A partially ossified solid and cystic Rathke cleft cyst.
A Rathke cleft cyst is considered to arise from the remnants of the Rathke pouch, and it consists of single cuboidal or columnar epithelium including cilia and goblet cells, which secrete mucus into the cyst. Magnetic resonance imaging characteristically shows a thin membranous cystic wall that enhances with Gd, and homogeneous intensity of the content suggesting fluid collection. Cases with an irregularly thickened and/or calcified cyst wall, presumably due to chronic inflammation of the wall, are rare. A 21-year-old woman presented with an extremely rare case of a solid and cystic Rathke cleft cyst with partial ossification, manifesting as bitemporal hemianopia. Magnetic resonance imaging showed a massive solid sellar lesion extending upward and compressing the optic chiasm and floor of the third ventricle. Transsphenoidal surgery was performed, resulting in total removal of the lesion and immediate recovery of visual function. Postoperative histological examination disclosed that the major part of the lesion consisted of various phases of clotting and granulation with significant fibrosis. Mature bone formation and abundant cholesterin clefts were also seen. Single cuboidal epithelium including goblet cells and cilia was found along this granulation, and the diagnosis was a Rathke cleft cyst. An ossified Rathke cleft cyst is extremely rare, and a solid Rathke cleft cyst has not before been reported. This case illustrates the extremely long and complex nature of this disease.


Influence of fluoride availability of dentifrices on eroded enamel remineralization in situ.
Remineralization of eroded enamel by dentifrices containing similar sources/concentrations of fluoride was investigated in situ. Fifty-three subjects completed a double-blind crossover study with 3 randomly assigned dentifrice treatments: placebo (0 ppm F, PD); reference (1,450 ppm NaF, RD) and test (1,450 ppm NaF + 5% KNO(3), TD). Fluoride availability for each dentifrice was analyzed in vitro by standard tests (1-min fluoride release rate and enamel fluoride uptake). The subjects wore palatal appliances holding bovine enamel specimens previously eroded in vitro. Surface microhardness was determined before and after the in vitro erosive challenge, after in situ remineralization and after a second in vitro erosive challenge. ANOVA and pairwise comparisons were performed (alpha=0.05). TD was superior to RD in the fluoride release tests, but similar to RD in the enamel fluoride uptake test. The mean percent surface microhardness recovery was 21.9 (standard deviation 8.0) for PD, 28.6 (8.0) for RD and 36.0 (8.0) for TD. The mean percent relative erosion resistance change was -58.8 (12.7) for PD, -31.3 (12.7) for RD and -27.3 (12.6) for TD. Both fluoride-containing dentifrices provided superior remineralization (p<0.001) and erosion resistance (p<0.001) compared to PD. The percent surface microhardness recovery demonstrated by the TD was significantly greater than for the RD (p<0.001). There was no significant difference (p=0.073) between TD and RD in relative resistance to further erosive challenge. The results suggest that fluoride availability may be different in dentifrices with similar sources/concentrations of fluoride, providing different levels of remineralization of eroded enamel.


A new captorhinid reptile, Gansurhinus qingtoushanensis, gen. et sp. nov., from the Permian of China.
Captorhinids, a clade of Paleozoic reptiles, are represented by a rich fossil record that extends from the Late Carboniferous into the Late Permian. Representatives of this clade dispersed from the equatorial regions of Laurasia into the temperate regions of Pangea during the Middle and Late Permian. This rich fossil record shows that there was an evolutionary trend from faunivorous to omnivorous and herbivorous feeding habits within this clade. The discovery of well-preserved captorhinid materials in the Middle Permian of China allows us to determine that the new taxon, Gansurhinus qingtoushanensis, gen. et sp. nov, is a member of Moradisaurinae, a clade of captorhinids with multiple tooth rows arranged in parallel. The presence of this moradisaurine in the Middle Permian of south central Asia leads us to suggest that paleogeographic changes during the Permian, with part of what is today China becoming a large peninsula of Pangea, allowed these early reptiles as well as other terrestrial vertebrates to extend their geographic ranges to this region of the Late Paleozoic supercontinent.


