Assessment of the risk factors for hearing loss in adult Nigerian population.
A reduction in hearing sensitivity is common in adults and was previously considered to be normal as age increases. However, other health variables may play a role in the sensory changes. This prospective, comparative, hospital-based study assessed the risk factors (RFs) associated with sensorineural hearing losses (SNHL) in adult patients in a specialized tertiary hospital clinic in South-western Nigeria. Patients with clinical diagnosis of hearing impairment (bilateral SNHL) were the test subjects and age and sex-matched comparable group without SNHL were the Controls. Using a structured questionnaire, variables assessed included current and past medical history, family and social history, use of medications including ototoxic drugs, and prolonged medications. One hundred and twenty-seven patients participated in the study comprising of 76 test subjects with SNHL (including 14 with suspected ARHL) and 51 controls. 59.8% of the participants were males. Univariate analysis revealed statistically-significant differences in family history, alcohol consumption, smoking, exposure to noise, previous ear discharge, previous head injury, hypertension, diabetes, osteoarthritis, ototoxic drugs usage, prolonged medication and obesity between the two categories of subjects. Logistic regression analysis revealed family history, smoking, noise exposure, head injury, hypertension had significantly increased odds of developing SNHL. It was concluded that the RFs for SNHL in adult Nigerians were multifactorial while some of the RFs may be amenable to primary prevention. Legislation and public health education could facilitate reduction of SNHL in our community.


Incidence of Non-Traumatic Subconjunctival Hemorrhage in an Indian Rural Population.
To determine the incidence of non-traumatic subconjunctival hemorrhage (NTSH) in Indian rural population and analyze the associated risk factors. The study included patients diagnosed having subconjunctival hemorrhage (SCH) who attended the out-patient department (OPD) of ophthalmology. Demographic characteristics of subjects included age, gender, medical and ocular history, and location of hemorrhage. The incidence rate of NTSH in this study was 3.07 per 1000 patients per year attending OPD. The men to women ratio for NTSH was 1.26 (95% CI). The commonest site of presentation was nasal side (n=36, 51.4%). Right eye (n= 37, 54.3%) was affected more than the left eye (n=28, 40%). The analysis showed 24 patients (34.3%) did not have any etiological factor attributable to SCH. Conjunctivochalasis (CCH) was associated in 15 patients (21.4%). An antiplatelet agent was associated with SCH in 7 patients (10%). Other factors associated with SCH were hypertension, leukemia, and anemia (n=6, 8.6%). This study indicates that NTSH occurs in 3 out of 1000 individuals per year in the rural population presenting to the OPD. Nasal conjunctiva was commonly involved. CCH was associated with 15 patients. Use of antiplatelet agents, hypertension and blood disorders are associated with the risk of NTSH. Patients presenting for the first time with NTSH should be screened for systemic etiological factors.


Magnitude of fatigue in cancer patients receiving radiotherapy and its short term effect on quality of life.
Fatigue is one of the most common, ongoing symptoms reported by patients undergoing radiotherapy and has profound effects on the quality of life. This study attempts to identify the magnitude of fatigue and its implication on the quality of life during radiotherapy. A prospective study was conducted from March 2004 to September 2005, on 90 patients with histologically proven cancer, receiving radiotherapy. Pretreatment and weekly assessment of fatigue and QOL was done during radiation treatment using Brief Fatigue Inventory Scale and EORTC QLQ C30 respectively and repeated one month after completion of radiotherapy. All the scores were measured in the 0 to 100 scale. STATISTICAL METHODS USED: Trimean, SPSS 11.0 and Sysstat 8.0 were used for statistical analysis. Fatigue was present in 87.8% of patients initially and increased gradually over the course of radiotherapy and peaked in the last week. However at follow up it was nearing the pretreatment level. There was significant reduction in the functional scores ( P < 0.001) of QOL (physical, role and emotional function), which returned to pretreatment level at follow up. In the seventh week impairment of cognitive function (P=0.059) was noted. Significant reduction of social function (P < 0.001) at second week and global health status (P < 0.001) at fifth week was noted while financial difficulty was seen from second week onwards. Fatigue is transiently increased by radiotherapy before reaching pretreatment level after few weeks of completion of radiotherapy. QOL is also affected by fatigue which follows the same pattern.


Preemptive priming readily overcomes structure-based mechanisms of virus escape.
A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial "hole" in the naïve T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.


Uniqueness of the Gossypium mustelinum genome revealed by GISH and 45S rDNA FISH.
Gossypium mustelinum ((AD)4 ) is one of five disomic species in Gossypium. Three 45S ribosomal DNA (rDNA) loci were detected in (AD)4 with 45S rDNA as probe, and three pairs of brighter signals were detected with genomic DNA (gDNA) of Gossypium D genome species as probes. The size and the location of these brighter signals were the same as those detected with 45S rDNA as probe, and were named GISH-NOR. One of them was super-major, which accounted for the fact that about one-half of its chromosome at metaphase was located at chromosome 3, and other two were minor and located at chromosomes 5 and 9, respectively. All GISH-NORs were located in A sub-genome chromosomes, separate from the other four allopolyploid cotton species. GISH-NOR were detected with D genome species as probe, but not A. The greatly abnormal sizes and sites of (AD)4 NORs or GISH-NORs indicate a possible mechanism for 45S rDNA diversification following (AD)4 speciation. Comparisons of GISH intensities and GISH-NOR production with gDNA probes between A and D genomes show that the better relationship of (AD)4 is with A genome. The shortest two chromosomes of A sub-genome of G. mustelinum were shorter than the longest chromosome of D sub-genome chromosomes. Therefore, the longest 13 chromosomes of tetraploid cotton being classified as A sub-genome, while the shorter 13 chromosomes being classified as D sub-genome in traditional cytogenetic and karyotype analyses may not be entirely correct.


BURSA OF FABRICIUS IN CHICKENS: POSSIBLE HUMORAL FACTOR.
Chicks bursectomized by testosterone injection on the 5th day of incubation showed a marked inability to produce antibodies to Salmonella typhimurium. When portions of the bursa of Fabricius were enclosed in cell-impermeable Millipore diffusion chambers and implanted subcutaneously or intraperitoneally, the antibody-producing capacity of these animals was restored. Evidence strongly suggests that the bursa of Fabricius elaborates a non-cellular agent capable of restoring immunologic reactivity in bursectomized chicks.


Comparative proteomic analysis of peritoneal dialysate from chronic glomerulonephritis patients.
Peritoneal dialysis (PD) frequently contributes to peritoneal damage which cannot be easily identified without invasive techniques, implying the urgent need for biomarkers and revealing mechanisms. Chronic glomerulonephritis (CGN) is one of the leading causes of receiving dialysis treatment. Here, we attempted to analyze the peritoneal dialysate collected from CGN patients when they receive continuous ambulatory peritoneal dialysis (CAPD) treatment for the first time and after a year to reveal the protein changes that resulted from PD. Proteins were displayed by two-dimensional gel electrophoresis (2DE). Altered gel spots were digested followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for protein identification. Eight proteins were found to have differential expression levels between two groups. Their differential expressions were validated by Western blots in other sets of peritoneal dialysates. Proteins identified with higher levels in the first-time dialysate suggested their dominant appearance in CGN patients, while those that showed higher levels in peritoneal dialysate collected after one year may result from initial peritoneal inflammation or changes in the permeability of the peritoneum to middle-sized proteins. All the identified proteins may provide a perceptiveness of peritoneal changes caused by PD and may function as potential biomarkers or drug targets.


The Interplay of Chromatin Landscape and DNA-Binding Context Suggests Distinct Modes of EIN3 Regulation in Arabidopsis thaliana.
The plant hormone ethylene regulates numerous developmental processes and stress responses. Ethylene signaling proceeds via a linear pathway, which activates transcription factor (TF) EIN3, a primary transcriptional regulator of ethylene response. EIN3 influences gene expression upon binding to a specific sequence in gene promoters. This interaction, however, might be considerably affected by additional co-factors. In this work, we perform whole genome bioinformatics study to identify the impact of epigenetic factors in EIN3 functioning. The analysis of publicly available ChIP-Seq data on EIN3 binding in Arabidopsis thaliana showed bimodality of distribution of EIN3 binding regions (EBRs) in gene promoters. Besides a sharp peak in close proximity to transcription start site, which is a common binding region for a wide variety of TFs, we found an additional extended peak in the distal promoter region. We characterized all EBRs with respect to the epigenetic status appealing to previously published genome-wide map of nine chromatin states in A. thaliana. We found that the implicit distal peak was associated with a specific chromatin state (referred to as chromatin state 4 in the primary source), which was just poorly represented in the pronounced proximal peak. Intriguingly, EBRs corresponding to this chromatin state 4 were significantly associated with ethylene response, unlike the others representing the overwhelming majority of EBRs related to the explicit proximal peak. Moreover, we found that specific EIN3 binding sequences predicted with previously described model were enriched in the EBRs mapped to the chromatin state 4, but not to the rest ones. These results allow us to conclude that the interplay of genetic and epigenetic factors might cause the distinct modes of EIN3 regulation.


The antioxidant response of the liver of male Swiss mice raised on a AIN 93 or commercial diet.
Reactive oxygen species (ROS) are formed under natural physiological conditions and are thought to play an important role in many human diseases. A wide range of antioxidants are involved in cellular defense mechanisms against ROS, which can be generated in excess during stressful conditions, these include enzymes and non-enzymatic antioxidants. The aim of this study was to evaluate the antioxidant responses of mice to two diets control, commercial and the purified AIN 93 diet, commonly used in experiments with rodents. Malondialdehyde (MDA) and hydrogen peroxide (H2O2) concentrations and superoxide dismutase (SOD) and glutathione reductase (GR) activities determined in the liver were lower in the group of mice fed with the AIN 93 diet, while catalase (CAT) activity was higher in the same group, when compared to the group fed on the commercial diet. Liver glutathione peroxidase (GSH-Px) activity was similar in the groups fed on either AIN 93 or the commercial diets. Two SOD isoforms, Mn-SODII and a Cu/Zn-SODV, were specifically reduced in the liver of the AIN 93 diet fed animals. The clear differences in antioxidant responses observed in the livers of mice fed on the two diets suggest that the macro- and micro-nutrient components with antioxidant properties, including vitamin E, can promote changes in the activity of enzymes involved in the removal of the ROS generated by cell metabolism.


