Helical structure of human native collagen.
A "fibroleiomyoma" of the lung obtained from a 40-year-old man as a surgical specimen was studied with both the light and the electron microscope. The unusual collagen in this tumor displayed a filamentous helical structure. The filaments measured 50 Angstroms across. Most of the fibrils did not show periodicity. Some, however, showed periodicity of about 700 A. Those with periodicity were smaller in diameter than the fibrils without periodicity. These observations suggest a helical structure of native collagen and may also represent weak cross-linking of tropocollagen in this tumor. This is the first report of collagen showing a helical filamentous structure from human material.


Description of a system designed to assist primary dental care clinicians in decision-making with regard to specialist periodontal referrals and report of two clinical audits using the system.
Identifying which patients are at risk of significant periodontal breakdown and may need specialist care is a process fraught with problems. This paper summarises factors that should be considered by referring clinicians, describes a system to assist them, and presents the results of two sequential audits carried out in general dental practice using the system. AIMS, MATERIALS AND METHODS: The author aims to present the system and the results of two sequential audits, carried out in the same eight general dental practices by 23 general dental practitioners (GDPs) after training from a specialist in periodontics. The system is based on the use of the Basic Periodontal Examination (BPE), a constant pressure periodontal probe, and a computer screen that prompts the clinician who is performing periodontal screening. A series of risk factors, including smoking, presence of relevant systemic disease and age, is used to modulate the score. Patients are then classified into one of three complexity groups. Those in the Complexity 3 group are deemed to be potentially at risk of significant periodontal breakdown and in need of referral for specialist advice and/or care, in accordance with the published British Society of Periodontology guidelines. In each audit a random sample of the records of ten dentate patients over the age of 20 years, who attended for recall or new examinations by each of the 23 GDPs over a calendar month, were assessed to see whether or not BPE scores had been recorded and whether or not those classified as Complexity 3 (and in need of referral) had been correctly identified and referred. In both audits the total random sample of patient records was 225 (ten for 22 dentists and five for the remaining dentist who only worked for a short time during the months of the audit). In the first audit cycle 139 (62%) of the random sample of records included a BPE score and 11 (8%) of the patients concerned were identified as Complexity 3 and referred for specialist advice and/or treatment. All 11 accepted the referral and when examined by the specialist in periodontics were confirmed as Complexity 3. In the second audit cycle, which took place seven months later, 179 (80%) of the random sample of patient records included a BPE score and 14 patients were assessed by their GDPs as being Complexity 3. All 14 accepted a referral and were deemed to be Complexity 3 when they were subsequently examined by the specialist in periodontics. Although the full potential of the system was not investigated during the two audits, these preliminary results suggest that it may assist referring clinicians in identifying which patients to refer and encourage clinicians to perform periodontal screening.


Mediating millisecond reaction time around particles and cells.
Precise spatiotemporal control of how particles and cells interact with reagents is critical for numerous laboratory and industrial processes. Novel tools for exerting this control at shorter time scales will enable development of new chemical processes and biomedical assays. Previously, we have developed a generalized approach to manipulate cells and particles across fluid streams termed rapid inertial solution exchange (RInSE), which utilizes inertial lift forces at finite Reynolds number and high Peclet number to transfer particles from an initial solution to another within a millisecond. Here, we apply these principles toward developing a continuous flow microfluidic platform that enables transient chemical treatments of cells and particles (on the order of 1 ms). We also demonstrate how the reactant stream can be employed as a diffusion barrier, preventing adverse reactions between coflowing solutions. In order to demonstrate the utility of the method, we applied it to various operations in molecular biology and automated cell staining including cell permeabilization, fluorescent staining, and molecular delivery to viable cells. We expect this method will enable previously unexplored studies of the dynamics of molecular events, improve uniformity of reactions carried on the surface of beads, and increase uniformity in cell-based assays through automation.


[Changes in the elastic fibers of the skin in rats after long-term motor loading and immobilization].
The histologic changes were followed up that took place in the elastic fibers of the skin of a total of 30 female rats of the Wistar line at the initial age of 45 days. The animals were kept under the conditions of enhanced or lowered locomotor activity. It was found that as functional elements in the particular layers of the skin the elastic fibers altered considerably their specific morphologic characteristic under the effect of a varying loading the body with muscular activity. The skin of those of the animals that were loaded with enhanced locomotion presented a strongly developed hyperplastic net of elastic fibers of considerable thickness and density. On the other hand, the skin of the animals that were immobilized showed atrophic and reduction processes involving the elastic tissue; in such case the characteristic structure and network arrangement were only presented by sporadic fibres and bundles. The changes seen in the structure and organization of the elastic tissue once again demonstrated the importance of the higher or lower functional loading of the body with physical work for the development of hyper- or hypotrophic processes in the various tissues and organs.


Comparison of NF-RO and RO-NF for the Treatment of Mature Landfill Leachates: A Guide for Landfill Operators.
Reverse osmosis (RO) and nanofiltration (NF) are among the state-of-the-art technologies for treating landfill leachates. Due to the complexity and variance in the composition of leachates, numerous combinations of multiple technologies are used for their treatment. One process chain for the treatment of raw leachate is RO followed by further concentration of RO-retentate using NF (RO-NF scheme). The aptness of this process train used by some landfill sites around the world (usually with the aim of volume reduction so as to re-inject the concentrate into the landfill) is questionable. This study investigated two schemes RO-NF and NF-RO (nanofiltration of raw leachate followed by reverse osmosis of NF permeate) to identify their merits/demerits. Experiments were conducted in bench scale using commercial membranes: DOW Filmtec NF270 and SW30HR. Filtration trials were performed at different pressures to compare the water and solute transports in the individual stages of the two schemes. Based on the water fluxes and compositions of retentates and permeates; osmotic pressures, energy demands, and other possible operational advantages were discussed. NF-RO offers some advantages and flexibility for leachate treatment besides being energy efficient compared to RO-NF, wherein osmotic pressure steadily increases during operation in turn increasing operation and maintenance costs.


Non-solvolytic synthesis of aqueous soluble TiO2 nanoparticles and real-time dynamic measurements of the nanoparticle formation.
Highly aqueously dispersible (soluble) TiO2 nanoparticles are usually synthesized by a solution-based sol-gel (solvolysis/condensation) process, and no direct precipitation of titania has been reported. This paper proposes a new approach to synthesize stable TiO2 nanoparticles by a non-solvolytic method - direct liquid phase precipitation at room temperature. Ligand-capped TiO2 nanoparticles are more readily solubilized compared to uncapped TiO2 nanoparticles, and these capped materials show distinct optical absorbance/emission behaviors. The influence of ligands, way of reactant feeding, and post-treatment on the shape, size, crystalline structure, and surface chemistry of the TiO2 nanoparticles has been thoroughly investigated by the combined use of X-ray diffraction, transmission electron microscopy, UV-visible (UV-vis) spectroscopy, and photoluminescence (PL). It is found that all above variables have significant effects on the size, shape, and dispersivity of the final TiO2 nanoparticles. For the first time, real-time UV-vis spectroscopy and PL are used to dynamically detect the formation and growth of TiO2 nanoparticles in solution. These real-time measurements show that the precipitation process begins to nucleate after an initial inhibition period of about 1 h, thereafter a particle growth occurs and reaches the maximum point after 2 h. The synthesis reaction is essentially completed after 4 h.


Successful Implementation of a Direct Observation Program in an Ambulatory Block Rotation.
Direct observation of clinical skills is a cornerstone of competency-based education and training. Ensuring direct observation in a consistent fashion has been a significant challenge for residency programs. The purpose of this study was to evaluate the effects of a novel evaluation system, designed to achieve ongoing direct observation of residents, examine changes in resident observation practices, and understand faculty attitudes toward direct observation and the evaluation system. Internal medicine residents on an ambulatory block rotation participated in a new evaluation system, which replaced a single end-of-rotation summative evaluation with 9 formative evaluations based on direct observation. Faculty received training in direct observation and use of the forms, and residents were given responsibility to collect 9 observations per rotation. Faculty members contacted residents at the beginning and middle of the rotation to ensure completion of the observations. Residents and faculty also completed postrotation surveys to gauge the impact of the new system. A total of 507 patient encounters were directly observed, and 52 of 57 (91%) residents completed all 9 observations. Residents reported considerably more direct observation than prior to the intervention, and most reported changes to their clinical skills based on faculty feedback. Faculty reported improvements in their attitudes, increased their use of direct observation, and preferred the new system to the old one. A novel evaluation system replacing summative evaluations with multiple formative evaluations based on direct observation was successful in achieving high rates of observations, and improving faculty attitudes toward direct observation.


Serial functional imaging poststroke reveals visual cortex reorganization.
Visual cortical reorganization following injury remains poorly understood. The authors performed serial functional magnetic resonance imaging (fMRI) on patients with visual cortex infarction to evaluate early and late striate, ventral, and dorsal extrastriate cortical activation. Patients were studied with fMRI within 10 days and at 6 months. The authors used a high-level visual activation task designed to activate the ventral extrastriate cortex. These data were compared to those of age-appropriate healthy control participants. The results from 24 healthy control individuals (mean age 65.7 +/- SE 3.6 years, range 32-89) were compared to those from 5 stroke patients (mean age 73.8 +/- SE 7 years, range 49-86). Patients had infarcts involving the striate and ventral extrastriate cortex. Patient activation patterns were markedly different to controls. Bilateral striate and ventral extrastriate activation was reduced at both sessions, but dorsal extrastriate activated voxel counts remained comparable to controls. Conversely, mean percent magnetic resonance signal change increased in dorsal sites. These data provide strong evidence of bilateral poststroke functional depression of striate and ventral extrastriate cortices. Possible utilization or surrogacy of the dorsal visual system was demonstrated following stroke. This activity could provide a target for novel visual rehabilitation therapies.