Distribution, persistence, and recall of serum and salivary antibody responses to peroral immunization with protein antigen I/II of Streptococcus mutans coupled to the cholera toxin B subunit.
After peroral immunization of mice with surface protein antigen (Ag) I/II of Streptococcus mutans conjugated to the cholera toxin B (CTB) subunit, cells actively secreting immunoglobulin A (IgA) antibodies specific for Ag I/II, but not for CT, were induced in the salivary glands; salivary IgA anti-Ag I/II antibodies and total salivary IgA were also elevated. The development of large numbers of IgA and IgG antibody-secreting cells in the mesenteric lymph nodes and spleen and high levels of serum IgA and IgG antibodies to Ag I/II and CT demonstrated that a response to both antigens occurred. At least two to three intragastric doses of 15 micrograms or more of Ag I/II-CTB conjugate, plus free CT as an adjuvant, were needed to induce the salivary IgA anti-Ag I/II response, which peaked at about 35 days and persisted at lower levels for 5 to 6 months. A single booster intragastric immunization did not induce enhanced salivary IgA anti-Ag I/II antibodies relative to the primary response, but serum IgA and IgG antibodies to both Ag I/II and CT showed evidence of marked anamnestic responses. The results indicated that relatively long-term mucosal IgA antibody responses could be induced by peroral immunization with small quantities of a CTB-conjugated protein. However, additional factors governed the distribution of cells secreting antibodies of different specificities, or capable of mounting anamnestic responses, between different compartments of the mucosal and circulatory immune systems.


AAV-mediated, optogenetic ablation of Müller Glia leads to structural and functional changes in the mouse retina.
Müller glia, the primary glial cell in the retina, provide structural and metabolic support for neurons and are essential for retinal integrity. Müller cells are closely involved in many retinal degenerative diseases, including macular telangiectasia type 2, in which impairment of central vision may be linked to a primary defect in Müller glia. Here, we used an engineered, Müller-specific variant of AAV, called ShH10, to deliver a photo-inducibly toxic protein, KillerRed, to Müller cells in the mouse retina. We characterized the results of specific ablation of these cells on visual function and retinal structure. ShH10-KillerRed expression was obtained following intravitreal injection and eyes were then irradiated with green light to induce toxicity. Induction of KillerRed led to loss of Müller cells and a concomitant decrease of Müller cell markers glutamine synthetase and cellular retinaldehyde-binding protein, reduction of rhodopsin and cone opsin, and upregulation of glial fibrillary acidic protein. Loss of Müller cells also resulted in retinal disorganization, including thinning of the outer nuclear layer and the photoreceptor inner and outer segments. High resolution imaging of thin sections revealed displacement of photoreceptors from the ONL, formation of rosette-like structures and the presence of phagocytic cells. Furthermore, Müller cell ablation resulted in increased area and volume of retinal blood vessels, as well as the formation of tortuous blood vessels and vascular leakage. Electrophysiologic measures demonstrated reduced retinal function, evident in decreased photopic and scotopic electroretinogram amplitudes. These results show that loss of Müller cells can cause progressive retinal degenerative disease, and suggest that AAV delivery of an inducibly toxic protein in Müller cells may be useful to create large animal models of retinal dystrophies.


The breadth of HIV-1 neutralizing antibodies depends on the conservation of key sites in their epitopes.
Developing HIV-1 vaccines that trigger broadly neutralizing antibodies (bnAbs) is a priority as bnAbs are considered key to elicitation of a protective immune response. To investigate whether the breadth of a neutralizing antibody (nAb) depended on the conservation of its epitope among circulating viruses, we examined Antibody:Envelope (Ab:Env) interactions and worldwide Env diversity. We found that sites corresponding to bnAb epitopes were as variable as other accessible, non-hypervariable Env sites (p = 0.50, Mann-Whitney U-test) with no significant relationship between epitope conservation and neutralization breadth (Spearman's ρ = -0.44, adjusted p = 0.079). However, when accounting for key sites in the Ab:Env interaction, we showed that the broadest bnAbs targeted more conserved epitopes (Spearman's ρ = -0.70, adjusted p = 5.0e-5). Neutralization breadth did not stem from the overall conservation of Ab epitopes but depended instead on the conservation of key sites of the Ab:Env interaction, revealing a mechanistic basis for neutralization breadth that could be exploited for vaccine design.


Seed-specific overexpression of a potato sucrose transporter increases sucrose uptake and growth rates of developing pea cotyledons.
During the storage phase, cotyledons of developing pea seeds are nourished by nutrients released to the seed apoplasm by their maternal seed coats. Sucrose is transported into pea cotyledons by sucrose/H+ symport mediated by PsSUT1 and possibly other sucrose symporters. PsSUT1 is principally localised to plasma membranes of cotyledon epidermal and subepidermal transfer cells abutting the seed coat. We tested the hypothesis that endogenous sucrose/H+ symporter(s) regulate sucrose import into developing pea cotyledons. This was done by supplementing their transport activity with a potato sucrose symporter (StSUT1), selectively expressed in cotyledon storage parenchyma cells under control of a vicilin promoter. In segregating transgenic lines, enhanced [(14)C]sucrose influx into cotyledons above wild-type levels was found to be dependent on StSUT1 expression. The transgene significantly increased (approximately 2-fold) transport activity of cotyledon storage parenchyma tissues where it was selectively expressed. In contrast, sucrose influx into whole cotyledons through the endogenous epidermal transfer cell pathway was increased by only 23% in cotyledons expressing the transgene. A similar response was found for rates of biomass gain by intact cotyledons and by excised cotyledons cultured on a sucrose medium. These observations demonstrate that transport activities of sucrose symporters influence cotyledon growth rates. The attenuated effect of StSUT1 overexpression on sucrose and dry matter fluxes by whole cotyledons is consistent with a large proportion of sucrose being taken up at the cotyledonary surface. This indicates that the cellular location of sucrose transporter activity plays a key role in determining rates of sucrose import into cotyledons.