In vitro oxidation of low-density lipoprotein in two species of nonhuman primates subjected to caloric restriction.
Caloric restriction (CR), which increases longevity and retards age-associated diseases in laboratory rodents, is being evaluated in nonhuman primate trials. CR reduces oxidative stress in rodents and appears to improve risk factors for cardiovascular disease in nonhuman primates. We tested the hypothesis that low-density lipoprotein (LDL) oxidizability is reduced in two monkey species (rhesus and cynomolgus) subjected to chronic CR. In both species, no significant differences occurred between CR and control animals on total, LDL, or high-density lipoprotein (HDL) cholesterol. In rhesus monkeys, triglycerides were higher in controls than CR (139 +/- 23 vs 66 +/- 8 mg/dl,p < .01, respectively). LDL from CR rhesus monkeys was reduced in triglyceride content and molecular weight compared to controls, whereas LDL composition in cynomolgus monkeys was similar in CR and control animals. In keeping with minor deviations in lipids, antioxidants, and LDL composition, no consistent differences in in vitro LDL oxidizability were apparent between CR and controls in either species.


[Visual, auditory, and bimodal activity in the banks of the lateral suprasylvian sulcus in the cat].
In addition to visually driven cells we found within the lateral suprasylvian visual cortex of cats a considerable number of auditory and/or bimodal cells. Most of the visually driven cells were direction and orientation selective with responses that were neither highly stimulus time locked nor very stable. Most of the auditory responses were also not very stable, had relatively high thresholds and were readily habituated. Previous studies have suggested that populations of cells within the lateral suprasylvian area are specialized for the analysis of optic flow fields. Given that a remarkable proportion of cells within this area can be also driven by auditory stimuli we hypothesize that the "optic flow" model may be extended to the bimodal domain rather than restricted to visual clues only. This, however, remains to be corroborated experimentally.


Genome-wide matching of genes to cellular roles using guilt-by-association models derived from single sample analysis.
High-throughput methods that ascribe a cellular or physiological function for each gene product are useful to understand the roles of genes that have not been extensively characterized by molecular or genetic approaches. One method to infer gene function is "guilt-by-association", in which the expression pattern of a poorly characterized gene is shown to co-vary with the expression of better-characterized genes. The function of the poorly characterized gene is inferred from the known function(s) of the well-described genes. For example, genes co-expressed with transcripts that vary during the cell cycle, development, environmental stresses, and with oncogenesis have been implicated in those processes. While examining the expression characteristics of several poorly characterized genes, we noted that we could associate each of the genes with a cellular phenotype by correlating individual gene expression changes with gene set enrichment scores from individual samples. We evaluated the effectiveness of this approach using a modest sized gene expression data set (expO) and a compendium of gene expression phenotypes (MSigDBv3.0). We found the transcripts that correlated best with enrichment in mitochondrial and lysosomal gene sets were mostly related to those processes (89/100 and 44/50, respectively). The reciprocal evaluation, ranking gene sets according to correlation of enrichment with an individual gene's expression, also reflected known associations for prominent genes in the biomedical literature (16/19). In evaluating the model, we also found that 4% of the genome encodes proteins that are associated with small molecule and small peptide signal transduction gene sets, implicating a large number of genes in both internal and external environmental sensing. Our results show that this approach is useful to infer functions of disparate sets of genes. This method mirrors the biological experimental approaches used by others to associate individual genes with defined gene expression changes. Moreover, the approach can be used beyond discovering genes related to a cellular process to discover meaningful expression phenotypes from a compendium that are associated with a given gene. The effectiveness, versatility, and breadth of this approach make possible its application in a variety of contexts and with a variety of downstream analyses.


Self-perceived symptoms and care needs of patients with severe to very severe chronic obstructive pulmonary disease, congestive heart failure or chronic renal failure and its consequences for their closest relatives: the research protocol.
Recent research shows that the prevalence of patients with very severe chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF) and chronic renal failure (CRF) continues to rise over the next years. Scientific studies concerning self-perceived symptoms and care needs in patients with severe to very severe COPD, CHF and CRF are scarce.Consequently, it will be difficult to develop an optimal patient-centred palliative care program for patients with end-stage COPD, CHF or CRF. The present study has been designed to assess the symptoms, care needs, end-of-life care treatment preferences and communication needs of patients with severe to very severe COPD, CHF or CRF. Additionally, family distress and care giving burden of relatives of these patients will be assessed. A cross-sectional comparative and prospective longitudinal study in patients with end-stage COPD, CHF or CRF has been designed. Patients will be recruited by their treating physician specialist. Patients and their closest relatives will be visited at baseline and every 4 months after baseline for a period of 12 months. The following outcomes will be assessed during home visits: self-perceived symptoms and care needs; daily physical functioning; general health status; end-of-life care treatment preferences; end-of-life care communication and care-giver burden of family caregivers. Additionally, end-of-life care communication and prognosis of survival will be assessed with the physician primarily responsible for the management of the chronic organ failure. Finally, if patients decease during the study period, the baseline preferences with regard to life-sustaining treatments will be compared with the real end-of-life care. To date, the symptoms, care needs, caregiver burden, end-of-life care treatment preferences and communication needs of patients with very severe COPD, CHF or CRF remain unknown. The present study will increase the knowledge about the self-perceived symptoms, care-needs, caregiver burden, end-of-life care treatment preferences and communication needs from the views of patients, their loved ones and their treating physician. This knowledge is necessary to optimize palliative care for patients with COPD, CHF or CRF. Here, the design of the present study has been described. A preliminary analysis of the possible strengths, weaknesses and clinical consequences is outlined.


Continuing Cardiopulmonary Symptoms, Disability, and Financial Toxicity 1 Month After Hospitalization for Third-Wave COVID-19: Early Results From a US Nationwide Cohort.
Patients discharged after COVID-19 report ongoing needs. To measure incident symptoms after COVID-19 hospitalization. Preplanned early look at 1-month follow-up surveys from patients hospitalized August 2020 to January 2021 in NHLBI PETAL Network's Biology and Longitudinal Epidemiology: COVID-19 Observational (BLUE CORAL) study. English- or Spanish-speaking hospitalized adults without substantial pre-COVID-19 disability with a positive molecular test for SARS-CoV-2. Overall, 253 patients were hospitalized for a median of 5 days (interquartile range [IQR], 3-8), and had a median age of 60 years (IQR, 45-68). By race/ethnicity, 136 (53.8%) were non-Hispanic White, 23 (9.1%) were non-Hispanic Black, and 83 (32.8%) were Hispanic. Most (139 [54.9%]) reported a new or worsened cardiopulmonary symptom, and 16% (n = 39) reported new or increased oxygen use; 213 (84.2%) patients reported not feeling fully back to their pre-COVID-19 level of functioning. New limitations in activities of daily living were present in 130 (52.8%) patients. Financial toxicities, including job loss or change (49 [19.8%]), having a loved one take time off (93 [37.8%]), and using up one's savings (58 [23.2%]), were common. Longer lengths of hospital stay were associated with greater odds of 1-month cardiopulmonary symptoms (adjusted odds ratio [aOR], 1.82 per additional week in the hospital; 95% CI, 1.11-2.98) and new disability (aOR, 2.06; 95% CI, 1.21-3.53). There were not uniform demographic patterns of association. We prioritized patients' reports of their own incident problems over objective testing. Patients who survived COVID-19 in the United States during late 2020/early 2021 still faced new burdens 1 month after hospital discharge.


Separation of integument and nucellar tissues from cotton ovules (Gossypium hirsutum L.) for both high- and low-throughput molecular applications.
Here we present a quick and low-cost method to separate the different layers of tissue from the ovules and young seeds of cotton (Gossypium hirsutum L.) for use in high- and low-throughput molecular applications. This method is performed at room temperature using standard laboratory equipment and does not require embedding of the samples, time-consuming fixation, or micro-sectioning procedures. We show that the three main tissues can be efficiently separated from isolated ovules collected on the day of anthesis. RNA and genomic DNA extracted from tissues separated by this method are of good quality and suitable for a variety of molecular applications to study the early stages of cotton seed and fiber development.


Formulation of sage essential oil (Salvia officinalis, L.) monoterpenes into chitosan hydrogels and permeation study with GC-MS analysis.
This study deals with the formulation of natural drugs into hydrogels. For the first time, compounds from the sage essential oil were formulated into chitosan hydrogels. A sample preparation procedure for hydrophobic volatile analytes present in a hydrophilic water matrix along with an analytical method based on the gas chromatography coupled with the mass spectrometry (GC-MS) was developed and applied for the evaluation of the identity and quantity of essential oil components in the hydrogels and saline samples. The experimental results revealed that the chitosan hydrogels are suitable for the formulation of sage essential oil. The monoterpene release can be effectively controlled by both chitosan and caffeine concentration in the hydrogels. Permeation experiment, based on a hydrogel with the optimized composition [3.5% (w/w) sage essential oil, 2.0% (w/w) caffeine, 2.5% (w/w) chitosan and 0.1% (w/w) Tween-80] in donor compartment, saline solution in acceptor compartment, and semi-permeable cellophane membrane, demonstrated the useful permeation selectivity. Here, (according to lipophilicity) an enhanced permeation of the bicyclic monoterpenes with antiflogistic and antiseptic properties (eucalyptol, camphor and borneol) and, at the same time, suppressed permeation of toxic thujone (not exceeding its permitted applicable concentration) was observed. These properties highlight the pharmaceutical importance of the developed chitosan hydrogel formulating sage essential oil in the dermal applications.