Bio-protection in oenology by Metschnikowia pulcherrima: from field results to scientific inquiry.
Finding alternatives to the use of chemical inputs to preserve the sanitary and organoleptic quality of food and beverages is essential to meet public health requirements and consumer preferences. In oenology, numerous manufacturers already offer a diverse range of bio-protection yeasts to protect must against microbiological alterations and therefore limit or eliminate sulphites during winemaking. Bio-protection involves selecting non-Saccharomyces yeasts belonging to different genera and species to induce negative interactions with indigenous microorganisms, thereby limiting their development and their impact on the matrix. Although the effectiveness of bio-protection in the winemaking industry has been reported in numerous journals, the underlying mechanisms are not yet well understood. The aim of this review is to examine the current state of the art of field trials and laboratory studies that demonstrate the effects of using yeasts for bio-protection, as well as the interaction mechanisms that may be responsible for these effects. It focuses on the yeast Metschnikowia pulcherrima, particularly recommended for the bio-protection of grape musts.


Development of high impedance measurement system for water leakage detection in implantable neuroprosthetic devices.
There has been a push for a greater number of channels in implantable neuroprosthetic devices; but, that number has largely been limited by current hermetic packaging technology. Microfabricated packaging is becoming reality, but a standard testing system is needed to prepare these devices for clinical trials. Impedance measurements of electrodes built into the packaging layers may give an early warning of device failure and predict device lifetime. Because the impedance magnitudes of such devices can be on the order of gigaohms, a versatile system was designed to accommodate ultra-high impedances and allow future integrated circuit implementation in current neural prosthetic technologies. Here we present the circuitry, control software, and preliminary testing results of our designed system.


Genetic fine structure of a Salmonella enterica serovar Typhi strain associated with the 2005 outbreak of typhoid fever in Kelantan, Malaysia.
Among enteric pathogens, Salmonella enterica serovar Typhi is responsible for the largest number of food-borne outbreaks and fatalities. The ability of the pathogen to cause systemic infection for extended durations leads to a high cost of disease control. Chronic carriers play important roles in the evolution of Salmonella Typhi; therefore, identification and in-depth characterization of isolates from clinical cases and carriers, especially those from zones of endemicity where the pathogen has not been extensively studied, are necessary. Here, we describe the genome sequence of the highly virulent Salmonella Typhi strain BL196/05 isolated during the outbreak of typhoid in Kelantan, Malaysia, in 2005. The whole-genome sequence and comparative genomics of this strain should enable us to understand the virulence mechanisms and evolutionary dynamics of this pathogen in Malaysia and elsewhere.


Homozygosity mapping of autosomal recessive retinitis pigmentosa locus (RP22) on chromosome 16p12.1-p12.3.
Autosomal recessive retinitis pigmentosa (arRP) is a genetically and clinically heterogeneous and progressive degenerative disorder of the retina, leading usually to severe visual handicap in adulthood. To date, disease loci/genes have been mapped/identified only in a minority of cases. DNA samples were collected from 20 large consanguineous Indian families, in which arRP segregated and that were suitable for homozygosity mapping of the disease locus. After excluding linkage to all known arRP loci, a genome-wide scan was initiated. In two families, homozygosity mapping, haplotype analysis, and linkage data mapped the disease locus (RP22) in an approximately 16-cM region between D16S287 and D16S420 on the proximal short arm of chromosome 16. No mutation has been found by direct sequencing in the gene (CRYM) encoding micron crystallin, which maps in the critical region.


Occupational need in severe dementia: a descriptive study.
This project represents the first phase of a larger study, the whole of which is intended to demonstrate the occupational need of elderly persons, in hospital or residential settings, who have severe dementia and to identify those therapeutic approaches which serve to meet such need. One hundred and nine severely impaired persons in nine dementia care units were each observed over the course of a day, using the dementia care mapping instrument. Results indicate a severe dearth of occupational provision for this client group, most of whom spent the greater part of their day unoccupied. They also highlight the conditions of minimum well-being experienced by most residents for most of the time. The anomaly of those units whose dementia care mapping scores did not match the perceived quality of their social and physical environments is discussed. A hypothesis of an altered perception of environment in severely impaired persons is proposed.


Neuroimaging and pathological findings in a child with cerebral sparganosis. Case report.
The authors report the case of a 6-year-old boy with cerebral sparganosis due to infection with a plerocercoid tapeworm larva of Spirometra mansoni. Magnetic resonance imaging revealed an area of irregular long T2 signal in the right frontal lobe. When compared with images obtained 2 years earlier, the lesion appeared to have migrated into the parietal lobe. During surgery for the removal of a granuloma, the parasite was discovered and excised. Following surgery, the patient's neurological deficits markedly improved. The authors review the pathological and imaging features of cerebral sparganosis.


A novel dominant negative Smad2 mutation in a TGFbeta resistant human carcinoma cell line.
An important biological mechanism contributing to the transformed phenotype of cancer cells is the ability to escape normal growth regulatory signals. In epithelial cells, transforming growth factor beta (TGFbeta) inhibits cell cycle progression in the G1-phase. The abnormal ability of cancer cells to escape TGFbeta-induced cell cycle inhibition may lead to deregulated mitosis, providing a growth advantage to these clones. The effects of TGFbeta are mediated through type I and type II receptors, which are transmembrane proteins possessing cytoplasmic serine/threonine kinase domains for signal propagation. TGFbeta binds to the type II receptor which then phosphorylates the cytoplasmic domain of the type I receptor. The receptor complex recruits and phosphorylates the downstream signaling proteins, Smad2 and Smad3, which then associate with Smad4. The Smad complex translocates to the nucleus to regulate target gene expression resulting in cell cycle inhibition. We have identified a new Smad2 mutation in a TGFbeta-resistant human carcinoma line. The mutant Smad2 protein exhibits decreased association with the receptor complex, is not phosphorylated in response to TGFbeta, fails to associate with Smad4 and does not localize to the nucleus. Expression of the mutant Smad2 protein in a TGFbeta sensitive carcinoma line induces resistance to this growth inhibitory factor and deregulates TGFbeta-responsive gene expression. These results indicate that this novel Smad2 mutant protein has dominant negative activity in cultured cells.


Hypothermia Presenting in Wernicke Encephalopathy: A Case Report.
Wernicke encephalopathy (WE) is a neurologic disorder characterized by clinical symptoms, such as nystagmus, ataxia, and mental confusion. Hypothermia in patients with WE is a rare complication, and its pathogenic mechanism and therapy are yet to be ascertained. Herein, we presented a case of a 61-year-old man who was diagnosed with WE 3 months earlier. We investigated the cause of hypothermia (35.0℃) that occurred after an enema (bowel emptying). Brain magnetic resonance imaging revealed mammillary body and hypothalamus atrophy. In the autonomic function test, the sympathetic skin response (SSR) test did not evoke SSR latencies on both hands. In addition, abnormal orthostatic hypotension was observed. Laxative and stool softener medication were administered, and his diet was modified, which led to an improvement in constipation after 2 weeks. Moreover, there was no recurrence of hypothermic episode. This is the first reported case of late-onset hypothermia secondary to WE.


[Advance in research of poultry major histocompatibility complex-structure].
The structure of poultry major histocompatibility complex(MHC) is closely associated with avianimmunology and avian disease control. This review summaried the structures of poultry MHC, including chicken, turkey, duck, goose, and quail. It was suggested that there were some common characteristics among these MHCs: all of them have conservative MHC region containing MHC I, MHC II, and unknown functional genes; they are simple and contracted; the lengths of introns of MHC I gene are shorter than those of mammals; all have 8 exons and 7 introns in MHC I genes in chicken, turkey, duck, and goose; all have 6 exons and 5 introns in MHC II genes; the structure patterns of BG genes in chicken, turkey, and quail are identical; and all have microsatellite repetitive motifs. However, there are differences among species: MHC I and MHC II genes are duplicated, while there are several copies in duck, goose, and quail; and the numbers of BG genes are different. It will be helpful to further study avian disease and avian immunologenetics through analysing MHC structures of the major poultrys.


Polymorphism in emergence of deciduous dentition: A cross-sectional study of Indian children.
The aim of the present study was to evaluate the timing and sequence of the eruption of deciduous teeth in Indian children. This cross-sectional study focused on children aged 5-36 months. One hospital was randomly selected from four geographic zones of the city. A total of 400 children from each hospital, fulfilling the inclusion criteria, constituted the sample. The examination was carried out by a single, trained examiner. The tooth was recorded as "present" or "absent" on the day of examination. The mean age of emergence was calculated using a probit model. Independent sample t-test was used to assess the statistical significance of differences in the mean age of tooth emergence. The deciduous mandibular central incisor was the first tooth to erupt in the oral cavity (8.15±1.69 months). Girls showed delayed eruption compared to boys; however, no interarch variation was observed in the mean age of tooth eruption. There was also no difference in the sequence of eruption of deciduous teeth, as reported in other studies. The present study establishes a chronological table for the eruption of deciduous teeth in Indian children. There was delayed eruption of deciduous teeth when compared to the reference ranges of Western populations.


Two-photon excitation STED microscopy by utilizing transmissive liquid crystal devices.
Transmissive liquid crystal devices (tLCDs) enable the modification of optical properties, such as phase, polarization, and laser light intensity, over a wide wavelength region at a high conversion efficiency. By utilizing tLCDs, we developed a new two-photon excitation stimulated emission depletion microscopy technique based on a conventional two-photon microscope. Spatial resolution was improved by compensating for phase shifts distributed in the optical path. Using this technique, we observed the fine structures of microtubule networks in fixed biological cells.