Alternative function of a protein kinase homology domain in 2', 5'-oligoadenylate dependent RNase L.
RNase L is the 2',5'-oligoadenylate (2-5A)-dependent endoribonuclease that functions in interferon action and apoptosis. One of the intriguing, albeit unexplained, features of RNase L is its significant homology to protein kinases. Despite the homology, however, no protein kinase activity was detected during activation and RNA cleavage reactions with human RNase L. Similarly, the kinase plus ribonuclease domains of RNase L produced no detectable protein kinase activity in contrast to the phosphorylation obtained with homologous domains of the related kinase and endoribonuclease, yeast IRE1p. In addition, neither ATP nor pA(2'p5'A)3was hydrolyzed by RNase L. To further investigate the function of the kinase homology in RNase L, the conserved lysine at residue 392 in protein kinase-like domain II was replaced with an arginine residue. The resulting mutant, RNase LK392R, showed >100-fold decreases in 2-5A-dependent ribonuclease activity without reducing 2-5A- or RNA-binding activities. The greatly reduced activity of RNase LK392Rwas correlated to a defect in the ability of RNase L to dimerize. These results demonstrate a critical role for lysine 392 in the activation and dimerization of RNase L, thus suggesting that these two activities are intimately linked.


Difficulty for consumers in choosing commercial bilberry supplements by relying only on product label information.
Various kinds of bilberry supplements have recently become available on the market. However, it is doubtful whether consumers receive accurate information to be able to compare different supplements. We aimed to investigate whether consumers can obtain the expected benefits by relying only on the information printed on the product labels of commercial bilberry supplements. The quality of 20 supplements was investigated by the spectrophotometric method and ultra high performance liquid chromatography (UHPLC). Each peak was identified by liquid chromatography-mass spectrometry and quantified using an external standard. The percentage of the actual measured value relative to the indicated value on the product label was determined using the spectrophotometric method. The daily dosage was calculated from the total amount of anthocyanins quantified by UHPLC and information on the product label. In 14 of 20 supplements, the total anthocyanin content expressed as delphinidin equivalents was within 20% of the labeled value. However, the extent of degradation could not be determined by the spectrophotometric method. In fresh bilberry fruit, anthocyanidins were barely detected. In 8 of 20 supplements, the anthocyanidin content was >1.0%. The daily dosage of anthocyanins varied by about 66-fold among supplements, and the dosage of 6 supplements was less than the recommended level in Japan. Consumers cannot always obtain the expected benefits by relying only on product label information. Therefore, new rules concerning product label information are required to make it possible for consumers to take the equivalent amounts of anthocyanins for whichever bilberry supplement they choose.


[Negligible amounts of cholesterol-raising diterpenes in coffee made with coffee pads in comparison with unfiltered coffee].
To determine the amounts of the serum-cholesterol raising diterpenes cafestol and kahweol in coffee made with coffee pads and the Senseo coffee machine as opposed to filtered and unfiltered coffee. Observational. In five cities in the Netherlands coffee was purchased in three major supermarkets resulting in a total of 30 samples of coffee pads. The levels of cafestol and kahweol were determined by gas chromatography. As controls, the diterpene levels in filtered and unfiltered coffee were also measured. Coffee prepared using coffee pads contained on average 0.76 mg/l cafestol (95% CI: 0.69-0.82) and 0.85 mg/l kahweol (95% CI: 0.77-0.94). Filtered coffee contained 0.76 mg/l cafestol (95% CI: 0.63-0.88) and 0.81 mg/l kahweol (95% CI: 0.63-0.99). Unfiltered coffee contained 72.5 mg/l cafestol (95% CI: 48.5-96.4) and 71.5 mg/l kahweol (95% CI: 45.0-98.1). Coffee prepared using coffee pads and the Senseo coffee machine contained minute levels of diterpenes comparable to those of filtered coffee. Its effect on serum-cholesterol levels is therefore likely to be negligible.