Suspected Metallic Embolism following Endovascular Treatment of Intracranial Aneurysms.
We describe a case series of suspected metallic embolism after coil embolization for intracranial aneurysms. Between January 2012 and December 2014, 110 intracranial aneurysms had been treated by coil embolization in our institution. In 6 cases, the postprocedural MR imaging revealed abnormal spotty lesions not detected on the preprocedural MR imaging. The lesions were also undetectable on the postprocedural CT scan. They were demonstrated as low-intensity spots on T1WI, T2WI, DWI, and T2*-weighted imaging. On DWI, they were accompanied by bright "halo," and on T2*-weighted imaging, they showed a "blooming" effect. In 3 of the 6 cases, follow-up MR imaging was available and all the lesions remained and demonstrated no signal changes. Although histologic examination had not been performed, these neuroradiologic findings strongly supported the lesions being from metallic fragments. No specific responsible device was detected after reviewing all the devices used for the neuroendovascular treatment in the 6 cases.


Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism.
Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH4). Physiologically, phenylalanine availability is governed by nutrient intake, whereas liver BH4 is kept at constant level. In phenylketonuria, PAH deficiency leads to elevated blood phenylalanine and is often caused by PAH protein misfolding with loss of function. Here, we report secondary hepatic BH4 deficiency in Pah-deficient mice. Alterations in de novo synthesis and turnover of BH4 were ruled out as molecular causes. We demonstrate that kinetically instable and aggregation-prone variant Pah proteins trap BH4, shifting the pool of free BH4 towards bound BH4. Interference of PAH protein misfolding with metabolite-based control of l-phenylalanine turnover suggests a mechanistic link between perturbation of protein homeostasis and disturbed regulation of metabolic pathways.


Effect of sodium hyaluronate on corneal wound healing.
With the development of the use of sodium hyaluronate for endothelial cell protection during anterior segment surgery, we were interested in the effect of sodium hyaluronate on corneal wound healing. Therefore, the following experiment was performed. Corneal incisions were made in both eyes of 14 albino rabbits. Sodium hyaluronate was used to fill the anterior chamber of the test eye, and balanced salt solution was used in the control eye. The wounds were sutured wih 10-0 nylon. On the seventh postoperative day, and strength was measured. After suture removal, the intraocular pressure was raised until the wound burst. Results showed no statistical difference between these and control eye.


Thrombophilia and outcome in severe infection and sepsis.
Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. In severe infection and sepsis, activation of coagulation frequently occurs, which contributes to the development of multiple organ dysfunction. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in the presence of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. This article reviews experimental and clinical evidence regarding such a relationship, with a particular focus on deficiencies of natural anticoagulant proteins (protein C and antithrombin), the factor V Leiden mutation, and genetic variation in the fibrinolytic system.


Widely tunable reflection-type Fabry-Perot interferometer based on relaxor ferroelectric poly(vinylidenefluoride-chlorotrifluoroethylene-trifluoroethylene).
A reflection-type Fabry-Perot interferometer (FPI) with a large tunability has been demonstrated on relaxor ferroelectric poly(vinylidenefluoride-chlorotrifluoroethylene-trifluoroethylene) [P(VDFCTFE-TrFE)] 78.9/13.9/7.2 mol% with a thickness of 9.2 microm. The optical path length of the FPI is modulated by the electrostrictive strain of the terpolymer under electric field, where the low-loss distributed Bragg reflector and aluminium film are employed as the mirrors in the FPI. A positive strain of 20% has been achieved in the terpolymer film under a field of 30 MV/m, which leads to the FPI with a tunable range of more than 200 nm at wavelengths around 680 nm.


Tunable subwavelength ultrasound focusing in mesoscale spherical lenses using liquid mixtures.
In this work, we present a configurable spherical lens for underwater focusing applications, which consists on a hollow ABS container filled with a liquid mixture. Two miscible liquids with different sound speeds are required to implement this novel configurable lens. We show that by adjusting the mixing ratio between the volumes of both liquids, the sound speed of the liquid mixture can be accurately selected. This results in a modification of the acoustic jet properties and a continuous tuning on the lens focal length. This procedure can be fully automatized providing a dynamic control mechanism that can shift the lens focal length to any desired value inside a continuous range in both directions. Depending on the acoustic properties of the selected liquids, subwavelength resolution or even beyond the diffraction limit resolution can be achieved. We provide experimental measurements for ethanol-water mixtures achieving subwavelength resolution for a certain focal length ranging between 34.6 and 42.8 mm.


ALISA: A microplate assay to measure protein thiol redox state.
Measuring protein thiol redox state is central to understanding redox signalling in health and disease. The lack of a microplate assay to measure target specific protein thiol redox state rate-limits progress on accessibility grounds: redox proteomics is inaccessible to most. Developing a microplate assay is important for accelerating discovery by widening access to protein thiol redox biology. Beyond accessibility, enabling high throughput time- and cost-efficient microplate analysis is important. To meet the pressing need for a microplate assay to measure protein thiol redox state, we present the Antibody-Linked Oxi-State Assay (ALISA). ALISA uses a covalently bound capture antibody to bind a thiol-reactive fluorescent conjugated maleimide (F-MAL) decorated target. The capture antibody-target complex is labelled with an amine-reactive fluorescent N-hydroxysuccinimide ester (F-NHS) to report total protein. The covalent bonds that immobilise the capture antibody to the epoxy group functionalised microplate enable one to selectively elute the target. Target specific redox state is ratiometrically calculated as: F-MAL (i.e., reversible thiol oxidation)/F-NHS (i.e., total protein). After validating the assay principle (i.e., increased target specific reversible thiol oxidation increases the ratio), we used ALISA to determine whether fertilisation-a fundamental biological process-changes Akt, a serine/threonine protein kinase, specific reversible thiol oxidation. Fertilisation significantly decreases Akt specific reversible thiol oxidation in Xenopus laevis 2-cell zygotes compared to unfertilised eggs. ALISA is an accessible microplate assay to advance knowledge of protein thiol redox biology in health and disease.


Scanning electron microscopy study of the choroid plexus in the monkey (Cebus apella apella).
The cells of the choroid plexus of the lateral ventricles of the monkey Cebus apella apella were examined through scanning electron microscopy at contributing to the description of such structures in primates. The animals were anesthetized previously with 3% hypnol intraperitoneally and after perfusion with 2.5% glutaraldehyde, samples of the choroid plexus were collected after exhibition of the central portion and inferior horn of the lateral ventricles. The ventricular surface of those cells presents globose form as well as fine interlaced protrusions named microvilli. Among those, it is observed the presence of some cilia. Resting on the choroid epithelial cells there is a variable number of free cells, with fine prolongations which extend from them. They are probably macrophages and have been compared to Kolmer cells or epiplexus cells, located on choroid epithelium. The choroid plexus of the encephalic lateral ventricles of the monkey Cebus apella apella at scanning electron microscopy is similar to that of other primates, as well as to that of other species of mammals mainly cats and rats, and also humans.


[Identification of mouse lines with HA-tagged prostaglandin receptors].
Prostaglandins are a class of poly-unsaturated fatty acids-derived bioactive lipids with important physiological function by binding to specific receptors. Prostaglandin receptors lack specific antibodies, which greatly impedes the research on our understanding of the signaling of prostaglandins. The aim of this study was to identify nine mouse lines with amino terminal (-NH2, -N) HA-tagged prostaglandin receptors by using the combination of artificial sperm and CRISPR-Cas9 technology. The guide RNA expression plasmid and labeled targeting vector plasmids were transferred into "artificial sperm cells". The "artificial sperm cells" containing labeled proteins were selected and injected into mouse oocytes, and implanted into pseudopregnant mice to obtain labeled mice. The genomic DNA of the prostaglandin receptor tagged mice was extracted, and the genotypes of mice were detected by PCR method. We also isolated mouse peritoneal macrophages to verify the protein expression of HA-labeled prostaglandin receptor by Western blot. Specific DNA bands were amplified in prostaglandin receptor labeled mice, and specific HA protein bands were detected in macrophage proteins, which was not detected in wild type mice. In summary, we successfully constructed 9 mouse lines with HA-tagged prostaglandin receptors, providing a powerful tool for further study of the pathophysiological functions of prostaglandin signaling both in vivo and in vitro.


Effects of stratospheric aerosols and thin cirrus clouds on the atmospheric correction of ocean color imagery: simulations.
Using simulations, we determine the influence of stratospheric aerosol and thin cirrus clouds on the performance of the proposed atmospheric correction algorithm for the moderate resolution imaging spectroradiometer (MODIS) data over the oceans. Further, we investigate the possibility of using the radiance exiting the top of the atmosphere in the 1.38-microm water vapor absorption band to remove their effects prior to application of the algorithm. The computations suggest that for moderate optical thicknesses in the stratosphere, i.e., tau(s) < or approximately 0.15, the stratospheric aerosol-cirrus cloud contamination does not seriously degrade the MODIS except for the combination of large (approximately 60 degrees) solar zenith angles and large (approximately 45 degrees) viewing angles, for which multiple-scattering effects can be expected to be particularly severe. The performance of a hierarchy of stratospheric aerosol/cirrus cloud removal procedures for employing the 1.38-microm water vapor absorption band to correct for stratospheric aerosol/cirrus clouds, ranging from simply subtracting the reflectance at 1.38 microm from that in the visible bands, to assuming that their optical properties are known and carrying out multiple-scattering computations of their effect by the use of the 1.38-microm reflectance-derived concentration, are studied for stratospheric aerosol optical thicknesses at 865 nm as large as 0.15 and for cirrus cloud optical thicknesses at 865 nm as large as 1.0. Typically, those procedures requiring the most knowledge concerning the aerosol optical properties (and also the most complex) performed the best; however, for tau(s) < or approximately 0.15, their performance is usually not significantly better than that found by applying the simplest correction procedure. A semiempirical algorithm is presented that permits accurate correction for thin cirrus clouds with tau(s) as large as unity when an accurate estimate of the cirrus cloud scattering phase function is provided, and as large as 0.5 when a coarse approximation to the phase function is used. Given estimates of the stratospheric aerosol optical properties, the implementation of the algorithm by using a set of lookup tables appears to be straightforward.


