8.2 mm(3) (p <0.001 for both). No significant differences of changes in PAV and TAV were observed across baseline quintiles of low-density lipoprotein cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, or CRP. Moreover, across all measured lipoproteins and CRP, most patients demonstrated plaque regression (defined as any change from baseline in PAV or TAV <0). In conclusion, high-intensity statin therapy attenuated the natural progression of coronary atherosclerosis in all strata of patients with coronary artery disease irrespective of baseline lipoprotein or CRP levels. These findings provide support for the latest United States guideline recommendations for the broad use of high-intensity statin therapy in all patients with atherosclerosis, regardless of baseline lipid status.


[The incretory function of the pancreas in patients with pulmonary tuberculosis and diabetes mellitus].
Serum C-peptide levels were studied in 88 patients with pulmonary tuberculosis concurrent with diabetes mellitus. The pancreatic incretory function in combined pathology was found to be related both to the type and severity of diabetes mellitus and the severity of tuberculosis. Specific and medicamental intoxication negatively affects residual insulin secretion and the body's insulin-sensitivity. High functional capacity of B-cells of the pancreas and insulin resistance in noninsulin dependent diabetes, on the one hand, and rapid depletion of the insular apparatus in serious chronic tuberculosis, on the other, made it possible to recommend combined hypoglycemic therapy with insulin and oral sugar-lowering drugs to patients with a prolonged severe course of each of the diseases (pulmonary tuberculosis and Type II diabetes) in their combination.


Microglia in the cerebral wall of the human telencephalon at second trimester.
We have recently begun to gain a clearer understanding of the phasing and patterns of colonization of the developing human brain by microglia. In this study we investigated the distribution, morphology and phenotype of microglia specifically within the wall of the human telencephalon from 12 to 24 gestational weeks (gw), a period that corresponds to the development of thalamocortical fibres passing through the transient subplate region of the developing cerebral wall. Sections from a total of 45 human fetal brains were immunoreacted to detect CD68 and MHC class II antigens and histochemically reacted with RCA-1 and tomato lectins. These markers were differentially expressed by anatomically discrete populations of microglia in the cerebral wall: two cell populations were noted during the initial phase of colonization (12-14 gw): (i) CD68++ RCA-1+ MHC II- amoeboid cells aligned within the subplate, and (ii) RCA-1++ CD68- MHC II- progenitors in the marginal layer and lower cortical plate that progressively ramified within the subplate, without seemingly passing through an 'amoeboid' state. At this stage microglia were largely absent from the germinal layers and the intermediate zone. From 14 to 15 gw, however, MHC class II positive cells were also detected within germinal layers and in the corpus callosum, and these cells, which coexpressed CD68 antigen (a marker associated with phagocytosis), further populated the lower half of the telencephalon from 18 to 24 gw. These findings are discussed in relation to developmental events that take place during the second trimester within the wall of the telencephalon.


Application of NIR spectroscopy in polymorphic analysis: study of pseudo-polymorphs stability.
The accelerated transformation of three azithromycin pseudo-polymorphs (viz. the anhydrous, monohydrate (MH), and dihydrate (DH) forms) at a high temperature and moisture level was examined by near infrared spectroscopy (NIRS). The most marked spectral differences between the pseudo-polymorphs occurred in the 1800-2200 nm region, which corresponds to the first overtone for water. The qualitative analysis of the NIR spectra for the pseudo-polymorphs following storage in a stove at 60 degrees C at 100% relative humidity for 60 days suggests that the crystalline forms (viz. the MH and DH) are stable, whereas the amorphous (anhydrous) form evolves to the DH. This was confirmed by determining the amounts of water and DH present in anhydrous azithromycin and the MH by use of partial least-squares regression (PLSR). The method used to quantify the DH in MH samples was developed and validated in accordance with the standards of the International Conference of Harmonization (ICH) and the European Medicines Agency (EMEA) with a view to its subsequent application by the pharmaceutical industry. The limits of detection (LD) and quantitation (LQ) for the DH in MH provided by the NIRS method were consistent with those obtained by X-ray diffraction (XRD) methodology. This testifies to the accuracy of the proposed method.