Spontaneous Coronary Artery Dissection Associated With Pregnancy.
Spontaneous coronary artery dissection (SCAD) is the most common cause of pregnancy-associated myocardial infarction and remains poorly characterized. This study sought to assess presentation, clinical factors, and outcomes of pregnancy-associated spontaneous coronary artery dissection (P-SCAD) compared with spontaneous coronary artery dissection not associated with pregnancy (NP-SCAD). A Mayo Clinic registry was established in 2010 to include comprehensive retrospective and prospective SCAD data. Records were reviewed to identify women who were pregnant or ≤12 weeks postpartum at time of SCAD. Complete records were available for 323 women; 54 women met criteria for P-SCAD (4 during pregnancy) and they were compared with 269 women with NP-SCAD. Most events occurred within the first month postpartum (35 of 50). Compared with NP-SCAD, P-SCAD patients more frequently presented with ST-segment elevation myocardial infarction (57% vs. 36%; p = 0.009), left main or multivessel SCAD (24% vs. 5%; p < 0.0001; and 33% vs. 14%; p = 0.0027, respectively), and left ventricular function ≤35% (26% vs. 10%; p = 0.0071). Among women with imaging of other vascular territories, P-SCAD was less likely with a diagnosis of fibromuscular dysplasia and extracoronary vascular abnormalities (42% vs. 64%; p = 0.047; and 46% vs. 77%; p = 0.0032, respectively). Compared with U.S. birth data, women with P-SCAD were more often multiparous (p = 0.0167), had a history of infertility therapies (p = 0.0004), and had pre-eclampsia (p = 0.001). On long-term follow-up (median 2.3 years) recurrent SCAD occurred in 51 patients, with no difference in the Kaplan Meier 5-year recurrence rates (10% vs. 23%; p = 0.18). P-SCAD patients had more acute presentations and high-risk features than women with NP-SCAD did. The highest frequency of P-SCAD occurred during the first postpartum month and P-SCAD patients less often had extracoronary vascular abnormalities. Hormonal, hemodynamic variations, and yet-undefined mechanisms might be significant contributors to P-SCAD. (The "Virtual" Multicenter Spontaneous Coronary Artery Dissection [SCAD] Registry [SCAD]; NCT01429727; Genetic Investigations in Spontaneous Coronary Artery Dissection [SCAD]; NCT01427179).


Pseudobulbar Affect: What Nurses, Stroke Survivors, and Caregivers Need to Know.
Pseudobulbar affect (PBA) is a neurologic condition that can happen after a patient has had some kind of neurological insult. In this syndrome, involuntary, uncontrollable, and inappropriate emotional outbursts unrelated or out of proportion to the situation are common symptoms. This can be very frustrating and scary. Because stroke survivors and their caregivers are overloaded with information during the transition from hospital to home, information about PBA is not usually discussed. In a survey by the National Stroke Association, 53% of stroke survivors reported that they had some of the symptoms of this disorder. Even if they discussed these symptoms with their health care providers, less than half were given a diagnosis, and less than a quarter received any kind of treatment. The purpose of this article is to give nurses more information about PBA so they can share this with patients and families/significant others and encourage them to seek help if they experience these symptoms once discharged. It is hoped that increased knowledge about this condition will lead to better diagnosis and treatment and increased quality of life for stroke survivors.


Elective neurosurgical humanitarian care in a deployed setting.
OBJECTIVEActive-duty neurosurgical coverage has been provided at Bagram Air Force Base in Afghanistan since 2007. Early operative logs were reflective of a large number of surgical procedures performed to treat battlefield injuries. However, with maturation of the war effort, the number of operations for battlefield injuries has decreased with time. Consequently, procedures performed for elective neurosurgical humanitarian care (NHC) increased in number and complexity prior to closure of the Korean Hospital in 2015, which resulted in effective termination of NHC at Bagram. Monthly neurosurgical caseloads for deployed personnel have dropped precipitously since this time, renewing a debate as to whether the benefits of providing elective NHC in Afghanistan outweigh the costs of such a strategy. To date, there is a paucity of information in the literature discussing the overall context of such a determination.METHODSThe author retrospectively reviewed his personal database of all patients who underwent neurosurgical procedures at Bagram during his deployment there from April 17 to October 29, 2014. Standardized clinical parameters had been recorded in the ABNS NeuroLog system. All cases of nonelective surgical care for battlefield injuries were identified and excluded. Records of all other procedures, which represented elective NHC delivered during this period, were accessed to extract salient clinical and radiological data.RESULTSDuring the 6-month deployment, 49 patients (29 male and 20 female, age range 18 months to 63 years) were treated by the author in elective NHC. Procedures were performed for spinal degenerative disease (n = 28), cranial tumors (n = 11), pediatric conditions (n = 6), Pott's disease (n = 2), peripheral nerve impingement (n = 1), and adult hydrocephalus (n = 1). The duration of follow-up ranged from 3 to 23 weeks. Complications referable to surgery included asymptomatic, unilateral lumbar screw fracture detected 3 months postoperatively and treated with revision of hardware (n = 1); wound infection requiring cranial flap explantation and staged cranioplasty (n = 1); and unanticipated return to the operating room for resection of residual tumor in a patient with a solitary metastatic lesion involving the mesial temporal lobe/ambient cistern (n = 1). There were no instances of postoperative neurological decline.CONCLUSIONSElective NHC can be safely and effectively implemented in the deployed setting. Benefits of a military strategy that supports humanitarian care include strengthening of the bond between the US/Afghan military communities and the local civilian population as well as maintenance of skills of the neurosurgical team during the sometimes-lengthy intervals between cases in which emergent neurosurgical care is provided for treatment of battlefield injuries.