PET Study of Sphingosine-1-phosphate Receptor 1 Expression in Response to S. aureus Infection.
Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in S. aureus-infected mice. A rodent local muscle bacterial infection model was developed by injecting S. aureus to the lower hind limb of Balb/c mice. The changes of S1PR1 expression in response to bacterial infection and blocking treatment were assessed using ex vivo biodistribution and in vivo positron emission tomography (PET) after intravenous injection of an S1PR1-specific radiotracer [18F]TZ4877. The specificity of [18F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals. Immunohistochemical studies were performed to confirm the increase of S1PR1 expression in response to infection. Ex vivo biodistribution data showed that the uptake of [18F]TZ4877 was increased 30.6%, 54.3%, 74.3%, and 115.3% in the liver, kidney, pancreas, and thymus of the infected mice, respectively, compared to that in normal control mice, indicating that S1PR1 is involved in the early immune response to bacterial infection. NIBR-0213 or S1PR1-specific DsiRNA pretreatment reduced the tissue uptake of [18F]TZ4877, suggesting that uptake of [18F]TZ4877 is specific. Our PET/CT study data also confirmed that infected mice have increased [18F]TZ4877 uptake in several organs comparing to that in normal control mice. Particularly, compared to control mice, a 39% increase of [18F]TZ4877 uptake was observed in the infected muscle of S. aureus mice, indicating that S1PR1 expression was directly involved in the inflammatory response to infection. Overall, our study suggested that S1PR1 plays an important role in the early immune response to bacterial infection. The uptake of [18F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [18F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases.


Electrical status epilepticus in sleep.
Electrical status epilepticus in sleep (ESES) describes an electroencephalographic pattern showing significant activation of epileptiform discharges in sleep. The terms continuous spike wave in slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) describe the clinical epileptic syndromes seen with ESES. Although there is an overlap between these 2 syndromes, children with CSWS present with a more global regression have more problematic epilepsy and have EEG foci located predominantly in frontotemporal or frontocentral regions. In contrast, children with LKS present with an acquired auditory agnosia, fewer seizures, and EEG foci in the posterotemporal regions. ESES requires a high degree of clinical suspicion because slow-wave sleep must be recorded to confirm this diagnosis. Treatment of ESES extends beyond just control of the seizures; amelioration of the continuous epileptiform discharge must occur to improve neuropsychological outcome. Although there is little evidence to guide treatment, conventional antiepileptic drugs play only a minimal role. Steroid therapy and high-dose benzodiazepines are most commonly used, but other therapies including intravenous gamma-globulin, the ketogenic diet, and surgical therapy with multiple subpial transaction have shown efficacy in small case series. Although epilepsy resolves with time in most cases, many children are left with significant cognitive or language impairment. Longer duration of ESES appears to be the major predictor of poor outcome; markedly abnormal neuronal activity during a critical period for synaptogenesis may result in aberrant synapse formation, explaining the poorer neuropsychological outcome. Early recognition and effective therapy are necessary to improve long-term prognosis in this condition.


The anatomy of crime: physicians under the oppressive regime of Saddam Hussein.
In the aftermath of the US-led invasion of Iraq in 2003, disturbing reports started to emerge about the participation of Iraqi physicians in human rights abuses in southern Iraq under Hussein's regime. While such heinous acts of ear amputations, falsification of medical-legal reports of torture, falsification of death certificates, removal of patient's organs without consent, and many other violations were true, there was no attempt to explain why it happened. There is no doubt that such behaviors reflected long years of threats, displacement and loss of jobs, confiscation, verbal and physical abuse, jail, and the ultimate punishment of torture to death that befell Iraqi physicians. With so many recipes on the menu, could any physician refuse to cooperate? Based on the recounted injustice in this article, which is only the tip of the iceberg, it is only fair to say that, under the circumstances, Iraqi physicians had no choice but to become unwilling accomplices. They should indeed be viewed as survivors of an abusive regime rather than collaborators. In the midst of the struggle to rebuild Iraq, measures should be taken to prevent future breaches of the medical code of ethics. This can only be achieved with a new constitution that ensures the independence of professional medical associations from state authority, and with the support of the international community that can exert pressure on all oppressive regimes. The civilized world must not tolerate and should not turn a blind eye to any violation of the basic rights of every human, for which too much blood has already been shed.


A meta-analysis of the potential antidepressant effects of buprenorphine versus placebo as an adjunctive pharmacotherapy for treatment-resistant depression.
Numerous reports have suggested that buprenorphine may have antidepressant effects. Many individuals with depressive disorders don't respond to first-line treatment and are classified with treatment-resistant depression (TRD). Novel therapies for depression are required to better treat this population. This meta-analysis of randomized placebo-controlled trials sought to evaluate the potential antidepressant effects of buprenorphine as an adjunctive pharmacological treatment for individuals with TRD. PubMed, Embase, CINAHL, Web of Science, and ClinicalTrials.gov databases were searched until June 2019 for original peer-reviewed reports of buprenorphine used for the treatment of depression. Standardized mean differences (SMD) were generated from random effects models. Risk of publication bias was assessed using a funnel plot. Potential sources of heterogeneity were explored in subgroup analyses. In six studies that met inclusion criteria, depression symptom severity in individuals with TRD was not significantly decreased after an adjunctive intervention with buprenorphine when compared to placebo (SMD = -0.07, 95% CI: -0.21-0.06, p = 0.30). Five of the six studies utilized a combination of buprenorphine/samidorphan. In these studies, depression symptom severity was also not significantly reduced after intervention compared to placebo (SMD = -0.08, 95% CI: -0.21 - 0.05, p = 0.23). Five included studies were performed by the same research group with significant conflicts of interest. This meta-analysis did not reveal a significant reduction in depression symptom severity in individuals with TRD after an adjunctive intervention with buprenorphine when compared to placebo. However, more optimal doses of buprenorphine (2 mg/day) and longer treatment lengths should be explored.


Latest progress in low-intensity pulsed ultrasound for studying exosomes derived from stem/progenitor cells.
Stem cells have self-renewal, replication, and multidirectional differentiation potential, while progenitor cells are undifferentiated, pluripotent or specialized stem cells. Stem/progenitor cells secrete various factors, such as cytokines, exosomes, non-coding RNAs, and proteins, and have a wide range of applications in regenerative medicine. However, therapies based on stem cells and their secreted exosomes present limitations, such as insufficient source materials, mature differentiation, and low transplantation success rates, and methods addressing these problems are urgently required. Ultrasound is gaining increasing attention as an emerging technology. Low-intensity pulsed ultrasound (LIPUS) has mechanical, thermal, and cavitation effects and produces vibrational stimuli that can lead to a series of biochemical changes in organs, tissues, and cells, such as the release of extracellular bodies, cytokines, and other signals. These changes can alter the cellular microenvironment and affect biological behaviors, such as cell differentiation and proliferation. Here, we discuss the effects of LIPUS on the biological functions of stem/progenitor cells, exosomes, and non-coding RNAs, alterations involved in related pathways, various emerging applications, and future perspectives. We review the roles and mechanisms of LIPUS in stem/progenitor cells and exosomes with the aim of providing a deeper understanding of LIPUS and promoting research and development in this field.


Defined Host-Guest Chemistry on Nanocarbon for Sustained Inhibition of Cancer.
Signal transducer and activator of transcription factor 3 (STAT-3) is known to be overexpressed in cancer stem cells. Poor solubility and variable drug absorption are linked to low bioavailability and decreased efficacy. Many of the drugs regulating STAT-3 expression lack aqueous solubility; hence hindering efficient bioavailability. A theranostics nanoplatform based on luminescent carbon particles decorated with cucurbit[6]uril is introduced for enhancing the solubility of niclosamide, a STAT-3 inhibitor. The host-guest chemistry between cucurbit[6]uril and niclosamide makes the delivery of the hydrophobic drug feasible while carbon nanoparticles enhance cellular internalization. Extensive physicochemical characterizations confirm successful synthesis. Subsequently, the host-guest chemistry of niclosamide and cucurbit[6]uril is studied experimentally and computationally. In vitro assessments in human breast cancer cells indicate approximately twofold enhancement in IC50 of drug. Fourier transform infrared and fluorescence imaging demonstrate efficient cellular internalization. Furthermore, the catalytic biodegradation of the nanoplatforms occur upon exposure to human myeloperoxidase in short time. In vivo studies on athymic mice with MCF-7 xenograft indicate the size of tumor in the treatment group is half of the controls after 40 d. Immunohistochemistry corroborates the downregulation of STAT-3 phosphorylation. Overall, the host-guest chemistry on nanocarbon acts as a novel arsenal for STAT-3 inhibition.