Seeing the unseen of Chinese herbal medicine processing (Paozhi): advances in new perspectives.
Processing (Paozhi) represents a unique Chinese pharmaceutic technique to facilitate the use of Chinese herbal medicines (CHMs) for a specific clinical need in the guidance of Traditional Chinese Medicine (TCM) theory. Traditionally, most CHMs require a proper processing to meet the needs of specific clinical syndromes before being prescribed by TCM practitioners. During processing, significant changes in chemical profiles occur, which inevitably influence the associated pharmacological properties of a CHM. However, although processing is formed in a long-term practice, the underlying mechanisms remain unclear for most CHMs. The deepening understanding of the mechanism of processing would provide scientific basis for standardization of processing. This review introduced the role of processing in TCM and several typical methods of processing. We also summarized the up-to-date efforts on the mechanistic study of CHM processing. The processing mechanisms mainly include the following aspects: (i) directly reducing contents of toxic constituents; (ii) structural transformation of constituents; (iii) improving solubility of constituents; (iv) physically changing the existing form of constituents; (v) and influence by excipients. These progress may give new insights into future researches.


Segmentation of the metacarpus and phalange in musculoskeletal ultrasound images using local active contours.
This work presents a method for the automatic segmentation of metacarpus and phalange bones in ultrasound images of the second metacarpophalangeal joint (MCPJ) using Active Contours. The MCPJ is known to be the one of the first structures to be affected by rheumatic diseases like rheumatoid arthritis. The early detection and follow-up of this disease is important to prevent irreversible damage of the joints, which occurs continuously and faster if no treatment is used. To our knowledge, there is no automatic system to quantify the extension of the lesions resulting from rheumatic activity. The objective of this work is to identify the metacarpus and the phalange bones using local active contours. To our knowledge, there is no well established method for this problem and this technique has not been used yet in these structures. Results proved that the automatic segmentation is possible with an error of 3 pixels for a confidence of 80%.


Transcriptomic profile of tobacco in response to Phytophthora nicotianae infection.
Black shank, caused by Phytophthora nicotianae (P. nicotianae), is a serious disease of cultivated tobacco (Nicotiana tabacum) worldwide. The interactions between tobacco and P. nicotianae are complex and the outcomes of the interactions depend on the tobacco genotype, P. nicotianae strain, and environmental conditions. In this study, we used RNA-sequencing (RNA-Seq) to investigate and compare transcriptional changes in the stems of tobacco upon inoculation with P. nicotianae strain race 0. We used two tobacco varieties: RBST (named from resistance to black shank and tobacco mosaic virus), which was resistant to the P. nicotianae strain race 0, and Honghuadajinyuan (HD), which was susceptible to P. nicotianae race 0. Samples were collected 12 and 72-hour post inoculation (hpi). Analysis of differentially expressed genes (DEGs) and significantly enriched GO terms indicated that several basic defense mechanisms were suppressed in both varieties, which included response to wounding (GO: 0009611), and defense response to fungus (GO: 0050832). We also found some genes that may especially be related to mechanisms of resistance in RBST, such as the one encoding a chitinase. These results will provide a valuable resource for understanding the interactions between P. nicotianae and tobacco plants.


Stent-graft treatment of thoracoabdominal aortic aneurysms after complete visceral debranching.
Complex thoracoabdominal aortic aneurysm repair remains a difficult problem from both open and endoluminal approaches. The reduced morbidity and mortality rates reported to be associated with aortic stent-graft procedures makes this option more attractive, but it is hampered by the need for adequate proximal and distal seal zones. While branched and fenestrated aortic stent-grafts are being refined, an alternative is a two-stage surgical and endoluminal approach that is particularly useful for aneurysms involving the aortic visceral segment. The present report describes stent-graft repair in two patients after complete visceral artery revascularization or "debranching."


Outcomes of Hemi-Descemet Membrane Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy.
To report the mid-term outcomes of hemi-Descemet membrane endothelial keratoplasty (hemi-DMEK) performed for Fuchs endothelial corneal dystrophy (FECD). In this prospective, interventional case series, we evaluated clinical outcomes of 10 eyes from 10 patients who underwent hemi-DMEK for FECD. Main outcome measures were best-corrected visual acuity (BCVA), endothelial cell density (ECD), central pachymetry, and postoperative complications. At 1 year postoperatively, 7/7 eyes (excluding 2 eyes with low visual potential) reached a BCVA of ≥20/40 (≥0.5), 6/7 (86%) ≥20/25 (≥0.8), 4/7 (57%) ≥20/20 (≥1.0), and 2/7 (29%) 20/17 (≥1.2). BCVA remained stable until 2 years postoperatively (P ≥ 0.05) and further improved thereafter (P < 0.05). Mean ECD decreased from 2740 (±180) cells/mm preoperatively to 850 (±300) cells/mm (n = 9) at 1 year (P ≤ 0.05) and showed an annual decrease of on average 6% to 7% thereafter (P ≥ 0.05 between consecutive follow-ups). Pachymetry decreased from preoperatively 745 (±153) μm to 533 (±63) μm (n = 9) and 527 (±35) μm (n = 8) at 1 and 3 years postoperatively, respectively. Within the first 6 postoperative months, 4/10 eyes underwent rebubbling for visually significant graft detachment. One eye received secondary circular DMEK for persistent graft detachment 1 month postoperatively; another eye developed secondary graft failure 2.5 years postoperatively, and 1 eye was suspected for an allograft reaction 1.5 years postoperatively. Hemi-DMEK may render visual outcomes comparable to those achieved by conventional DMEK. Despite low ECD counts by 6 months, ECD levels remain fairly stable thereafter. Hence, hemi-DMEK may become a potential alternative technique for treatment of FECD while increasing the yield of the endothelial tissue pool.


Bone density, microarchitecture and strength estimates in white versus African American youth with obesity.
African Americans (AA) have more favorable bone density and microarchitecture compared to Whites (W), which may explain their observed lower fracture rates. Obesity has deleterious effects on bone microarchitecture and strength estimates and is associated with an increase in fracture risk. Adolescence and young adulthood are periods of active bone accrual and also periods characterized by an increasing prevalence of obesity. The effect of obesity on the relationship between race and bone parameters remains unclear, particularly in youth. To assess differences in BMD, bone microarchitecture and strength estimates in AA and W adolescents and young adults with moderate to severe obesity. We hypothesized that racial differences in bone endpoints in lean youth would also be noted in youth with moderate to severe obesity. We evaluated 24 AA and 48 W adolescent and young adults with a mean age of 18.2 ± 2.4 years and a median body mass index (BMI) of 44.8 (40.5-49.4) kg/m2 who underwent dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT), extended cortical analysis (ECA) and micro-finite element analysis (FEA) to obtain measures of volumetric bone mineral density (vBMD), bone geometry, microarchitecture, and strength estimates at the distal radius and tibia. We found no differences between AA and W for total fat and lean mass, and areal BMD Z-scores (p > 0.05 for all). At the distal radius, no significant differences were detected in vBMD, bone geometry or microarchitecture (p > 0.05 for all); however, stiffness and failure load were higher in the AA group (p = 0.031 and 0.047 respectively). At the distal tibia, cortical vBMD was higher in AA vs. W (p = 0.012), while trabecular number was higher and trabecular separation lower in W vs. AA (p ≤ 0.028). Stiffness and failure load trended higher in AA vs. W (p = 0.052 and p = 0.048, respectively). Groups did not differ for any other bone parameter (p > 0.05). Racial differences in bone endpoints appear to be less marked in those with moderate to severe obesity, suggesting that effects of obesity may blunt the effect of race on bone endpoints.


Epizootic ulcerative syndrome affecting fish in the Zambezi river system in southern Africa.
In late 2006, diseased fish of a variety of species began to appear in the Chobe and upper Zambezi rivers in southern Africa. In April 2007, investigations showed that the levels of pesticides and heavy metals in the tissues of the fish were very low, discounting pollution as an underlying cause for the disease. However, histological evidence showed that the disease closely resembled the epizootic ulcerative syndrome caused by the oomycete Aphanomyces invadans, a serious aquatic pathogen that has been isolated from freshwater and estuarine fish in Japan, south-east Asia, Australia and the usa since the 1970s, but not previously recorded in Africa.


Longitudinal aspects of emotion recognition in patients with traumatic brain injury.
Changes in emotional and social behaviour are relatively common following traumatic brain injury (TBI). Impairments in recognising the emotional state of others may underlie some of the problems in social relationships that these patients experience. The few previous studies examining emotion recognition in TBI typically assessed patients once, long after the onset of brain injury, making it difficult to distinguish the direct effect of brain injury from the effects of environmental changes. This study examined 30 patients with TBI shortly after brain injury and 32 orthopaedic control patients on their recognition of emotions expressed in the face and the voice using discrimination and labelling tasks. These patients were followed up 1 year later to examine the longitudinal development of emotion recognition deficits. TBI patients were found to be impaired on emotion recognition compared to the control patients both early after injury and 1 year later. The fact that impairments in emotion recognition were evident early after TBI and no evidence of recovery over time was found, suggests a direct effect of brain injury.