Verification of a comprehensive framework for mobility using data from the Canadian Longitudinal Study on Aging: a structural equation modeling analysis.
Mobility within and between life spaces is fundamental for health and well-being. Our objective was to verify a comprehensive framework for mobility. This was a cross-sectional study. We used structural equation modeling to estimate associations between latent factors with data from the Canadian Longitudinal Study on Aging for participants 65-85 years of age (65+, n = 11,667) and for adults with osteoarthritis (OA) aged 45-85 (n = 5,560). Latent factors included life space mobility, and physical, psychosocial, environmental, financial, and cognitive elements. Personal variables (age, sex, education) were covariates. The models demonstrated good fit (65+: CFI = 0.90, RMSEA (90% CI) = 0.025 (0.024, 0.026); OA: CFI = 0.90, RMSEA (90% CI) = 0.032 (0.031, 0.033)). In both models, better psychosocial and physical health, and being less afraid to walk after dark (observed environmental variable) were associated with greater life space mobility. Greater financial status was associated with better psychosocial and physical health. Higher education was related to better cognition and finances. Older age was associated with lower financial status, cognition, and physical health. Cognitive health was positively associated with greater mobility only in the 65 + model. Models generated were equivalent for males and females. Associations between determinants described in the mobility framework were verified with adults 65-85 years of age and in an OA group when all factors were considered together using SEM. These results have implications for clinicians and researchers in terms of important outcomes when assessing life space mobility; findings support interdisciplinary analyses that include evaluation of cognition, depression, anxiety, environmental factors, and community engagement, as well as physical and financial health. Public policies that influence older adults and their abilities to access communities beyond their homes need to reflect the complexity of factors that influence life space mobility at both individual and societal levels.


Reversible Venting Stitch for Fenestrating Valve-less Glaucoma Shunts.
The purpose of this is to describe a venting stitch modification for valveless glaucoma aqueous shunts and characterize early postoperative intraocular pressure (IOP) and glaucoma medication use following the modification. Retrospective chart review of 61 sequential patients undergoing Baerveldt glaucoma implant (BGI)-350 implantation at the Doheny Eye Institute. Twenty-four patients received a glaucoma shunt with venting stitch modification (modified BGI) and 37 patients received an unmodified shunt (BGI-only). IOP, number of glaucoma medications, and number of hypotony cases (intraocular pressure ≤5 mm Hg) were compared between the groups. T-tests were used for statistical analysis. At postoperative-day 1, mean IOP was significantly lower compared with preoperatively in the modified BGI group (14 mm Hg; reduced by 51%; P<0.0001) but not the BGI-only group (27 mm Hg; P=0.06). IOP difference between groups persisted till immediately before tube opening (P=0.005) and fewer IOP-lowering medications needed in the modified BGI group (P<0.0001). One case (4.2%) of postoperative hypotony was encountered with BGI modification, which resolved after the stitch was removed in clinic. The venting stitch valveless shunt modification allows for effective, reliable, and safe control of early postoperative IOP.


GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder.
Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5β-THP; pregnenolone; 3α,5α-androsterone; 3α,5β-androsterone; 3α,5α-A-diol; 3α5β-A-diol; 3α,5α-THDOC; 3α5β-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.