Kinin-enhancing drugs for unexplained subfertility in men.
Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is felt by patients and doctors alike. As a result, a variety of empirical, non-specific treatments have been used in an attempt to improve semen characteristics and fertility. One suggested treatment for idiopathic oligo- and/or asthenospermia is the administration of kallikrein (kallidinogenase), a kinin-releasing enzyme (or kininogenase). The kinin biological system is complex and involves kininogen (the substrate), kininogenases (the activating enzymes), kinins (the effectors) and kininases (the inactivating enzymes). All four components of the kinin system have been found in the genitalia and in semen. Kallikrein releases 2 major kinins, kallidin and bradykinin, from seminal plasma kininogens. Activated kinins in semen affect sperm motility and metabolism. In vitro addition of kallikrein to semen has been shown to have a positive effect on sperm motility, sperm velocity, cervical mucus penetration, penetration of zona-free hamster eggs and post-thaw survival and motility rate after semen cryopreservation. The latter observation, however, was not confirmed in a more recent comparison of motility stimulants for cryopreserved semen using computerised sperm motion analysis. In vitro treatment of semen with kallikrein has been employed in a clinical context during sperm preparation prior to insemination. Although the kinin system may also be involved in the regulation of spermatogenesis in vivo, a clear mechanism of action is missing. Multiple suggestions on how an increase in kinin levels in the genital tract influences spermatogenesis at the testicular levels have been made by various authors. To determine whether treatment of the male with drugs enhancing kinin levles increases pregnancy rates among couples where failure to conceive has been attributed to idiopathic oligo- and/or asthenospermia. Effects on sperm parameters and sex hormones were studied as secondary outcomes. The Cochrane Subfertility Review Group specialised register of controlled trials was searched". SIxteen RCTs on the therapeutic use of androgens (clomiphene citrate or tamoxifen) in subfertile men were identified. Six trials were excluded. Methodological characteristics of trials Baseline characteristics of the studied groups Outcomes: Pregnancy rates, semen parameters (sperm concentration, motility and morphology), endocrinology (serum FSH, testosterone and oestradiol)


Alterations in membrane-bound and cytoplasmic K-ras protein levels in mouse lung induced by treatment with lovastatin, cholestyramine, or niacin: effects are highly mouse strain dependent.
Agents that either increase (cholestyramine, CS) or decrease (lovastatin, Lov) de novo peripheral cholesterol synthesis may increase (CS) or decrease (Lov) ras protein membrane localization by altering protein prenylation, and potentially have pro- or anti-carcinogenic effects. Male A/J, Swiss, and C57/BL6 mice were treated with 2 or 4% CS, 1% dietary niacin, or 25mg/kg of Lov three times per week (Lov-3X) or five times per week (Lov-5X). After 3 weeks, serum cholesterol and triglycerides were determined enzymatically. Membrane and cytoplasmic K-ras proteins in lung were determined by immunoprecipitation followed by western blotting with a K-ras specific antibody. Results confirmed the hypothesis only in isolated instances. A/J mice had a significant 30% increase in cytoplasmic K-ras and a 40% decrease in membrane K-ras from Lov treatment, as predicted. C57/BL6 mice had a significant 77% increase in membrane K-ras, as expected from CS feeding. At variance with the hypothesis, Swiss mice had increased levels (3-28%) of membrane K-ras with all treatments (including Lov), and C57/BL6 mice treated with Lov had a 58-78% increase in cytoplasmic K-ras without any reduction in the levels of membrane K-ras. Niacin, predicted to have no effect on ras membrane localization, decreased cytoplasmic K-ras in A/J mice, increased both membrane and cytoplasmic K-ras in Swiss mice, and had no effect in C57/BL6 mice. Results may have differed from those predicted because of strain-dependent differences in response to the cholesterol-lowering agents. A difference in response among the mouse strains suggests that individual genetic differences may alter the effect of hypocholesterolemic agents on K-ras membrane localization, and potentially the risk of ras-dependent cancer.


Use of methamphetamine and alcohol among people with opioid use disorder and HIV in Vietnam: a qualitative study.
Heroin use continues to drive HIV transmission in Vietnam, but methamphetamine and alcohol use are growing rapidly and, as in other countries, polysubstance use is widespread. The objective of this study was to understand the interplay between heroin, methamphetamine, and alcohol use among people with opioid use disorder (OUD) and HIV in Vietnam. We conducted 44 in-depth, face-to-face qualitative interviews with people with OUD and HIV who participated in the BRAVO trial of buprenorphine versus methadone in five Vietnam HIV clinics. Interviews probed participants' experiences of heroin, methamphetamine, and alcohol use and their interplay with HIV/OUD treatment. Interviews were professionally transcribed and analyzed using a thematic analysis approach. Of 44 participants interviewed 42 were male, on average 38.8 years of age, with 30 reporting a history of methamphetamine use and 33 reporting a history of alcohol use. Several themes emerged: 1) Methamphetamine and alcohol were perceived to have lower addiction potential than heroin 2) Social settings were key facilitators of alcohol and methamphetamine use 3) Some participants, but not all, used methamphetamine to help quit heroin 4) Consuming alcohol blunted the effects of heroin, while paradoxically serving as a catalyst for heroin use 5) Use of methamphetamine was perceived by many participants to be incompatible with treatment for HIV. Participant experiences reflected a significant impact of polysubstance use on treatment of HIV and OUD. Patterns of polysubstance use are subject to common preconceptions of alcohol and methamphetamine as having a low addictive potential, and these substances are deeply enmeshed in the social life of many people with OUD in Vietnam. Interventions to address complex social norms and potential harms of polysubstance use are urgently needed as the population of people receiving medication for OUD (MOUD) increases in Vietnam and globally. BRAVO - NCT01936857 , September 2013.


[Hyperprolactinemia and disorders of the menstrual cycle].
The authors presented physiological conditions associated with increased prolactin values (sleep, stress, hypoglycemia, nipples stimulation, pregnancy and lactation) as well as the causes of pathological hyperprolactinemia. The results of radioimmunoassay study have been analyzed in concern to the values of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) obtained from the serum of 100 women with increased PRL levels. The "HOECHT" sets were used for the analysis, whereas the values up to 20.9 microgrammes per litre were rated normal. The patients were distributed into 4 groups in concern to the level of PRL increase: 1st group--twenty (n = 20) patients with PRL values from 21-29.9 micrograms/l, 90 blood samples analyzed; 2nd group-forty (n = 40) patients with PRL values f; 30-49.9 micrograms/l, 183 blood samples analyzed; 3rd group--twenty (n = 20) patients with PRL values from 50-99.9 micrograms/l, 83 blood samples analyzed; 4th group--twenty patients (n = 20) with PRL values more than 100 micrograms/l, 78 blood samples analyzed. The values of FSH and LH recorded in the women with hyperprolactinemia were compared with mean values of the same hormones presented in IU/l from the follicular phase of the cycle in the control group which comprised 50 women of reproductive age having normal ovulatory menstrual cycle. The mean values of FSH and LH in the 1st group have not presented with statistically significant difference in relation to the control group. Prevalence of menstrual disorders was 30%, which was statistically significantly higher than in general population. FSH values in the 2nd group were almost the same as in the control group whereas the values of LH were significantly higher. The rate of polycistic ovary syndrome (PCOS) in this group has been significant, also the increased rate of anovulatory cycles from 30 to 67.5%. A mild increase of menstrual cycle rhythm disorders, from 35 to 40% has been recorded. The values of FSH and LH in the 3rd group were significantly lower than in the control group. The significance level was higher for FSH (p < 0.01) then LH (p < 0.05). There was a sudden increase of the cycle rhythm disorders in this group reaching 90%. The 4th group presented with significantly lower values of FSH and LH in relation to the control group, whereas the cycle rhythm disorders occurred in all patients. The obtained results were compared with the literature data and some explanations given. The values of FSH an LH were statistically significantly lower in the 3rd and 4th group. The 2nd group was characteristic for the sudden increase of the number of anovulatory cycles from 30 to 67.5%, whereas the 3rd group presented with the abrupt increase of menstrual cycle rhythm disorders, from 40 to 90%.


Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis.
Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3'-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.


Role of chemokine (C-C motif) ligand 24 in spatial arrangement of the inner cell mass of the bovine embryo.
The process of spatial rearrangement of cells of the inner cell mass (ICM) that are destined to become hypoblast is not well understood. The observation that the chemokine (C-C motif) ligand 24 (CCL24) and several other genes involved in chemokine signaling are expressed more in the ICM than in the trophectoderm of the bovine embryo resulted in the hypothesis that CCL24 participates in spatial organization of the ICM. Temporally, expression of CCL24 in the bovine embryo occurs coincidently with blastocyst formation: transcript abundance was low until the late morula stage, peaked in the blastocyst at Day 7 of development and declined by Day 9. Treatment of embryos with two separate antagonists of C-C motif chemokine receptor 3 (the prototypical receptor for CCL24) decreased the percent of GATA6+ cells (hypoblast precursors) that were located in the outside of the ICM. Similarly, injection of zygotes with a CCL24-specific morpholino decreased the percent of GATA6+ cells in the outside of the ICM. In conclusion, CCL24 assists in spatial arrangement of the ICM in the bovine embryo. This experiment points to new functions of chemokine signaling in the bovine embryo and is consistent with the idea that cell migration is involved in the spatial organization of hypoblast cells in the blastocyst.


A patient and primary care perspective: a patient's perspective on the treatment of depression.
This article describes patients' perspectives of depression and antidepressant treatment based on research by the Global Alliance of Mental Illness Advocacy Networks (GAMIAN-Europe). GAMIAN-Europe is an organization that works to raise the profile of mental health in establishments and institutions throughout Europe. According to data from numerous studies pooled by GAMIAN-Europe, mental health disorders-particularly depression-are misunderstood and undertreated in much of Europe. A lack of dialogue between physicians and patients combined with a lack of available "user friendly" health care information has significantly contributed to noncompliance of antidepressant treatment. Increased patient knowledge and involvement in their own treatment and health care may enhance physician-patient relationships, resulting in better communication, earlier diagnosis and treatment of depression, and increased treatment compliance.