[Changes in cerebral extracellular pH, cerebral blood flow and intracranial pressure induced by hypercarbic ventilation--assessment as a potential in vivo model of cerebral acidosis].
The effects of acidosis on ischemic brain damage are unclear and probably diverse. To establish an in vivo model of acidosis, the authors assess changes in extracellular brain pH (pHe), CBF and ICP induced by hypercarbic ventilation, and discuss the reliability and short comings of this experimental model. Acidosis was induced by increasing the inspired CO2 concentration in mechanically ventilated rats. pHe was measured with a pH-sensitive electrode implanted into the cortical mantle. The rats were divided into five groups according to the CO2 concentrations inspired: G-1, 0% control; G-2, -5-% CO2; G-3, -10-% CO2; G-4, -20-% CO2; G-5, -25-% CO2. Cortical blood flow was measured using a laser Doppler flowmeter, and ICP was also determined in each of the experimental groups. pHe decreased rapidly after the CO2 supply was turned on and remained almost constant at fixed concentrations of inspired CO2. pHe values diminished as the concentration of inspired CO2 decreased, as follows: G-2, -0.10 +/- 0.03; G-3, -0.31 +/- 0.08; G-4, -0.49 +/- 0.09; G-5, -0.64 +/- 0.10. The changes in pHe almost perfectly paralleled the changes in blood pH. The percentage increase in CBF was more than 200% in the G-2 groups and minimal increases in CBF, probably due to changes in blood pressure, were observed in from G-2 to G-5. Changes in CBF paralleled changes in systemic blood pressure, especially after the CO2 supply was turned off. ICP also rose after increasing the CO2 supply, and the pattern of changes was similar to that of CBF.(ABSTRACT TRUNCATED AT 250 WORDS)


Ferritin, Serum Iron and Hemoglobin as Acute Phase Reactants in Laparoscopic and Open Surgery of Cholecystectomy: An Observational Prospective Study.
Cytokines are expressed by various cells after several stimuli such as surgical tissue damage, producing a systemic inflammatory response (SIR). C-reactive protein (CRP) is used extensively in clinical practice after operative injury, but proinflammatory cytokines, iron status, albumin, neutrophil-to-lymphocyte (N/L) ratio and hemoglobin, as acute phase reactants, have been poorly documented. This study aims to show how they behave after surgery, comparing laparoscopic (LC) versus open cholecystectomy (OC). In total, 55 patients were included in a prospective non-randomized form to undergo a cholecystectomy: 8 patients OC (50% females) and 47 patients LC (68% females). Before (A1) and 24 h after surgery (A2), blood samples were taken for an ordinary analysis and IL6, IL8 and TNFα determination. There were no differences between LC and OC groups concerning age, CRP, IL6 and TNFα at day A1. In the LC group at day A2, CRP, IL6, IL8, TNF, ferritin, leukocytes and N/L ratio increased; hemoglobin, lymphocytes, prothrombin and albumin decreased (p < 0.05). In the OC group at day A2, only IL6 (p < 0,07), ferritin, leukocytes, N/L ratio and CRP (p < 0.05) increased; serum iron, hemoglobin, lymphocytes and albumin (p < 0.05) decreased. At day A2, OC vs. LC group, higher values were observed in IL6, ferritin and CRP (p ≤ 0.05), and lesser values were observed in serum iron and prothrombin (p < 0.05). In conclusion, classic markers of inflammation are altered after surgery, in a milder way in laparoscopic surgery. Ferritin can be used as an inflammatory marker, as has been described in COVID-19 infection.


Aberrant expression of trefoil factor family 1 in biliary epithelium in hepatolithiasis and cholangiocarcinoma.
Stepwise progression of intrahepatic cholangiocarcinoma (ICC) has been proposed in hepatolithiasis. We examined the participation of trefoil factor family 1 (TFF1), which is critical for mucosal protection and tumor suppression in the stomach, in the development and progression of ICC. We used 16 livers of ICC with hepatolithiasis, 11 of biliary epithelial dysplasia with hepatolithiasis, 16 of hepatolithiasis without dysplasia or carcinoma, 18 of ICC without hepatolithiasis, and 39 control livers. TFF1 expression in the biliary epithelium was increased in hepatolithiasis compared with control livers (p < 0.01). In biliary epithelial dysplasia and noninvasive ICC with hepatolithiasis, TFF1 was extensively expressed and MUC5AC gastric mucin was usually colocalized with TFF1. However, TFF1 expression was significantly decreased in invasive ICC despite preserved expression of MUC5AC. A total of four missense mutations were detected: three in two noninvasive ICC with hepatolithiasis (28.6%) and one in invasive ICC (11%). Loss of heterozygosity of the TFF1 gene was not detectable. The decreased expression of TFF1 in invasive ICC may be explained by the methylation of the TFF1 promoter region. Up-regulation of TFF1 coupled with MUC5AC in biliary epithelium in hepatolithiasis, biliary epithelial dysplasia, and noninvasive ICC may reflect the gastric metaplasia and early neoplastic lesion. Under such conditions, decreased TFF1 expression may lead to increased cell proliferation and then to the invasive character of ICC.


Asthma induced by suggestion: is it due to airway cooling?
The effect of suggestion on the airway response to 10 inhalations of normal saline followed by doubling concentrations of isoproterenol was assessed in 12 normal and 30 asthmatic subjects. It was suggested that the first 5 saline solutions contained a bronchoconstrictor and that the second 5 contained a bronchodilator, or vice versa, and that the first 4 isoproterenol solutions were inert, whereas the last was a bronchodilator. Nine asthmatic, but no normal subjects, bronchoconstricted after saline inhalation, with a mean fall in specific airway conductance (SGaw) of 40%. This was dose-dependent and was abolished when inhalations were carried out at 37 degrees C 100% relative humidity. Suggestion did not affect the airway response to saline or isoproterenol in either group, but it did influence the subjective impression of airway caliber recorded on a visual analogue scale. In this study, the bronchoconstriction after saline inhalation, previously attributed to the effect of suggestion, was caused by airway cooling.


Duodenal brush border intestinal alkaline phosphatase activity affects bicarbonate secretion in rats.
We hypothesized that duodenal HCO(3)(-) secretion alkalinizes the microclimate surrounding intestinal alkaline phosphatase (IAP), increasing its activity. We measured AP activity in rat duodenum in situ in frozen sections with the fluorogenic substrate ELF-97 phosphate and measured duodenal HCO(3)(-) secretion with a pH-stat in perfused duodenal loops. We examined the effects of the IAP inhibitors L-cysteine or L-phenylalanine (0.1-10 mM) or the tissue nonspecific AP inhibitor levamisole (0.1-10 mM) on AP activity in vitro and on acid-induced duodenal HCO(3)(-) secretion in vivo. AP activity was the highest in the duodenal brush border, decreasing longitudinally to the large intestine with no activity in stomach. Villous surface AP activity measured in vivo was enhanced by PGE(2) intravenously and inhibited by luminal L-cysteine. Furthermore, incubation with a pH 2.2 solution reduced AP activity in vivo, whereas pretreatment with the cystic fibrosis transmembrane regulator (CFTR) inhibitor CFTR(inh)-172 abolished AP activity at pH 2.2. L-Cysteine and L-phenylalanine enhanced acid-augmented duodenal HCO(3)(-) secretion. The nonselective P2 receptor antagonist suramin (1 mM) reduced acid-induced HCO(3)(-) secretion. Moreover, L-cysteine or the competitive AP inhibitor glycerol phosphate (10 mM) increased HCO(3)(-) secretion, inhibited by suramin. In conclusion, enhancement of the duodenal HCO(3)(-) secretory rate increased AP activity, whereas inhibition of AP activity increased the HCO(3)(-) secretory rate. These data support our hypothesis that HCO(3)(-) secretion increases AP activity by increasing local pH at its catalytic site and that AP hydrolyzes endogenous luminal phosphates, presumably ATP, which increases HCO(3)(-) secretion via activation of P2 receptors.


Prevalence and associated risk factors of hypertension among people aged 50 years and more in Banepa Municipality, Nepal.
Hypertension is a cardiovascular disorder rapidly emerging as a major public health problem in developing countries and is the most widely recognized modifiable risk factor for cardiovascular diseases. The objective of this study was to find out the prevalence and associated risk factors with hypertension among people aged 50 years and more in Banepa Municipality, Kavre, Nepal. It is a cross- sectional, population based study which was carried out in Banepa Municipality from May 15 to June 15, 2009. Among total 11 wards of Banepa municipally, wards number 1, 3, 5, 6, 7, and 10 were selected by using Simple Random Sampling Technique and 405 subjects of people aged 50 years and more were selected for study from the selected wards by using Cluster Sampling. The structured interview method was used for collection of data. Mercury sphygmomanometers with standard cuff were used to measure the indirect auscultatory arterial blood pressure. Two consecutive blood pressure readings were taken and average of them was calculated to determine single value of blood pressure. The prevalence of hypertension was 44.9 percent (47.75% in male and 42.73% in females). Among them, only 32.9 percent (60/182) were previously diagnosed as hypertension. The higher proportion of hypertensive cases were in age > 65 years (55.49%) than in the age group < 65 years (36.32%). The prevalence of hypertension was seen positively associated with non vegetarian eating habits, alcohol consumption, and > 25 Body max index. Taking green leafy vegetable at least once a week was negatively associated with the prevalence of the hypertension. These findings provide important information on the prevalence, associated factors of hypertension in Banepa Municipality. Effective public health measures and strategies are needed to improve prevention, diagnosis and access to treatment of these 50 years and above population.


Nasal Absorption Enhancement of Mometasone Furoate Nanocrystal Dispersions.
We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF). MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice. The particle size range of MF prepared with the bead mill treatment was 80-200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions. We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.


Shewanella-mediated biosynthesis of manganese oxide micro-/nanocubes as efficient electrocatalysts for the oxygen reduction reaction.
Developing efficient electrocatalysts for the oxygen reduction reaction (ORR) is critical for promoting the widespread application of fuel cells and metal-air batteries. Here, we develop a biological low-cost, ecofriendly method for the synthesis of Mn2 O3 micro-/nanocubes by calcination of MnCO3 precursors in an oxygen atmosphere. Microcubic MnCO3 precursors with an edge length of 2.5 μm were fabricated by dissimilatory metal-reducing Shewanella loihica PV-4 in the presence of MnO4 (-) as the sole electron acceptor under anaerobic conditions. After calcining the MnCO3 precursors at 500 and 700 °C, porous Mn2 O3 -500 and Mn2 O3 -700 also showed microcubic morphology, while their edge lengths decreased to 1.8 μm due to thermal decomposition. Moreover, the surfaces of the Mn2 O3 microcubes were covered by granular nanoparticles with average diameters in the range of 18-202 nm, depending on the calcination temperatures. Electrochemical measurements demonstrated that the porous Mn2 O3 -500 micro-/nanocubes exhibit promising catalytic activity towards the ORR in an alkaline medium, which should be due to a synergistic effect of the overlapping molecular orbitals of oxygen/manganese and the hierarchically porous structures that are favorable for oxygen absorption. Moreover, these Mn2 O3 micro-/nanocubes possess better stability than commercial Pt/C catalysts and methanol-tolerance property in alkaline solution. Thus the Shewanella-mediated biosynthesis method we provided here might be a new strategy for the preparation of various transition metal oxides as high-performance ORR electrocatalysts at low cost.