Geographical spread of SARS in mainland China.
To describe the spatiotemporal diffusion of the severe acute respiratory syndrome (SARS) epidemic in mainland China, and to analyse the spatial pattern of SARS transmission from the Beijing epicentre to its neighbouring areas. Probable SARS cases occurring between November 2002 and May 2003 in mainland China were compiled from different sources and geo-coded into a geographical information database based on onset location. Spatial analyses including kernel density estimation, and spatial statistical and tracking analyses were performed to characterise the spatiotemporal distribution of SARS cases based on onset location/date. SARS cases that got infected in Beijing but were reported in three provinces surrounding Beijing were mapped, and logistic regression using a 'case-control' design at the county level was performed to analyse the impact of travel-related risk factors in the diffusion pattern. The SARS epidemic in mainland China spanned a large geographical extent but clustered in two areas: first in Guangdong Province, and about 3 months later in Beijing with its surrounding areas in Shanxi Province, Inner Mongolia Autonomic Region, Hebei Province and Tianjin. Counties in the neighbourhood of Beijing that were crossed by a national highway or inter-provincial freeway showed the highest risk of acquiring SARS infections, even after correction for population density and medical staff density. Being intersected by a railway did not significantly associate with risk of SARS. This study provides the first complete documentation of the spatial and temporal characteristics of the SARS epidemic in mainland China. Our analyses confirmed that SARS had benefited from national highways and inter-provincial freeways for its spread from epicentres to neighbouring areas, whereas trains showed no significant association. This knowledge may be important for the control of re-emerging SARS, or other future emerging human-to-human transmittable infections.


Microcystins Containing Doubly Homologated Tyrosine Residues from a Microcystis aeruginosa Bloom: Structures and Cytotoxicity.
Four new microcystin congeners are described including the first three examples of microcystins containing the rare doubly homologated tyrosine residue 2-amino-5-(4-hydroxyphenyl)pentanoic acid (Ahppa) (1-4). Large-scale harvesting and biomass processing allowed the isolation of substantial quantities of these compounds, thus enabling complete structure determination by NMR as well as cytotoxicity evaluation against selected cancer cell lines. The new Ahppa-toxins all incorporate Ahppa residues at the 2-position, and one of these also has a second Ahppa at position 4. The two most lipophilic Ahppa-containing microcystins showed 10-fold greater cytotoxic potency against human tumor cell lines (A549 and HCT-116) compared to microcystin-LR (5). The presence of an Ahppa residue in microcystin congeners is difficult to ascertain by MS methods alone, due to the lack of characteristic fragment ions derived from the doubly homologated side chain. Owing to their unexpected cytotoxic potency, the potential impact of the compounds on human health should be further evaluated.


Histological study and LYVE-1 immunolocalization of mouse mesenteric lymph nodes with "In Vivo Cryotechnique".
The "in vivo cryotechnique" (IVCT) is a powerful tool to directly freeze living animal organs in order to maintain biological components in frozen tissues, reflecting their native states. In this study, mesenteric lymph nodes of living mice were directly frozen with IVCT, and we did morphological studies and immunohistochemical analyses on a hyaluronic acid receptor, LYVE-1. In lymph nodes, widely open lymphatic sinuses were observed, and many lymphocytes adhered to inner endothelial cells along subcapsular sinuses. The LYVE-1 was clearly immunolocalized at inner endothelial cells of subcapsular sinuses, as well as those of medullary sinuses. Conventional pre-embedding electron microscopy also showed LYVE-1 immunolocalization along both the apical and basal sides of cell membranes of inner endothelial cells. By triple-immunostaining for LYVE-1, smooth muscle actin, and type IV collagen, the LYVE-1 was immunolocalized only in the inner endothelial cells, but not in outer ones which were surrounded by collagen matrix and smooth muscle cells. Thus, the functional morphology of lymph nodes in vivo was demonstrated and LYVE-1 immunolocalization in inner endothelial cells of subcapsular sinuses suggests hyaluronic acid incorporation into lymph node parenchyma.


Meiosis, spermatogenesis and nucleolar behavior in the seminiferous tubules of Alydidae, Coreidae and Rhopalidae (Heteroptera) species.
We studied the karyotype, spermatogenesis and nucleolar activity at spermatogenesis in five species of Heteropera: Hyalymenus sp and Neomegalotomus pallescens, Alydidae; Catorhintha guttula and Hypselonotus fulvus, Coreidae; and Niesthrea sidae, Rhopalidae. They showed a red (Alydidae) or orange (Coreidae and Rhopalidae) membrane covering the testes, which consisted of seven testicular lobes, except in N. pallescens, which had only five. All the species had m-chromosomes, an X0 sex chromosome system and 10 (Hyalymenus sp, N. pallescens, and N. sidae), 16 (H. fulvus) or 22 (C. guttula) autosomes. Similar to the other species described to date, all these species showed holocentric chromosomes, interstitial chiasmata in most autosomes, and autosomes dividing reductionally in the first meiotic division and equationally in the second, while sex chromosomes, divided equationally and reductionally in the first and second meiotic divisions, respectively. In addition, we observed that the sex chromosome is heteropycnotic at prophase and that heteropycnotic chromosomal material is found in the nuclei at spermatogenesis; variation in size, shape and location of the nucleolar material occurs during spermatogenesis, denoting a variable degree of activity in the different stages.


Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada.
To evaluate viscosupplementation with intraarticular hylan G-F 20 in current clinical practice. A retrospective study of all patients with osteoarthritis of the knee treated with hylan by 5 Canadian clinicians over a period of 2.5 years. A total of 1537 injections were performed in 336 patients involving 458 knees. The overall response and the change of activity level were judged better or much better for 77 and 76% of the treated knees after the first course of treatment (3 weekly injections), and 87 and 84% after a 2nd course. The mean time elapsing between the first and 2nd course, 8.2 +/- 0.5 months, is an evaluation of the duration of benefits. Local adverse events were observed in 28 patients (32 knees), with an overall rate of 2.7% adverse events per injection, 7.0% per joint, and 8.3% per patient. No systemic adverse events were noted in any patient. The adverse events were characterized by pain and/or transient swelling of the injected joint, mostly mild or moderate in intensity, and 72% of the adverse events were considered to be possibly or probably related to the injection. The incidence of adverse events is significantly influenced by the injection technique: 5.2% adverse events per injection with a medial approach to a partially bent knee, and 2.4% (straight medial) and 1.5% (straight lateral). After an adverse event, clinical improvement still occurred in 69% of the affected knees. Hylan G-F 20 provided good clinical benefits and an acceptable safety profile in current clinical practice. The occurrence of adverse events after an intraarticular hylan injection is infrequent and unpredictable and is not necessarily hylan related, although injection related.


[Peculiar lexicon in hysteria].
A psycholinguistic association experiment was used to examine 19 hysterical patients with different functional-neurological motor disorders, such as unilateral or bilateral pseudopareses, pseudoataxia and 9 healthy individuals (a control group). The method included three tests: a free associative experiment and different types of the directed associative experiment (grammatically mediated or semantically mediated). According to these tests verbal activity was significantly decreased in the patients as compared with controls and patients with left-sided pseudoparesis as compared with the right-sided one. In addition, there were correlations of verbal activity with the degree of paresis (a positive correlation) and with the level of demonstrability of personality (a negative one).


Validation, comparison, and combination of algorithms for automatic detection of pulmonary nodules in computed tomography images: The LUNA16 challenge.
Automatic detection of pulmonary nodules in thoracic computed tomography (CT) scans has been an active area of research for the last two decades. However, there have only been few studies that provide a comparative performance evaluation of different systems on a common database. We have therefore set up the LUNA16 challenge, an objective evaluation framework for automatic nodule detection algorithms using the largest publicly available reference database of chest CT scans, the LIDC-IDRI data set. In LUNA16, participants develop their algorithm and upload their predictions on 888 CT scans in one of the two tracks: 1) the complete nodule detection track where a complete CAD system should be developed, or 2) the false positive reduction track where a provided set of nodule candidates should be classified. This paper describes the setup of LUNA16 and presents the results of the challenge so far. Moreover, the impact of combining individual systems on the detection performance was also investigated. It was observed that the leading solutions employed convolutional networks and used the provided set of nodule candidates. The combination of these solutions achieved an excellent sensitivity of over 95% at fewer than 1.0 false positives per scan. This highlights the potential of combining algorithms to improve the detection performance. Our observer study with four expert readers has shown that the best system detects nodules that were missed by expert readers who originally annotated the LIDC-IDRI data. We released this set of additional nodules for further development of CAD systems.


The uniquely distributed isoprenylated protein methyltransferase activity in the rat brain is highly expressed in the cerebellum.
Isoprenylated protein methyltransferase, the enzyme which catalyzes the reversible methylation of signal transducing G-proteins was studied in nine brain regions of the rat brain using S-farnesyl cysteine analogs as substrates. Enzyme activity, as determined with N-acetyl-S-farnesyl-L-cysteine (AFC) was found in the nuclear, synaptosomal and microsomal fractions of all brain regions but not in the cytosol. The enzyme is a unique methyltransferase with respect to its brain distribution. The rank order of activity of the enzyme is cerebellum >> midbrain > medulla > forebrain regions, where activities in cerebellar synaptosomal and nuclear fractions (28-32 pmol AFC [methyl-3H]ester formed/min/mg prot) are 20 to 30 times higher than those of the corresponding fraction of the forebrain regions. This distribution is reminiscent of that of neurotransmitter receptors and signal transduction molecules and suggests a regulatory role for the enzyme, particularly in the cerebellum.