Perceptions of Processed Foods Among Low-Income and Immigrant Parents.
Background. Parent-aimed guidance on the topic of processed foods may help limit highly processed foods in children's diets, but little is known about parent understanding and perceptions of these products. Aims. To determine how parent perceptions of processing align with processing classification systems used in research, and to identify opportunities for future research in communicating information about processed foods. Method. Six focus groups with lower income, racial/ethnic minority and immigrant parents of fourth to sixth graders (n = 37) were conducted. Parents were asked to discuss their views on terminology related to food processing, classification of foods according to their processing level, the healthfulness of select foods, and criteria for choosing snacks for their children. Focus groups were guided by a thematic approach. NVivo 12 (QSR International) was used to facilitate analyses. Results. Thirty mothers and seven fathers participated. Two thirds (62%) were foreign-born; 38% identified as Hispanic. The term "processing" lacked consistent meaning among parents, with variation by immigrant status. Participants associated highly processed foods with convenience, packaging, and added ingredients; "less-processed" versions of foods (e.g., fresh; homemade) were perceived as healthier. Children's preferences were the main criteria for choosing snacks. Foreign-born parents were more likely to associate processed foods with positive characteristics (e.g., properly cooked). Conclusion. The concept of food processing is an area of misconception among parents, providing an opportunity for education that may be extended to larger audiences. A universally accepted definition of food classification by processing level is necessary to effectively communicate the link between processing and healthfulness.


Predicting 5-year outcome in first-episode psychosis: construction of a prognostic rating scale.
The aim of this study was to construct a rating scale to predict long-term outcome on the basis of clinical and sociodemographic characteristics in patients with symptoms of psychosis who seek psychiatric help for the first time. Patients (N = 153) experiencing their first episode of psychosis (DSM-IV schizophrenia, schizophreniform disorder, schizoaffective disorder, brief psychotic episode, delusional disorder, affective psychosis with mood-incongruent delusions, or psychotic disorder not otherwise specified or being actively psychotic) were consecutively recruited from 17 psychiatric clinics in Sweden from January 1996 through December 1997 (24 months). Baseline characteristics were assessed with an extensive battery of psychiatric rating scales; duration of untreated psychosis, premorbid characteristics, and cognitive functioning were also assessed. The relationship between baseline characteristics and the 5-year outcome was analyzed using a stepwise logistic regression model. In the logistic regression analysis, 5 variables were found to have unique contributions in the prediction of outcome. In order of magnitude of the odds ratios, these variables were Global Assessment of Functioning (GAF) score during the year before first admission, education level, actual GAF score at first admission, gender, and social network. The sensitivity, i.e., correctly identified cases (poor outcome), was 0.84, and the specificity, i.e., the correctly identified non-cases (good outcome), was 0.77. To initiate adequate interventions, it is crucial to identify patients experiencing their first episode of psychosis who are likely to have an unfavorable long-term outcome. The predictive rating scale described here is a feasible tool for early detection of these patients.


Lectin-carbohydrate interactions on nanoporous gold monoliths.
Monoliths of nanoporous gold (np-Au) were modified with self-assembled monolayers of octadecanethiol (C18-SH), 8-mercaptooctyl α-D-mannopyranoside (αMan-C8-SH), and 8-mercapto-3,6-dioxaoctanol (HO-PEG2-SH), and the loading was assessed using thermogravimetric analysis (TGA). Modification with mixed SAMs containing αMan-C8-SH (at a 0.20 mole fraction in the SAM forming solution) with either octanethiol or HO-PEG2-SH was also investigated. The np-Au monoliths modified with αMan-C8-SH bind the lectin Concanavalin A (Con A), and the additional mass due to bound protein was assessed using TGA analysis. A comparison of TGA traces measured before and after exposure of HO-PEG2-SH modified np-Au to Con A showed that the non-specific binding of Con A was minimal. In contrast, np-Au modified with octanethiol showed a significant mass loss due to non-specifically adsorbed Con A. A significant mass loss was also attributed to binding of Con A to bare np-Au monoliths. TGA revealed a mass loss due to the binding of Con A to np-Au monoliths modified with pure αMan-C8-SH. The use of mass losses determined by TGA to compare the binding of Con A to np-Au monoliths modified by mixed SAMs of αMan-C8-SH and either octanethiol or HO-PEG2-SH revealed that binding to mixed SAM modified surfaces is specific for the mixed SAMs with HO-PEG2-SH but shows a significant contribution from non-specific adsorption for the mixed SAMs with octanethiol. Minimal adsorption of immunoglobulin G (IgG) and peanut agglutinin (PNA) towards the mannoside modified np-Au monoliths was demonstrated. A greater mass loss was found for Con A bound onto the monolith than for either IgG or PNA, signifying that the mannose presenting SAMs in np-Au retain selectivity for Con A. TGA data also provide evidence that Con A bound to the αMan-C8-SH modified np-Au can be eluted by flowing a solution of methyl α-D-mannopyranoside through the structure. The presence of Con A proteins on the modified np-Au surface was also confirmed using atomic force microscopy (AFM). The results highlight the potential for application of carbohydrate modified np-Au monoliths to glycoscience and glycotechnology and demonstrate that they can be used for capture and release of carbohydrate binding proteins in significant quantities.


Social inequalities in the prevalence of indicators of active aging in the Brazilian population: National Health Survey, 2013.
To analyze social inequalities in the prevalence of indicators of active aging in the Brazilian older adult population. This is a cross-sectional study with a sample of 11,177 older adults who participated in the Brazilian National Health Survey in 2013. We estimated the prevalence of five domains of active aging (social activities, civic engagement, leisure-time physical activity, paid work, and volunteer work) according to gender, ethnicity, schooling, income, and private health insurance. Prevalence ratios and confidence intervals were calculated using Poisson regression. The percentage of involvement in organized social activities, civic engagement, and physical activity was 25.1, 12.4, and 13.1%, respectively. Regarding work, 20.7% of the sample had a paid job, and 9.7% participated in volunteer work. Women had a higher prevalence of participation in organized social activities and volunteer work; while civic engagement and paid work were more frequent among men. White people were more likely to participate in social activities, volunteer work, and leisure-time physical activity, explained by their schooling. The strata with a higher level of schooling, income, and who had private health insurance showed a greater incidence of participation in all activities studied. The five activities analyzed are challenging for the proposed policy of active aging, as they are marked by considerable social inequality.


Combat surgeons before, during, and after war: the legacy of Loyal Davis.
By 1942, Loyal Davis had firmly established himself as a preeminent civilian neurosurgeon. With military operations rapidly escalating, he was recruited to serve in the European Theater of Operations as a consultant to the Surgeon General. Davis brought tremendous experience, insight, and leadership to this position; however, he found the military system in which he was suddenly immersed inefficient and impassive. His requests for even basic equipment became mired in endless bureaucracy even as his communiqués to the Chief Surgeon in the European Theater and to the Surgeon General's staff in Washington seemed to fall short of their intended recipients. Then, when he attempted to vent his frustrations to his academic colleagues, he was nearly court-martialed. Notwithstanding, Davis became the first to formally recognize high-altitude frostbite and also developed protective headgear for airmen, and later in his service, he joined a contingent of senior medical leaders who visited the Soviet Union to study their system of combat casualty care. Subsequent to his service on active duty, Davis returned to his academic practice at Northwestern where he used his position as editor of Surgery, Gynecology, and Obstetrics to advocate for change within the military medical corps. Others like Davis have contributed greatly to the advancement of combat casualty care both during active service and long after their time in uniform. This paper examines the lessons from Davis's experiences as a military neurosurgeon and his continued advocacy for change in the medical corps along with additional recent examples of change effected by former military surgeons. For those currently serving, these lessons illustrate the value of contributing wherever a need is recognized, and for those who have served in the past, they demonstrate the importance of having a continued voice with junior combat surgeons and the military leadership.


Sutural expansion using rigidly integrated endosseous implants: an experimental study in rabbits.
Rigidly integrated implants offer great promise for orthodontic and orthopedic anchorage in the oral and midfacial regions. Rigid anchorage can be used to control unwanted tooth movement, provide abutments in edentulous arches, and open the vertical dimension of occlusion. To evaluate the use of endosseous implants in the midface region, two flanged titanium implants were placed on either side of the midnasal suture of 18 New Zealand White rabbits. The rabbits were divided into an unloaded control and two experimental groups. One experimental group was loaded at 1 Newton (N) and the other at 3 N. All rabbits were euthanized after 12 weeks of loading. Stereologic point-hit and line-intercept methods were used to analyze microradiographic and multiple fluorochrome histology of the suture. All implants remained stable during the loading period. The distance between the implants increased significantly in the loaded groups compared with the control, and was significantly higher in the 3 N group than in the 1 N group. Percent bone volume was significantly decreased, while the percent suture volume tended to be increased in the loaded groups. Mineral apposition and bone formation rates at the sutural surfaces were increased in the loaded groups (P < 0.05), but did not differ between loaded groups. These results indicate that relatively low loads (1 or 3 N) applied to rigidly integrated endosseous implants across an unfused suture are satisfactory for achieving expansion under the conditions of this study. The 3 N load resulted in slightly more expansion, but did not affect the rate of bone formation at the suture.


Snap-top nanocarriers.
An approach to the design and fabrication of mechanized mesoporous silica nanoparticles is demonstrated at the proof of principle level. It relies on the reductive cleavage of disulfide bonds within an integrated nanosystem, wherein surface-bound rotaxanes incorporate disulfide bonds in their stalks, which are encircled by cucurbit[6]uril or alpha-cyclodextrin rings, until reductive chemistry is performed, resulting in the snapping of the stalks of the rotaxanes, leading to cargo release from the inside of the nanoparticles.