Investigational therapies targeting the granulocyte macrophage colony-stimulating factor receptor-α in rheumatoid arthritis: focus on mavrilimumab.
Mavrilimumab (formerly CAM-3001) is a high-affinity, immunoglobulin G4 monoclonal antibody (mAb) against the granulocyte macrophage colony-stimulating factor (GM-CSF) receptor-α chain. Phase I and II trials in patients with rheumatoid arthritis (RA) treated with mavrilimumab have shown encouraging results with respect to both safety and efficacy. No significant adverse events have so far been noted. The trials have demonstrated significant clinical benefit, meeting primary endpoints. Furthermore, for RA patients treated with mavrilimumab, who were tumour necrosis factor (TNF) inhibitor-inadequate responders, there are encouraging preliminary data indicating benefit and identifying potential biomarkers predictive of patients likely to find benefit. Here, we review the clinical trial data for mavrilimumab and discuss its potential as a treatment for RA in light of the competitive landscape in which it resides.


Altered expression and interaction of adherens junction proteins in the developing OLM of the Rho(-/-) mouse.
Retinitis Pigmentosa (RP) represents a major cause of progressive retinal disease worldwide and comprises a heterogeneous group of inherited diseases that are characterised by primary degeneration of rod photoreceptors and secondary degeneration of cone photoreceptors in the retina. The outer limiting membrane (OLM) which allows for the interaction of photoreceptors with surrounding photoreceptors and Müller cells is compromised in many degenerative retinal diseases. Using indirect immunostaining of retinal cryosections from C-129 Wild Type (WT) and C-129 Rho(-/-) mice, we have determined levels of expression of the adherens junction associated proteins ZO-1, beta-catenin and p120-catenin at the OLM from newborn and 1, 2, 3, 4 and 5-week old animals. We have also used immunoprecipitation analysis to determine changes in the association of E-cadherin with ZO-1, beta-catenin and p120-catenin and the association of alpha-catenin with ZO-1 and beta-catenin at these time points in WT and Rho(-/-) mice. We have found that ZO-1 expression at the OLM is present in WT and Rho(-/-) mice after 2weeks, but that levels of expression at the OLM decrease after this time point in the Rho(-/-) mice. beta-catenin expression in the Rho(-/-) mice became compromised at the OLM after 3 weeks, showing a distinct change in staining pattern after 4 weeks and no staining at the OLM after 5 weeks. Moreover, we have shown that p120-catenin expression is not evident at the OLM of the Rho(-/-) mice at the 4 or 5 week time point. To complement this data, we have performed immunoprecipitation analysis on neural retinal lysates from WT and Rho(-/-) mice and herein report fluctuations in the association of E-cadherin with ZO-1, and beta-catenin, while showing that the interaction of E-cadherin with p120-catenin is not established in the retina of C-129 WT and Rho(-/-) mice until 4 weeks after birth and remains un-changed up to and including 5 weeks after birth. Meanwhile, we report that the association of alpha-catenin with ZO-1 is decreased in retinas of the Rho(-/-) from newborn animals up to and including 5 weeks after birth. We have also shown that the association of alpha-catenin and beta-catenin is not well established in WT and Rho(-/-) mice until at least 5 weeks after birth. We hypothesize that these retinal changes at the OLM may contribute significantly to the pathogenesis of retinal degenerations and may represent a unique therapeutic target for intervention in conditions involving rapid photoreceptor cell death.


Manufacturing monodisperse chitosan microparticles containing ampicillin using a microchannel chip.
The purpose of this study was using a developed microfluidic chip to prepare size-controlled monodisperse chitosan microparticles encapsulating ampicillin. Our strategy is that a chitosan aqueous solution (the disperse phase) is fed into the microfluidic chip equipped with a cross-junction microchannel, and is sheared by the viscous oil flows (the continuous phase) to form monodisperse semi-product, chitosan emulsions. These fine emulsions are then gelled into stability upon gelation by injection of copper sulfate solution at the terminal microchannel of the microfluidic chip, and finally the uniform chitosan microparticles are formed in an efficient manner. The proposed chip is fabricated by a CO(2) laser machine on a conventional poly methyl methacrylate (PMMA) substrate. This microfluidic chip has four inlet ports, one cross-channel and one outlet port. We have demonstrated that one can control the size of chitosan microparticles from 100 to 800 microm in diameter (with a variation less than 5%) by altering the relative sheath/sample flow rate ratio. Experimental data showed that when given a steady continuous phase (oil flow), the emulsion size increases with the increase in average velocity of the dispersed phase flow (sample flow). In addition, the release of the model drug (ampicillin) from these microspheres is proved to be once-daily for clinical application. We also revealed that appropriate particle sizes for different release patterns are predictable, enabling better applications of chitosan as a drug carrier.


Stress-Induced Microstructural Alterations Correlate With the Cognitive Performance of Rats: A Longitudinal in vivo Diffusion Tensor Imaging Study.
Background: Stress-induced cellular changes in limbic brain structures contribute to the development of various psychopathologies. In vivo detection of these microstructural changes may help us to develop objective biomarkers for psychiatric disorders. Diffusion tensor imaging (DTI) is an advanced neuroimaging technique that enables the non-invasive examination of white matter integrity and provides insights into the microstructure of pathways connecting brain areas. Objective: Our aim was to examine the temporal dynamics of stress-induced structural changes with repeated in vivo DTI scans and correlate them with behavioral alterations. Methods: Out of 32 young adult male rats, 16 were exposed to daily immobilization stress for 3 weeks. Four DTI measurements were done: one before the stress exposure (baseline), two scans during the stress (acute and chronic phases), and a last one 2 weeks after the end of the stress protocol (recovery). We used a 4.7T small-animal MRI system and examined 18 gray and white matter structures calculating the following parameters: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). T2-weighted images were used for volumetry. Cognitive performance and anxiety levels of the animals were assessed in the Morris water maze, novel object recognition, open field, and elevated plus maze tests. Results: Reduced FA and increased MD and RD values were found in the corpus callosum and external capsule of stressed rats. Stress increased RD in the anterior commissure and reduced MD and RD in the amygdala. We observed time-dependent changes in several DTI parameters as the rats matured, but we found no evidence of stress-induced volumetric alterations in the brains. Stressed rats displayed cognitive impairments and we found numerous correlations between the cognitive performance of the animals and between various DTI metrics of the inferior colliculus, corpus callosum, anterior commissure, and amygdala. Conclusions: Our data provide further support to the translational value of DTI studies and suggest that chronic stress exposure results in similar white matter microstructural alterations that have been documented in stress-related psychiatric disorders. These DTI findings imply microstructural abnormalities in the brain, which may underlie the cognitive deficits that are often present in stress-related mental disorders.


Analysis of the prestarvation response in growing cells of Dictyostelium discoideum.
We have previously shown that growing cells of Dictyostelium discoideum (strains NC4 and AX3) produce a soluble substance that accumulates in the medium in proportion to cell density; this substance regulates the production of certain proteins previously thought to be induced by starvation [Clarke et al., 1987]. We suggest the name PSF (prestarvation factor) for this substance. During growth, Dictyostelium cells monitor the relative concentrations of PSF and food bacteria. When PSF reaches a sufficiently high level relative to the concentration of bacteria, synthesis of PSF-regulated proteins is induced. We propose the name prestarvation response for this induction, which takes place in exponentially growing cells several generations before the food bacteria are depleted. We have explored the mechanism by which the food bacteria inhibit the response of Dictyostelium cells to PSF. We find that the bacteria do not inactivate PSF or inhibit its production; instead, they affect the ability of NC4 cells to detect PSF, possibly by binding to the same cell surface receptor. In the absence of bacteria, as during axenic growth of AX3 cells, the prestarvation response occurs at much lower cell densities, probably accounting for the presence of certain developmentally regulated mRNAs and proteins in axenic cultures.


Protein loss induced by complement activation during peritoneal dialysis.
A variable loss of macromolecules during peritoneal dialysis has been noted in both humans and experimental animals. We investigated the potential role of the complement system for inducing protein loss during peritoneal dialysis, both to shed light on clinical variability of protein loss and to develop a model for quantitatively studying complement-induced microvascular protein leakage. Rats received intra-arterial injections of a fluorescent dye conjugated to rat serum albumin and underwent a 3.5-hr series of 15-min peritoneal dialysis exchanges. After the control exchanges, rats received either intra-arterial zymosan-activated rat serum, saline, unactivated rat serum, or endotoxin; other rats received an intraperitoneal injection of endotoxin, histamine, phenylephrine, or nitroprusside. The drainage volume from each exchange was measured, and the concentrations of labeled albumin, total protein, and urea were determined by spectroscopy. Zymosan-activated rat serum and endotoxin injections (both intraperitoneal and intra-arterial), each of which may activate the alternative pathway of complement, produced a dramatic increase in dialysate protein concentrations. In addition, histamine, which is a vasodilator but which may also be involved as a mediator of the activated complement system and/or endotoxemia, also produced an increase in dialysate protein concentrations. On the other hand, drugs which may alter peritoneal blood flow such as the vasodilator nitroprusside or the vasoconstrictor phenylephrine, did not affect dialysate protein concentrations. These data suggest that activation of the alternative pathway of complement may cause variation in protein loss during peritoneal dialysis and that in some situations, pharmacological control of this system could be an important therapeutic consideration.