Severe Gingivitis Associated with Ascorbic Acid-Deficiency in a Pediatric Patient.
Plaque-induced gingivitis, a common condition in children, responds well to proper oral hygiene practices. Persistent severe gingivitis, on the other hand, should prompt investigation of etiological factors. Nutritional elements are implicated in periodontal health. This case report describes a pediatric patient with severe persistent gingivitis caused by vitamin C deficiency. The events that led to a diagnosis of scurvy and a resolution of the systemic and localized manifestations of the disease, after vitamin C administration, are presented. It is recommended that vitamin C deficiency be considered in cases of refractory gingivitis, especially in pediatric patients with special health care needs who have aversion to foods rich in ascorbic acid.


The use of homologous antigen in the serological diagnosis of brucellosis caused by Brucella melitensis.
In the European Union the serological diagnosis of brucellosis caused by Brucella melitensis is performed using the heterologous antigen of B. abortus S99. The possible higher sensitivity or ability of an early detection of antibodies by a homologous antigen may prove very useful in the final phases of an eradication programme. Results obtained in sheep experimentally infected by B. melitensis biovar 3 were compared using B. abortus S99, B. melitensis M1, M2 and M3 antigens in the Rose Bengal plate test (RBPT), the complement fixation test (CFT) and an enzyme-linked immunosorbent assay (ELISA) test. Forty-six sheep from an officially brucellosis-free flock were experimentally infected intraconjunctivally with B. melitensis biovar 3. Prior to infection, all animals were tested first against Brucella antibodies, weekly for 2 months post-infection (PI) and then monthly for a further 7 months. All sera were tested against the antigens listed above using RBPT, CFT and ELISA. Using a Bayesian approach, test sensitivities were estimated and compared. Their ability for the early detection of antibodies was evaluated through a regression model based on a logit response model, using the number of days PI as the independent variable and the logit of the fraction of positive animals as the dependent variable. No significant differences were detected among the various antigens used, either in terms of sensitivity or in terms of antibody kinetics; however, the CFT was significantly less sensitive than the RBPT and ELISA and it also showed a lower rate of increase of percentage positive animals (beta-coefficient of regression analysis).


Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis.
Ovaries are among the most active organs. Frequently occurring events such as ovulation and ovarian atresia are accompanied with tissue destruction and repairing. Critical roles of immune cells or molecules in those events have been well recognized. IL-33 is a new member of the IL-1 cytokine gene family. Recent studies suggest its roles beyond immune responses. We systemically examined its expression in ovaries for its potential roles in ovarian functions. During ovulation, a high level of IL-33 was transiently expressed, making it the most significantly upregulated immune gene. During estrous cycle, IL-33 expression levels fluctuated along with numbers of ovarian macrophages and atresia wave. Cells with nuclear form of IL-33 (nIL-33(+) cells) were mostly endothelial cells of veins, either in the inner layer of theca of ovulating follicles during ovulation, or surrounding follicles during estrous cycle. Changes in number of nIL-33(+) cells showed a tendency similar to that in IL-33 mRNA level during estrous cycle. However, the cell number sharply declined before a rapid increase of macrophages and a surge of atresia. The decline in nIL-33(+) cell number was coincident with detection of higher level of the cytokine form of IL-33 by Western blot, suggesting a release of cytokine form of IL-33 before the surge of macrophage migration and atresia. However, IL-33 Ab, either by passive transfer or immunization, showed a limited effect on ovulation or atresia. It raises a possibility of IL-33's role in tissue homeostasis after ovarian events, instead of a direct involvement in ovarian functions.