MARS--does it stand the test of time?
Artificial liver support systems have been tested for decades in the management of liver failure. Generally, after some promising results published as case series, the device either disappears or fails to show significant benefit in controlled trials. Recently, the molecular absorbent recycling systems (MARS) or extracorporeal albumin dialysis (ECAD) technique appears to have broken this trend. Responding to the title one could summarize by saying this technique so far has stood the test of time. Data in support of its use in acute liver failure (ALF) is still scant and difficult to assess. However, in a well known but not very well defined entity of acute on chronic liver failure (AOCLF) the ECAD technique has been shown to improve survival compared to a similar randomized control group receiving standard supportive therapy. This well tolerated liver support system has real potential for widespread application if further well designed multicenter clinical trials continue to support its effectiveness. Its future lies probably in the management of the moribund hospitalized patient on the transplant list awaiting a donor liver.


Investigating Optimal Confinement Behaviour of Low-Strength Concrete through Quantitative and Analytical Approaches.
Reinforced concrete is used worldwide in the construction industry. In past eras, extensive research has been conducted and has clearly shown the performance of stress-strain behaviour and ductility design for high-, standard-, and normal-strength concrete (NSC) in axial compression. Limited research has been conducted on the experimental and analytical investigation of low-strength concrete (LSC) confinement behaviour under axial compression and relative ductility. Meanwhile, analytical equations are not investigated experimentally for the confinement behaviour of LSC by transverse reinforcement. The current study experimentally investigates the concrete confinement behaviour under axial compression and relative ductility of NSC and LSC using volumetric transverse reinforcement (VTR), and comparison with several analytical models such as Mander, Kent, and Park, and Saatcioglu. In this study, a total of 44 reinforced-column specimens at a length of 18 in with a cross-section of 7 in × 7 in were used for uniaxial monotonic loading of NSC and LSC. Three columns of each set were confined with 2 in, 4 in, 6 in, and 8 in c/c lateral ties spacing. The experimental results show that the central concrete stresses are significantly affected by decreasing the spacing between the transverse steel. In the case of the LSC, the core stresses are double the central stress of NSC. However, increasing the VTR, the capacity and the ductility of NSC and LSC increases. Reducing the spacing between the ties from 8 in to 2 in center to center can affect the concrete column's strength by 60% in LSC, but 25% in the NSC. The VTR and the spacing between the ties greatly affected the LSC compared to NSC. It was found that the relative ductility of the confined column samples was almost twice that of the unrestrained column samples. Regarding different models, the Manders model best represents the performance before the ultimate strength, whereas Kent and Park represents post-peak behaviour.


Molecular machinery and mechanism of cell secretion.
Secretion occurs in all living cells and involves the delivery of intracellular products to the cell exterior. Secretory products are packaged and stored in membranous sacs or vesicles within the cell. When the cell needs to secrete these products, the secretory vesicles containing them dock and fuse at plasma membrane-associated supramolecular structures, called porosomes, to release their contents. Specialized cells for neurotransmission, enzyme secretion, or hormone release use a highly regulated secretory process. Similar to other fundamental cellular processes, cell secretion is precisely regulated. During secretion, swelling of secretory vesicles results in a build-up of intravesicular pressure, allowing expulsion of vesicular contents. The extent of vesicle swelling dictates the amount of vesicular contents expelled. The discovery of the porosome as the universal secretory machinery, its isolation, its structure and dynamics at nanometer resolution and in real time, and its biochemical composition and functional reconstitution into artificial lipid membrane have been determined. The molecular mechanism of secretory vesicle swelling and the fusion of opposing bilayers, that is, the fusion of secretory vesicle membrane at the base of the porosome membrane, have also been resolved. These findings reveal, for the first time, the universal molecular machinery and mechanism of secretion in cells.


Stevens-Johnson syndrome and toxic epidermal necrolysis-challenges of recognition and management.
Skin adverse drug reactions (ADRs) generally present as transient erythematous macular/papular rashes. However these can many a times be the initial presentation of serious muco-cutaneous ADRs such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). The incidence of SJS varies from 1.2 to 6 per million patient-years and that of TEN to be 0.4 to 1.2 per million patient-years. The pathophysiological mechanism of SJS and TEN have not been fully elucidated. The aetiological factors of SJS and TEN are diverse; drugs being the cause in more than 80% cases of TEN and about 40-50% cases of SJS. Mucous membranes are affected in nearly all cases. The extent of epidermal sloughing may vary and forms a basis for the classification of an individual case as SJS or TEN. Prognosis of SJS is better than that of TEN; mortality rates being about 5% and 30%-40% respectively. Specific therapy for these conditions is yet not available. The use of systemic corticosteroids has been controversial. Early diagnoses can prevent/reduce the morbidity of such serious ADRs. This article provides a brief review of the clinical presentation and management of SJS and TEN.


Effects of Different Types of Exercise Training on the Cortisol Awakening Response in Children.
Context: Due to great variability of the hypothalamus-pituitary-adrenal (HPA)-axis, research has to produce better-controlled findings to make a more meaningful statement regarding the effect of exercise training (ET) on the cortisol awakening response (CAR), especially in children. Objective: The aim of the study was to investigate the effects of different ET interventions on the CAR in children. Design and setting: We conducted a short-term training study for 10 weeks in primary schools in Westphalia, Germany. Participants: 71 children (9-10 years old) were randomly assigned to a cardiovascular exercise group (n = 27), a motor exercise group (n = 23), or a control group (n = 21). Intervention: An experienced instructor trained the children in an after-school setting in 45 min sessions, three times a week over the course of 10 weeks. Main outcome measure: CAR (0, +30 min) was assessed on 2 schooldays one week apart before and after the 10-week intervention. A Shuttle Run Test was performed to determine the cardiovascular fitness. Motor fitness was assessed using the Heidelberg Gross Motor Test. Results: Children who enhanced their cardiovascular fitness over the course of the intervention showed an increased CAR after the intervention time (B = 0.213), whereas children who underwent a motor exercise intervention and at the same time gained in motor fitness exhibited a decreased CAR after intervention (B = -0.188). Conclusions: It has been speculated that other neurobiological pathways are activated by different exercise interventions. The extent to which these ET effects on CAR can be applied in clinical settings needs further investigation. Précis: The 10-weeks longitudinal effects of cardiovascular vs. motor exercise interventions (three times a week) on CAR in children show that these interventions exert different effects on hypothalamus-pituitary-adrenal (HPA) axis activity.


Mosaic maternal uniparental disomy of chromosome 15 in Prader-Willi syndrome: utility of genome-wide SNP array.
Prader-Willi syndrome is caused by the loss of paternal gene expression on 15q11.2-q13.2, and one of the mechanisms resulting in Prader-Willi syndrome phenotype is maternal uniparental disomy of chromosome 15. Various mechanisms including trisomy rescue, monosomy rescue, and post fertilization errors can lead to uniparental disomy, and its mechanism can be inferred from the pattern of uniparental hetero and isodisomy. Detection of a mosaic cell line provides a unique opportunity to understand the mechanism of uniparental disomy; however, mosaic uniparental disomy is a rare finding in patients with Prader-Willi syndrome. We report on two infants with Prader-Willi syndrome caused by mosaic maternal uniparental disomy 15. Patient 1 has mosaic uniparental isodisomy of the entire chromosome 15, and Patient 2 has mosaic uniparental mixed iso/heterodisomy 15. Genome-wide single-nucleotide polymorphism array was able to demonstrate the presence of chromosomally normal cell line in the Patient 1 and trisomic cell line in Patient 2, and provide the evidence that post-fertilization error and trisomy rescue as a mechanism of uniparental disomy in each case, respectively. Given its ability of detecting small percent mosaicism as well as its capability of identifying the loss of heterozygosity of chromosomal regions, genome-wide single-nucleotide polymorphism array should be utilized as an adjunct to the standard methylation analysis in the evaluation of Prader-Willi syndrome.


Synthesis and 11C-Radiolabelling of 2-Carboranyl Benzothiazoles.
Dicarba-closo-dodecaboranes, commonly known as carboranes, possess unique physico-chemical properties and can be used as hydrophobic moieties during the design of new drugs or radiotracers. In this work, we report the synthesis of two analogues of 2-(4-aminophenyl)benzothiazole (a compound that was found to elicit pronounced inhibitory effects against certain breast cancer cell lines in vitro) in which the phenyl ring has been substituted by a m-carborane cage. Two different synthetic strategies have been used. For the preparation of 1-(9-amino-1,7-dicarba-closo-dodecaboran-1-yl)-benzo-thiazole, the benzothiazole group was first introduced on one of the cluster carbon atoms of m-carborane and the amine group was further attached in three steps. For the synthesis of 1-(9-amino-1,7-dicarba-closo-dodecaboran-1-yl)-6-hydroxybenzothiazole, iodination was performed before introducing the benzothiazole group, and the amino group was subsequently introduced in six steps. Both compounds were radiolabelled with carbon-11 using [11C]CH3OTf as the labelling agent. Radiolabelling yields and radiochemical purities achieved should enable subsequent in vitro and in vivo investigations.


Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features.
The underlying causes of learning disability and dysmorphic features in many patients remain unidentified despite extensive investigation. Routine karyotype analysis is not sensitive enough to detect subtle chromosome rearrangements (less than 5 Mb). The presence of subtle DNA copy number changes was investigated by array-CGH in 50 patients with learning disability and dysmorphism, employing a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Twelve copy number abnormalities were identified in 12 patients (24% of the total): seven deletions (six apparently de novo and one inherited from a phenotypically normal parent) and five duplications (one de novo and four inherited from phenotypically normal parents). Altered segments ranged in size from those involving a single clone to regions as large as 14 Mb. No recurrent deletion or duplication was identified within this cohort of patients. On the basis of these results, we anticipate that array-CGH will become a routine method of genome-wide screening for imbalanced rearrangements in children with learning disability.