[Osteogenic effect of peptides anchored aminated tissue engineered bone for repairing femoral defect in rats].
To study the osteogenic effects of a new type of peptides anchored aminated-poly-D, L-lactide acid (PA/PDLLA) scaffold in repairing femoral defect in rats. The PDLLA scaffolds were treated by ammonia plasma and subsequent anchor of Gly-Arg-Gly-Asp-Ser (GRGDS) peptides via amide linkage formation. Thus PA/PDLLA scaffolds were prepared. The bone marrow was harvested from the femur and tibia of 4 4-week-old Sprague Dawley (SD) rats, and bone marrow mesenchymal stem cells (BMSCs) were isolated and cultured by whole bone marrow adherence method. BMSCs-scaffold composites were prepared by seeding osteogenic-induced BMSCs at passages 3-6 on the PA/PDLLA and PDLLA scaffolds. The right femoral defects of 8 mm in length were prepared in 45 adult male SD rats (weighing, 350-500 g) and the rats were divided into 3 groups (n=15) randomly. BMSCs-PA/PDLLA (PA/PDLLA group) or BMSCs-PDLLA (PDLLA group) composites were used to repair defects respectively, while defects were not treated as blank control (blank control group). General state of the rats after operation was observed. At 4, 8, and 12 weeks after operation, general, radiological, histological, micro-CT observations and real-time fluorescent quantitative PCR were performed. Two rats died after operation, which was added; the other rats survived to the end of the experiment. At each time point after operation, general and radiological observations showed more quick and obvious restoration in PA/PDLLA group than in PDLLA group; no bone repair was observed in blank control group. The X-ray scores were the highest in PA/PDLLA group, higher in PDLLA group, and the lowest in blank control group; showing significant difference in multiple comparison at the other time (P < 0.05) except between blank control group and PDLLA group at 4 weeks (P > 0.05). The X-ray scores showed an increasing trend in PDLLA group and PA/PDLLA group with time (P < 0.05). Histological and micro-CT observations showed the best osteogenesis in PA/PDLLA group, better in PDLLA group, and worst in blank control group. Comparison between groups had significant differences (P < 0.05) in bone mineral density, bone volume/total volume of range of interest, trabecular number, and structure model index. Significant differences (P < 0.05) were found in the expression levels of osteogenesis-related genes, such as osteocalcin, alkaline phosphatase, collagen type I, bone morphogenetic protein 2, and osteopontin when compared PA/PDLLA group with the other groups by real-time fluorescent quantitative PCR analysis. The PA/PDLLA scaffolds can accelerate the repair of femoral defects in rats.


First case of Furuncular Myiasis due to Cordylobia anthropophaga in a Latin American resident returning from Central African Republic.
Myiasis is a temporary infection of the skin or other organs with fly larvae.1 The larvae develop into boil-like lesions. Creeping sensations and pain are usually described by patients. Following the maturation of the larvae, spontaneous exiting and healing is experienced. Herein we present a case of a traveler returning from Central African Republic. She does not recall insect bites. She never took off her clothing for recreational bathing, nor did she visit any rural areas. The lesions appeared on unexposed skin. The specific diagnosis was performed by morphologic characterization of the larvae, resulting in Cordylobia anthropophaga, the dominant form of myiasis in Africa. To our knowledge, this is the first reported case of C. anthropophaga in Latin America.


High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study.
With the intention of starting an international protocol between Italy and Scandinavia on neoadjuvant treatment of extremity osteosarcoma using the four active drugs at maximum doses (doxorubicin 75 mg/m2 pre-operatively, and 90 mg/m2 post-operatively, cisplatin 120 mg/m2, methotrexate 12 g/m2, and ifosfamide 15 g/m2), a single center (the Rizzoli institute) performed a pilot study to closely monitor toxicity, safety, and tumor necrosis. Only 7 patients (10%) had a reduced number of the scheduled cycles. A total of 1,050 of the expected 1,076 cycles (98%) were administered. Delays and dose reduction were minimal, leading to a mean received dose intensity of 89%. Limb salvage surgery was performed in 59 cases (87%), with 6 amputations and 3 rotation plasties. Chemotherapy-induced necrosis higher than 95% was observed in 38 patients (56%). Eleven patients had total necrosis (16%). At a median follow-up of 60 months (range 50-65 months), 53 patients (73%) were continuously disease-free. Six of the relapsed patients were rescued with further treatments leading to an overall survival of 87%. Hematological toxicity was remarkable despite the use of G-CSF and hospitalization due to febrile neutropenia occurred in 25 patients (37%). Platelet transfusions were required in 77 of the 194 episodes of grade 4 thrombocytopenia, but no case of major bleeding was observed. Red blood cell transfusions were necessary in all patients (in 15 cases perioperatively only). Non-hematological toxicity comprised grade 1-2 nephrotoxicity in 3 cases, CNS toxicity in 2 cases, and dilata- tive cardiopathy leading to heart transplantation in 1 case. In conclusion, the pilot study was feasible in the vast majority of cases with toxicity not superior to that of the previous protocols where chemotherapy was given in lower doses. The rate of limb salvage procedures, event-free survival and overall survival seemed to be higher than in previous protocols. On the basis of this study, in March 1997 the Italian and Scandinavian Sarcoma Groups started a new protocol for osteosarcoma of the extremities.


Electroconvulsive therapy in older adults: 13-year trends.
To examine temporal trends in electroconvulsive therapy (ECT) use among all 12 million Ontario residents between January 1992 and December 2004 and to examine the differential trends in older adults, compared with younger ones. We undertook a time-series analysis to examine annual trends in the use and prevalence of ECT, using linked provincial datasets. Descriptive data were presented for the population as a whole, and then trends were described separately by age groups (younger and older). As a comparator, we similarly examined antidepressant prevalence for older adults over the same time period. Overall rates of ECT prevalence were stable. Annual population rates of individuals receiving ECT increased by about 27%, from 12.3 per 100 000 population in 1992 to 15.6 per 100 000 in 1997, and then decreased to 12.5 per 100 000 by 2004. The population rates of ECT were about threefold higher among older adults, relative to the younger population. Antidepressant prevalence increased by 90.1% among older adults over the same time period. The female-to-male ratio was relatively stable over time. The rate of ECT has been relatively stable since the early 1990s. Older adults were much more likely to be prescribed a course of ECT than younger adults. ECT remains a commonly prescribed treatment, particularly in old age.


Reliability of carotid doppler performed in a dedicated stroke prevention clinic.
Doppler ultrasound (DUS) is used as a screening tool to assess internal carotid artery (ICA) disease. Recent reports suggest that the DUS may be inaccurate in over 28% of patients. We sought to evaluate the accuracy of DUS, when performed in a dedicated stroke prevention clinic (SPC). We retrospectively reviewed the charts of patients who had a DUS performed in our SPC, followed by conventional cerebral angiography. Three groups of patients were defined. Group 1 had DUS measured ICA stenosis of >50%; Group II had a DUS measured ICA stenosis of <50%; Group III had complete ICA occlusion on DUS. Sixty-seven patients (69 arteries) were included in the study. There were 45 patients in Group I and based on the findings of cerebral angiography, carotid endarterectomy was considered inappropriate in only one patient--a misclassification rate of 2.2% (95% CI: 0 - 6.5%). Group II consisted of 19 patients and on cerebral angiography, none of these patients had a stenosis of >50%--a misclassification rate of 0%. Group III consisted of five patients in whom DUS showed complete ICA occlusion. The angiogram confirmed the occlusion in all five patients--a misclassification rate of 0%. Overall, misclassification rate was 1.45% (95% CI: 0 - 4.3%). Doppler ultrasound when performed in a stroke prevention clinic (SPC), has a high accuracy in measuring ICA stenosis of >50%. Doppler ultrasound is reliable in detecting complete ICA occlusion and finally DUS is a reliable screening tool to rule out clinically significant ICA stenosis.


Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior.
Glutamatergic neurotransmission is implicated in alcohol-drinking behavior in animal models. To investigate whether genetic variations in glutamatergic neurotransmission genes, which are known to alter alcohol effects in rodents, contribute to the genetic basis of alcoholism in humans. Association analysis of alcohol dependence and haplotype-tagging single nucleotide polymorphisms (SNPs) covering 10 glutamatergic genes. Resequencing of functional domains of these genes identified 204 SNPs. Haplotypes with a frequency of 5% or greater could be discriminated by 21 haplotype-tagging SNPs analyzed for association in 2 independent samples of alcohol-dependent adult patients and controls as well as adolescent trios. Four university medical centers in the south of Germany. One thousand three hundred thirty-seven patients and 1555 controls (study 1: 544 patients, 553 controls; study 2: 793 patients, 1002 controls). One hundred forty-four trios of 15-year-old adolescents assessed for risky drinking behavior. Genotype profiles for GLAST; N-methyl-d-aspartate-receptor subunits NR1, NR2A, and NR2B; MGLUR5; NNOS; PRKG2; CAMK4; the regulatory subunit of PI3K; and CREB were analyzed for association with alcohol dependence using multivariate statistical analysis. Risky adolescent drinking was tested using the transmission disequilibrium test. Analysis of study 1 revealed that NR2A and MGLUR5 have the greatest relevance for human alcohol dependence among the genes selected with odds ratios of 2.35 and 1.69, respectively. Replication analysis in study 2 confirmed an association of alcohol dependence with NR2A (odds ratio, 2.01) but showed no association with MGLUR5. Combined analysis of study 1 and study 2 exhibited a more significant association on the Cochran-Mantel-Haenszel test (P < .001) for NR2A; NR2A was associated with positive family history, early onset of alcoholism, and maximum number of drinks in adults as well as risky drinking patterns in adolescents. Genetic variations in NR2A have the greatest relevance for human alcohol dependence among the glutamatergic genes selected for their known alteration of alcohol effects in animal models.