[Prevention of catheter-related infection: usefulness and cost-effectiveness of antiseptic catheters in children].
To evaluate the cost-effectiveness of the antiseptic-impregnated catheter compared with conventional catheters in preventing catheter- related blood stream infections (CR-BSI). Cost-effectiveness analysis; clinical trial, experimental, randomized, controlled, prospective, open label. Patients and methods. A 172 patient cohort, under 1-year-old or less than 10 kg, postoperative cardiovascular children with central venous catheters (CVC) admitted to Cardiac Intensive Care Unit (UCI 35) at Hospital Nacional de Pediatría "Prof. Dr. Juan P. Garrahan", since September 2005 to December 2007. Demographic and CVC data were retrieved to compare: age, gender, weight, diagnosis, surgery, CVC days, costs and complications. Intervention. CVC Arrow, double-lumen, > 48 h of duration; intervention group: antiseptic-impregnated CVC vs. control group: CVC without antiseptics (conventional). The incidence of CR-IE (CR-Infected Events: colonization, local infection and/or CRBSI; combined end point) was 27% for antiseptic- impregnated CVC vs. 31% for conventional catheters (p= 0.6) with similar accumulated incidence of CR- BSI: 2.8 vs. 3.3 per 1000 dayscatheter. We found no differences between groups, except in weight: median 4.0 kg (r 2-17) vs. 4.7 kg (r 2-9) p= 0.0002 and age, median 2 months (r 1- 48) vs. 5 months (r 1- 24) p= 0.0019 in antiseptic-impregnated CVC group. These differences, though statistically significant were clinically non relevant. Median cost per patient during intensive care stay in the conventional CVC group was $3.417 (359-9.453) and in the antiseptic-impregnated-CVC group was $4.962 (239-24.532), p= 0.10. The use of antiseptic-impregnated CVC compared with conventional CVC did not decrease CR-BSI in this population. The cost per patients was higher in the antiseptic impregnated CVC group. These results do not support the routine use of this type of CVC in our population.


[Effect of ammonium chloride and urea on the activity of lactate dehydrogenase. A general model of catalysis].
The dependence of structural and functional properties of lactate dehydrogenase from the pig muscle (isoenzyme M4) on pH (6.9-8.5) on the effect of different forms of non-protein nitrogen (e.g. urea and ammonium chloride) has been investigated. It was shown that Vmax changes negligibly at pH 6.9-8.5 but K(m) increase markedly with pH elevation. At the alkali value of pH pyruvate inhibition disappeared. We have found that urea and ammonium chloride at the non-saturation concentrations inhibited the activity of lactate dehydrogenase. The inhibition constants (Ki and Ka) for urea and ammonium chloride were obtained from inhibition data. When analysing works of different authors and own results we propose the general model of catalysis of lactate dehydrogenase, which includes the formation of normal enzyme-substrate complex, abortive enzyme-NAD-pyruvate complex and the effect of different effectors, including nitrogen containing substances.


Zizimin2: a novel, DOCK180-related Cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes.
A novel superfamily of guanine nucleotide exchange factors for Rho GTPases includes DOCK180 and zizimin1. The zizimin subfamily includes three genes of which only zizimin1 has been cloned. We report here the cloning of zizimin2, identified in a screen for genes enriched in germinal center B cells. Zizimin2 and zizimin1 have similar primary structures and both proteins bound and activated Cdc42 but not the Cdc42-related proteins TC10 or TCL. Their tissue distributions are distinct, however, with zizimin2 expressed predominantly in lymphocytes and an opposite pattern for zizimin1. Zizimin3 was also analyzed and showed distinct GTPase specificity and tissue distribution.


Nonsense-mediated mRNA decay maintains translational fidelity by limiting magnesium uptake.
Inactivation of the yeast nonsense-mediated mRNA decay (NMD) pathway stabilizes nonsense mRNAs and promotes readthrough of premature translation termination codons. Although the latter phenotype is thought to reflect a direct role of NMD factors in translation termination, its mechanism is unknown. Here we show that the reduced termination efficiency of NMD-deficient cells is attributable to increased expression of the magnesium transporter Alr1p and the resulting effects of elevated Mg(2+) levels on termination fidelity. Alr1p levels increase because an upstream ORF in ALR1 mRNA targets the transcript for NMD. Our results demonstrate that NMD, at least in yeast, controls Mg(2+) homeostasis and, consequently, translational fidelity.