A Review on the Corrosion Behaviour of Nanocoatings on Metallic Substrates.
Growth in nanocoatings technology is moving towards implementing nanocoatings in many sectors of the industry due to their excellent abilities. Nanocoatings offer numerous advantages, including surface hardness, adhesive strength, long-term and/or high-temperature corrosion resistance, the enhancement of tribological properties, etc. In addition, nanocoatings can be applied in thinner and smoother thickness, which allows flexibility in equipment design, improved efficiency, lower fuel economy, lower carbon footprints, and lower maintenance and operating costs. Nanocoatings are utilised efficiently to reduce the effect of a corrosive environment. A nanocoating is a coating that either has constituents in the nanoscale, or is composed of layers that are less than 100 nm. The fine sizes of nanomaterials and the high density of their ground boundaries enable good adhesion and an excellent physical coverage of the coated surface. Yet, such fine properties might form active sites for corrosion attack. This paper reviews the corrosion behaviour of metallic, ceramic, and nanocomposite coatings on the surface of metallic substrates. It summarises the factors affecting the corrosion of these substrates, as well as the conditions where such coatings provided required protection.


[Several critical aspects of the value of peripheral markers in depression (TRH test and dexamethasone depression)].
Studies of depression carried out for over 10 years have led to the discovery of biological tracers for depression. The authors have performed numerous TRH and dexamethasone tests and in their opinion, the present enthusiasm for these tests should be tempered. In several aspects the various values attributed to them seem to be questionable. Owing to the difficulty in codifying these tests, the authors question their diagnostic, pronostic, therapeutic and predictive values. The authors' own experience as well as the evolution of the publications throughout the world have been taken into consideration. Finally, the problem of interferences and the doubtful specificity of endocrine tests for depression have been dealt with.


Simultaneous laser-induced synthesis and micro-patterning of a metal organic framework.
Micro-patterning of a metal organic framework (MOF) from a solution of precursors is achieved by local laser heating. Nano-sized MOFs are formed, followed by rapid assembly due to convective flows around a heat-induced micro-bubble. This laser-induced bottom-up technique is the first to suggest simultaneous synthesis and micro-patterning of MOFs, alleviating the need for pre-preparation and stabilization.


Effect of some commercial grades of microcrystalline cellulose on flowability, compressibility, and dissolution profile of piroxicam liquisolid compacts.
The technique of liquisolid compacts is a promising method toward enhancing the dissolution of poorly soluble drugs. Lower flowability and compressibility is one of the limitations of this technique. The evaluation of effects of different grades of microcrystalline cellulose (MCC) on flowability, compressibility, and dissolution of liquisolid systems were the aims of this study. For this means, several formulations were prepared using various grades of MCC as carrier. Propylene glycol (PG), silica, and sodium starch glycolate were used as nonvolatile solvent, coating material, and disintegrant, respectively. Then flowability, friability hardness, and dissolution rate of prepared formulations were studied. The effect of tablet aging on mentioned properties was also investigated. The results showed that among the evaluated different grades of MCC, compacts containing MCC PH 101 and 102 showed better dissolution profiles. Harder compacts were obtained using MCC PH 101 and 200 as carriers. Better flowability was observed in compacts containing MCC PH 101. Also, these compacts demonstrated acceptable friability. Aging had no effect on hardness and dissolution profile of liquisolid tablets. It could be concluded that MCC PH 101 is a suitable carrier for preparing liquisolid systems for having acceptable flowability, friability, hardness, and dissolution profile.


Central nervous system leukemia in children with acute nonlymphoblastic leukemia.
Factors contributing to the development of central nervous system (CNS) leukemia, and the impact of leukemic involvement of this site on subsequent remission length, were determined in 184 children with acute nonlymphoblastic leukemia who had been treated in two successive clinical trials. Preventive CNS therapy in both studies consisted of intrathecal methotrexate (12 mg/m2) given monthly during the first six months of therapy and then every three months until all treatment was stopped. Children with CNS leukemia at diagnosis or relapse were given intrathecal chemotherapy weekly for four weeks and then monthly throughout the remainder of the treatment course. Those continuing in complete remission received 2,400 rad cranial irradiation plus five doses of intrathecal methotrexate before cessation of therapy. The 38 children (20.7%) with CNS leukemia at diagnosis were more likely to have an initial leukocyte count greater than or equal to 25 X 10(9)/L (P = .01) and age less than 2 years (P = .03). The presence of CNS leukemia at diagnosis did not adversely affect the remission induction rate (P = .13) or the length of complete remissions (P = .73). CNS relapse ended initial remissions in 11 patients only and did not preclude subsequent long-term survival, as four of these children are off therapy and in second complete remission for 33+ to 78+ months. Three features at diagnosis were predictive of CNS relapse: monocytic or myelomonocytic leukemia (P = .002); age less than 2 years (P = .0001); and leukocyte count greater than or equal to 25 X 10(9)/L (P = .012). By stepwise Cox regression analysis, each factor was found to have independent predictive value. Despite the apparent effectiveness of intrathecal methotrexate as preventive CNS treatment, our findings indicate that more effective prophylaxis is needed for patients with features predisposing to CNS relapse.


Molecular mechanisms of renal and extrarenal manifestations caused by inactivation of the electrogenic Na(+)-HCO3 (-) cotransporter NBCe1.
The electrogenic Na(+)-HCO3 (-) cotransporter NBCe1 plays an essential role in bicarbonate absorption from renal proximal tubules, but also mediates the other biological processes in extrarenal tissues such as bicarbonate secretion from pancreatic ducts, maintenance of tissue homeostasis in eye, enamel maturation in teeth, or local pH regulation in synapses. Homozygous mutation in NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as short stature, ocular abnormalities, enamel abnormalities, and migraine. Functional analyses of NBCe1 mutants using different expression systems suggest that at least a 50% reduction of the transport activity may be required to induce severe pRTA. In addition to functional impairments, some NBCe1 mutants show trafficking defects. Some of the pRTA-related NBCe1 mutants showing the cytoplasmic retention have been shown to exert a dominant negative effect through hetero-oligomer complexes with wild-type NBCe1 that may explain the occurrence of extrarenal manifestations in the heterozygous carries of NBCe1 mutations. Both NBCe1 knockout (KO) and W516X knockin (KI) mice showed very severe pRTA and reproduced most of the clinical manifestations observed in human pRTA patients. Functional analysis on isolated renal proximal tubules from W516X KI mice directly confirmed the indispensable role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we will focus on the molecular mechanisms underling the renal and extrarenal manifestations caused by NBCe1 inactivation.


c-Src-induced activation of ceramide metabolism impairs membrane microdomains and promotes malignant progression by facilitating the translocation of c-Src to focal adhesions.
The proto-oncogenic tyrosine kinase c-Src is up-regulated in various human cancers, implicating its role in tumour progression. Upon activation, c-Src translocates to focal adhesions and initiates intracellular signalling cascades that promote malignant transformation, but the underlying mechanisms for c-Src translocation remain unclear. In the present study we show that c-Src up-regulation perturbs sphingolipid/cholesterol-enriched membrane microdomains by activating ceramide synthesis, resulting in promotion of c-Src translocation. Using an inducible c-Src expression system in Csk (C-terminal Src kinase)-deficient fibroblasts, we found that translocation of c-Src to focal adhesions/podosomes occurs in the later stages of cell transformation. Activated c-Src is liberated from microdomains and promotes the phosphorylation of FAK (focal adhesion kinase) and cortactin localized to focal adhesions/podosomes. In parallel with these events, anabolic metabolism of ceramides is activated by up-regulation of the de novo synthesis pathway. Inhibition of ceramide conversion into glucosylceramide promotes liberation of c-Src from microdomains, and inhibition of de novo ceramide synthesis restores the microdomain distribution of c-Src and suppresses malignant phenotypes such as increased cell motility and anchorage-independent cell growth. These results suggest that c-Src-induced activation of ceramide synthesis impairs the integrity of microdomains and contributes to malignant progression by promoting the translocation of c-Src to focal adhesions/podosomes.


The nasal frame osteotomy: technical note.
In the practice of orthognathic surgery, a patient presenting with a gummy smile and lip incompetence is readily diagnosed as having vertical maxillary excess, and a maxillary impaction osteotomy is usually the proposed treatment. If a short nose, an arched and upwardly displaced upper lip, and a broad face accompany these 2 features, nasal lengthening and caudal repositioning of the central portion of the upper lip by a nasal frame osteotomy should be considered instead. The technique of the nasal "frame" osteotomy, which was used in 1 patient with a 4-year follow-up, is described.


Changes in lysosomal morphology and enzyme activities during the development of adriamycin-induced cardiomyopathy.
Morphologic and enzymic changes in heart lysosomes were studied following a chronic treatment of animals with a cumulative dose of 15 mg/kg of adriamycin. Myocardial cell damage due to adriamycin included lysosomal changes, sarcotubular swelling, vacuolization and myofibrillar drop-out. These structural changes were more pronounced in the 6-week treated group as opposed to the 3-week treated group. The number of lysosomes per unit area increased from a control value of 3.6 +/- 1.7 to 17.8 +/- 4.0 in the 3-week treated group and 35.9 +/- 9.2 in the 6-week treated groups, respectively. The scatter in the size distribution of lysosomes was much wider in treated animals. Lysosomal hydrolases in the 3-week and 6-week adriamycin-treated group changed as follows: N acetyl beta-glucosaminidase activity fell in the homogenate (H) and nonsedimentable (NS) and rose in the serum (Ser) fractions; a drop in alpha-mannosidase was seen in the sedimentable (S) and Ser fractions; an increase in beta-galactosidase was noted in the H, S and Ser fractions; acid phosphatase was increased in H, S, NS and Ser fractions. Lanthanum staining, used as a cytochemical probe for normal membrane permeability, revealed intracytoplasmic localization of the tracer only in the 6-week group. Malondialdehyde content was increased significantly in the 3-week and 6-weed treated groups. These results show lysosomal changes in adriamycin-treated hearts which precede as well as accompany nonspecific permeability changes in the sarcolemma.(ABSTRACT TRUNCATED AT 250 WORDS)