Epigenomic Consequences of Coding and Noncoding Driver Mutations.
Chromatin alterations are integral to the pathogenic process of cancer, as demonstrated by recent discoveries of frequent mutations in chromatin-modifier genes and aberrant DNA methylation states in different cancer types. Progress is being made on elucidating how chromatin alterations, and how proteins catalyzing these alterations, mechanistically contribute to tissue-specific tumorigenesis. In parallel, technologies enabling the genome-wide profiling of histone modifications have revealed the existence of noncoding driver genetic alterations in cancer. In this review, we survey the current knowledge of coding and noncoding cancer drivers, and discuss their impact on the chromatin landscape. Translational implications of these findings for novel cancer therapies are also presented.


Analysis of gene expression in poultry red mite, Dermanyssus gallinae, by RNAscope in situ hybridization.
The poultry red mite (PRM; Dermanyssus gallinae) is a hematophagous ectoparasite that mainly infests chickens, and its infestation causes significant economic losses to the poultry industry. In this study, we examined the use of RNAscope-based in situ hybridization (ISH) to characterize gene expression in PRM. We analyzed the mRNA expression of Dermanyssus gallinae cathepsin D-1 (Dg-CatD-1) and Dermanyssus gallinae cystatin (Dg-Cys). RNAscope ISH analysis revealed that mRNA expression of Dg-CatD-1 was observed in the digestive tract, and Dg-Cystatin mRNA was expressed in the ovaries in addition to the digestive tract. RNAscope ISH could be applicable for the analysis of gene expression in each tissue of PRM and is an effective method to investigate the characteristics of target genes.


Genetic Predisposition to Dyslipidemia and Risk of Preeclampsia.
Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia. Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL-C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04). Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia.


Infectious RNA transcripts from Ross River virus cDNA clones and the construction and characterization of defined chimeras with Sindbis virus.
We have constructed a full-length cDNA clone of the virulent T48 strain of Ross River virus, a member of the alphavirus genus. Infectious RNA can be transcribed from this clone using SP6 or T7 RNA polymerase. The rescued virus has properties indistinguishable from those of the T48 strain of Ross River virus. We have used this clone, together with a full-length cDNA clone of Sindbis virus, to construct chimeric plasmids in which the 5' and the 3' nontranslated regions of the Sindbis and Ross River genomes were exchanged. The nontranslated regions of the two viral genomes differ in both size and sequence although they maintain specific conserved sequence elements. Virus was recovered from all four chimeras. Chimeras containing heterologous 3' nontranslated regions had replicative efficiencies equal to those of the parents. In contrast, the chimeras containing heterologous 5' nontranslated regions were defective in RNA synthesis and virus production, and the severity of the defect was dependent upon the host. Replication of a virus containing a heterologous 5' nontranslated region may be inefficient due to the formation of defective protein-RNA complexes, whereas, the presumptive complexes formed between host or virus proteins and the 3' nontranslated region to promote RNA synthesis appear to function normally in the chimeras.


A GIS-based methodology for selecting stormwater disconnection opportunities.
The purpose of this paper is to introduce a geographic information system (GIS)-based decision support tool that assists the user to select not only areas where (retrofit) sustainable drainage systems (SuDS) could be implemented within a large catchment (>100 ha), but also to allow discrimination between suitable SuDS techniques based on their likely feasibility and effectiveness. The tool is applied to a case study catchment within London, UK, with the aim of increasing receiving water quality by reducing combined sewer overflow (CSO) spill frequency and volume. The key benefit of the tool presented is to allow rapid assessment of the retrofit SuDS potential of large catchments. It is not intended to replace detailed site investigations, but may help to direct attention to sites that have the greatest potential for retrofit SuDS implementation. Preliminary InfoWorks CS modelling of 'global disconnections' within the case study catchment, e.g. the removal of 50% of the total impervious area, showed that CSO spill volume could be reduced by 55 to 78% during a typical year. Using the disconnection hierarchy developed by the authors, the feasibility of retrofit SuDS deployment within the case study catchment is assessed, and the implications discussed.


Choices for return of primary and secondary genomic research results of 790 members of families with Mendelian disease.
Although consensus is building that primary (PR) and secondary findings (SF) from genomic research should be offered to participants under some circumstances, data describing (1) actual choices of study participants and (2) factors associated with these choices are limited, hampering study planning. We conducted a cross-sectional analysis of choices made for return of PR and SF during informed consent by members of the first 247 families (790 individuals) enrolled in the Baylor-Hopkins Center for Mendelian Genomics, a genome sequencing study. Most (619; 78.3%) chose to receive SF and PR, 66 (8.4%) chose PR only, 65 (8.2%) wanted no results, and 40 (5.1%) chose SF only. Choosing SF was associated with an established clinical diagnosis in the proband (87.8 vs 79%, P=0.009) and European ancestry (EA) (87.7 vs 73%, P<0.008). Participants of non-European ancestry (NEA) were as likely as those of EA to choose SF when consented by a genetic counselor (GC) (82% NEA vs 88.3% EA, P=0.09) but significantly less likely when consented by a physician (67.4% NEA vs 85.4% EA, P=0.001). Controlling for proband diagnosis, individuals of NEA were 2.13-fold (95% CI: 1.11-4.08) more likely to choose SF when consented by a GC rather than a physician. Participants of NEA were 3-fold more likely than those of EA to decline all study results (14.7% NEA vs 5.4% EA, P<0.008). In this ethnically diverse population, whereas most participants desired PR and SF, more than 20% declined some or all results, highlighting the importance of research participant choice.


Trends and Variations in Reproduction and Intrinsic Rates: United States, 1990-2014.
Objective-This report presents trends in reproduction and intrinsic rates from 1990 through 2014. In addition, total fertility and gross reproduction rates by race and Hispanic-origin group are presented from 1990 through 2014, and net reproduction and intrinsic rates for selected race and Hispanic-origin group are presented from 2006 through 2014. Methods-Tabular and graphic data on the trends in the reproduction and intrinsic rates for the United States, by race and Hispanic origin of mother, are presented and described. Results-Rates of reproduction (total fertility, gross reproduction, and net reproduction), the intrinsic rate of natural increase, and the intrinsic birth rate were lower in 2014 than 1990. After a steady decline from 1990 through 1997, all rates increased from 1997 through 2007 but declined again from 2007 through 2013. The rates increased between 2013 and 2014. Among the race and Hispanic subgroups examined, the total fertility and gross reproduction rates were lower for all groups in 2014 compared with 1990. The net reproduction rate, intrinsic rate of natural increase, and intrinsic birth rate for the selected groups non-Hispanic white, non-Hispanic black, and Hispanic declined from 2006 through 2014.


Therapeutic potential of leukemia-derived dendritic cells: preclinical and clinical progress.
Human leukemia-derived dendritic cells show potential as tools for therapy. Leukemic cells of patients with chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and chronic myelomonocytic leukemia (CMML) will all undergo substantial differentiation toward dendritic cells (DC) and may be used to drive autologous T cells to acquire anti-leukemic cytotoxicity. This article describes the use of these human leukemia-derived dendritic cells for stimulation of allogeneic donor lymphocytes and presents a clinical trial of autologous CML DC-stimulated lymphocytes.


Dynamic spatial tuning of cervical muscle reflexes to multidirectional seated perturbations.
Human volunteers were exposed experimentally to multidirectional seated perturbations. To determine the activation patterns, spatial distribution and preferred directions of reflexively activated cervical muscles for human model development and validation. Models of the human head and neck are used to predict occupant kinematics and injuries in motor vehicle collisions. Because of a dearth of relevant experimental data, few models use activation schemes based on in vivo recordings of muscle activation and instead assume uniform activation levels for all muscles within presumed agonist or antagonist groups. Data recorded from individual cervical muscles are needed to validate or refute this assumption. Eight subjects (6 males, 2 females) were exposed to seated perturbations in 8 directions. Electromyography was measured with wire electrodes inserted into the sternocleidomastoid, trapezius, levator scapulae, splenius capitis, semispinalis capitis, semispinalis cervicis, and multifidus muscles. Surface electrodes were used to measure sternohyoid activity. Muscle activity evoked by the perturbations was normalized with recordings from maximum voluntary contractions. The multidirectional perturbations produced activation patterns that varied with direction within and between muscles. Sternocleidomastoid and sternohyoid activated similarly in forward and forward oblique directions. The semispinalis capitis, semispinalis cervicis, and multifidus exhibited similar spatial patterns and preferred directions, but varied in activation levels. Levator scapulae and trapezius activity generally remained low, and splenius capitis activity varied widely between subjects. All muscles showed muscle- and direction-specific contraction levels. Models should implement muscle- and direction-specific activation schemes during simulations of the head and neck responses to omnidirectional horizontal perturbations where muscle forces influence kinematics, such as during emergency maneuvers and low-severity crashes. N/A.


Oxidized linoleic acid metabolite-cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain.
Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [eg, cytochrome P450 (CYP)] are up-regulated after inflammation in the rat. However, it is not known whether such agonists are elevated in human inflammatory pain conditions. Because TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal vs inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues evoked significant inward currents in trigeminal ganglia neurons and were blocked by pretreatment with the TRPV1 antagonist IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in trigeminal ganglia neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of 2 CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicate that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.


Avoiding socialization pitfalls in accelerated second-degree nursing education: the returning-to-school syndrome model.
Second-degree students are highly motivated and tend to excel academically. However, nurse educators in accelerated programs face challenges in socializing these students to the nursing role. One pitfall is the hostility that may develop if students perceive a mismatch between their expectations and their new role as baccalaureate nursing (BSN) students in a fast-paced and intense program. This article discusses the applicability of the returning-to-school syndrome model in helping second-degree nursing students maneuver successfully through an accelerated BSN program. This 3-stage model has been previously applied in RN-to-BSN education. Using the model in an accelerated BSN curriculum to identify transition points and offer student support through specific stages can better prepare students to meet the challenges of accelerated education, as well as help nurse educators become more adept at providing resources and implementing supportive strategies at the appropriate time.


Using willingness to pay to value close substitutes: carrier screening for cystic fibrosis revisited.
Evidence suggests that previous uses of willingness to pay (WTP) to value close substitutes may have failed to discriminate between the alternatives being evaluated. This paper reports on the application of a new technique for measuring WTP in such contexts. The alternatives evaluated are two methods of screening for cystic fibrosis carrier status. The results suggest that the new method is more discriminating. Furthermore, the paper provides evidence, from reasons for respondents' WTP valuations and regression analyses, that the use of open-ended WTP questions is not valid. This is in line with the recommendations of a recent, influential, report on the use WTP techniques.


Human schistosomiasis decreases immune responses to allergens and clinical manifestations of asthma.
Studies have demonstrated that people living in areas endemic for helminths have a decreased reactivity to skin prick tests to aeroallergens and milder forms of asthma. Hypotheses to explain the inverse correlation between helminth infections and atopy include competition between helminth-induced polyclonal IgE and aeroallergen-specific IgE for high-affinity receptors present on mast cells, increased number of regulatory T cells, and high levels of regulatory cytokines, such as IL-10, produced during helminthic infections. Indeed, cells from asthmatic individuals infected with Schistosoma mansoni produce lower levels of IL-5 than asthmatics free of infections. In contrast, IL-10 is more readily produced by allergen-stimulated cells from asthmatics who are infected and is detected only at low levels by cells from helminth-free asthmatics. It is well known that Th2 cytokines are involved in the pathogenesis of allergies and asthma, and some studies indicate that IL-10 is the key cytokine that inhibits the Th2-inflammatory response in allergy. In this chapter we will discuss the association between S. mansoni infection, atopy and severity of asthma and possible mechanisms by which individuals living in helminth endemic areas are protected against the development of allergies.


Predicting Hepatitis B Virus (HBV) Surface Antigen Seroclearance in HBV e Antigen-Negative Patients With Chronic Hepatitis B: External Validation of a Scoring System.
Hepatitis B virus (HBV) surface antigen (HBsAg) seroclearance is the ultimate serological end point in chronic hepatitis B. This study aimed to develop and validate a prediction score for spontaneous HBsAg seroclearance in HBV e antigen (HBeAg)-negative patients with chronic hepatitis B due to HBV genotype B or C. The development cohort included 2491 untreated participants from the community-based REVEAL-HBV study, who were HBeAg negative, anti-hepatitis C virus negative, and cirrhosis free. The independent validation cohort consisted of 1934 hospital-based individuals from the National Taiwan University Hospital. Clinical markers included in the model were age and serum HBV DNA and HBsAg levels. Cox proportional hazards regression models were used to create the prediction model. A prediction score ranging from 0 to 27 was developed. Predicted probabilities of 5- and 10-year HBsAg seroclearance ranged from 0.95% to 30.49% and from 2.58% to 62.52%, respectively. When applied to the independent validation cohort, the areas under the receiver operating characteristic curves for the 5- and 10-year prediction of HBsAg seroclearance in the validation cohort were 0.82 (95% confidence interval [CI], .76-.88) and 0.74 (95% CI, .70-.78). Model fit was still adequate, according to Hosmer-Lemeshow goodness of fit tests. A clinically applicable prediction score for HBsAg seroclearance was developed and externally validated. This model can assist clinicians in further stratifying risk groups.


Dynamic strength of the interaction between lung surfactant protein D (SP-D) and saccharide ligands.
In order to investigate the dynamic strength of the interaction between lung surfactant protein D (SP-D) and different sugars, maltose, mannose, glucose, and galactose, we have used an atomic force microscope to monitor the interaction on a single molecule scale. The experiment is performed by measuring the rupture force when the SP-D-sugar bond is subjected to a continuously increasing force. Under these dynamic conditions, SP-D binds strongest to d-mannose and weakest to maltose and d-galactose. These results differ from equilibrium measurements wherein SP-D exhibits preference for maltose. On the basis of this finding, we propose that the binding of the disaccharide maltose to SP-D, which is energetically stronger than the binding of any of the monosacchrides, alters the structure of the binding site in a way that lowers the dynamic strength of the bond. We conclude that determining the strength of a protein-ligand bond under dynamic stress using an atomic force microscope is possibly more relevant for mimicking the actual nonequilibrium physiological situation in the lungs.


[Transvaginal echography in the study of urinary stress incontinence].
Hypermobility of the bladder neck in response to increased intraabdominal pressure is one cause of stress urinary incontinence in women. Vaginal ultrasound (u.s.) is reliable and minimally invasive method for demonstrating bladder neck hypermobility. The Authors studied 50 women with S.U.I. and 40 with no history of S.U.I. measuring the distance from the bladder neck to the midline of the symphysis pubis (P.V.) and the angle between the BP line and the midline of the symphysis pubis (A.I.U.). The continent women were characterized by a median A.I.U. of 70 degrees and mean B.P. of 25.6 mm, at rest, a median A.I.U. of 80 degrees and a mean B.P. of 20 mm. at stress. The incontinent women were characterized by a median A.I.U. of 80 degrees and mean P.V. of 22.5 mm. at rest, and a median A.I.U. of 95 degrees and mean P.V. of 10 mm. at stress. There is a significant difference between the two groups. The Authors recommend the vaginal u.s. as reliable, practical, economical and patient accepted method to study the bladder neck mobility.


The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy.
Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.


Simultaneous deletion of p21Cip1/Waf1 and caspase-3 accelerates proliferation and partially rescues the differentiation defects of caspase-3 deficient hematopoietic stem cells.
Specialized blood cells are generated through the entire life of an organism by differentiation of a small number of hematopoietic stem cells (HSC). There are strictly regulated mechanisms assuring a constant and controlled production of mature blood cells. Although such mechanisms are not completely understood, some factors regulating cell cycle and differentiation have been identified. We have previously shown that Caspase-3 is an important regulator of HSC homeostasis and cytokine responsiveness. p21cip1/waf1 is a known cell cycle regulator, however its role in stem cell homeostasis seems to be limited. Several reports indicate interactions between p21cip1/waf1 and Caspase-3 in a cell type dependent manner. Here we studied the impact of simultaneous depletion of both factors on HSC homeostasis. Depletion of both Caspase-3 and p21cip1/waf1 resulted in an even more pronounced increase in the frequency of hematopoietic stem and progenitor cells. In addition, simultaneous deletion of both genes revealed a further increase of cell proliferation compared to single knock-outs and WT control mice, while apoptosis or self-renewal ability were not affected in any of the genotypes. Upon transplantation, p21cip1/waf1-/- bone marrow did not reveal significant alterations in engraftment of lethally irradiated mice, while Caspase-3 deficient HSPC displayed a significant reduction of blood cell production. However, when both p21cip1/waf1 and Caspase-3 were eliminated this differentiation defect caused by Caspase-3 deficiency was abrogated.


Modality-specific and supramodal mechanisms of apraxia.
This study investigated the relation of apraxia to the nature of the stimulus which is given to elicit the gesture. Patients were required to perform a movement imitation test and to demonstrate the use of the same ten objects, once on verbal command, once with the object shown but not handled, and once with the object handled but not seen. One set of comparisons concerned the performance on two tasks involving the visual modality, movement imitation and use of objects presented visually. Although the majority of left brain-damaged patients either failed or passed both tests, there were at least 13 patients who showed an exceedingly poor performance on demonstration of use as compared to imitation. We infer that the distinction between ideational and ideomotor apraxia is warranted. Another set of comparisons concerned the performance on the use of objects presented in the verbal, visual and tactile modalities. A greater percentage of patients failed on the verbal or visual modalities than on the tactile modality. Out of 64 left brain-damaged patients who were diagnosed as apraxic in at least one modality, 23 had an exceedingly poor score on one test as compared to their score on either or both other tests. Fourteen patients selectively failed on verbal presentation, 14 on visual presentation and 2 on tactile presentation. These findings are viewed as supporting the hypothesis that apraxia results from the disconnection between the areas where information is processed and the areas where the movement is programmed.


Modulation of phenolic metabolism under stress conditions in a Lotus japonicus mutant lacking plastidic glutamine synthetase.
This paper was aimed to investigate the possible implications of the lack of plastidic glutamine synthetase (GS2) in phenolic metabolism during stress responses in the model legume Lotus japonicus. Important changes in the transcriptome were detected in a GS2 mutant called Ljgln2-2, compared to the wild type, in response to two separate stress conditions, such as drought or the result of the impairment of the photorespiratory cycle. Detailed transcriptomic analysis showed that the biosynthesis of phenolic compounds was affected in the mutant plants in these two different types of stress situations. For this reason, the genes and metabolites related to this metabolic route were further investigated using a combined approach of gene expression analysis and metabolite profiling. A high induction of the expression of several genes for the biosynthesis of different branches of the phenolic biosynthetic pathway was detected by qRT-PCR. The extent of induction was always higher in Ljgln2-2, probably reflecting the higher stress levels present in this genotype. This was paralleled by accumulation of several kaempferol and quercetine glycosides, some of them described for the first time in L. japonicus, and of high levels of the isoflavonoid vestitol. The results obtained indicate that the absence of GS2 affects different aspects of phenolic metabolism in L. japonicus plants in response to stress.