Histomorphometric evaluation of natural mineral combined with a synthetic cell-binding peptide (P-15) in critical-size defects in the rat calvaria.
The objective of this study was to histomorphometrically evaluate the synthetic peptide analog P-15 bound to anorganic bovine mineral (Pepgen/P15) in critical-size defects in the rat calvaria. A 5-mm-diameter critical-size defect was prepared in 48 rat skulls and divided into 4 equal groups: Pepgen/P15 particles covered by a membrane, Pepgen/P15 particles uncovered, nongrafted membrane-protected sites, and nongrafted uncovered control sites. At 12 weeks, histomorphometric measurements were made of the percentage area of newly formed bone and residual particles, the length of internal and external bone bridging, and linearly, the regenerated marginal and central total tissue augmentation height. Nongrafted, membrane-protected sites gained 60.6% of newly formed bone, followed by 50.6% and 44.2% (P < .05 versus membrane only) at the grafted covered and uncovered sites, respectively. All experimental sites contained significantly (P < .005) more bone than did control sites (19.9%). In both types of grafted sites, the percentage area of Pepgen/P15 particles was similar. Mean internal and external length of bone bridging at nongrafted membrane-protected sites (76.7% and 71.2%, respectively) was significantly greater (P < .005) than that of the grafted covered (43.95% and 51.8%, respectively), grafted uncovered (28.7% and 23.9%, respectively), and control (28% and 25.5%, respectively) groups, except for internal bone bridging in the grafted covered sites. Regenerated marginal and central augmentation heights (0.92 mm and 1.02 mm, respectively) were greatest in the grafted covered group, followed by the non-grafted membrane-protected (0.88 mm and 0.51 mm, respectively), and grafted uncovered (0.89 mm and 0.12 mm, respectively) groups, all of which were significantly greater (P < .001) than the control group (0.63 mm and 0.04 mm, respectively). While anorganic bovine mineral/cell-binding peptide contributes in volume, membrane application significantly increases the amount of bone regeneration.


Assembling Reads Improves Taxonomic Classification of Species.
Most current approach to metagenomic classification employ short next generation sequencing (NGS) reads that are present in metagenomic samples to identify unique genomic regions. NGS reads, however, might not be long enough to differentiate similar genomes. This suggests a potential for using longer reads to improve classification performance. Presently, longer reads tend to have a higher rate of sequencing errors. Thus, given the pros and cons, it remains unclear which types of reads is better for metagenomic classification. We compared two taxonomic classification protocols: a traditional assembly-free protocol and a novel assembly-based protocol. The novel assembly-based protocol consists of assembling short-reads into longer reads, which will be subsequently classified by a traditional taxonomic classifier. We discovered that most classifiers made fewer predictions with longer reads and that they achieved higher classification performance on synthetic metagenomic data. Generally, we observed a significant increase in precision, while having similar recall rates. On real data, we observed similar characteristics that suggest that the classifiers might have similar performance of higher precision with similar recall with longer reads. We have shown a noticeable difference in performance between assembly-based and assembly-free taxonomic classification. This finding strongly suggests that classifying species in metagenomic environments can be achieved with higher overall performance simply by assembling short reads. Further, it also suggests that long-read technologies might be better for species classification.


The association of trajectories of protein intake and age-specific protein intakes from 2 to 22 years with BMI in early adulthood.
No study has analysed how protein intake from early childhood to young adulthood relate to adult BMI in a single cohort. To estimate the association of protein intake at 2, 11, 15, 19 and 22 years with age- and sex-standardised BMI at 22 years (early adulthood), we used linear regression models with dietary and anthropometric data from a Filipino birth cohort (1985-2005, n 2586). We used latent growth curve analysis to identify trajectories of protein intake relative to age-specific recommended daily allowance (intake in g/kg body weight) from 2 to 22 years, then related trajectory membership to early adulthood BMI using linear regression models. Lean mass and fat mass were secondary outcomes. Regression models included socioeconomic, dietary and anthropometric confounders from early life and adulthood. Protein intake relative to needs at age 2 years was positively associated with BMI and lean mass at age 22 years, but intakes at ages 11, 15 and 22 years were inversely associated with early adulthood BMI. Individuals were classified into four mutually exclusive trajectories: (i) normal consumers (referent trajectory, 58 % of cohort), (ii) high protein consumers in infancy (20 %), (iii) usually high consumers (18 %) and (iv) always high consumers (5 %). Compared with the normal consumers, 'usually high' consumption was inversely associated with BMI, lean mass and fat mass at age 22 years whereas 'always high' consumption was inversely associated with male lean mass in males. Proximal protein intakes were more important contributors to early adult BMI relative to early-childhood protein intake; protein intake history was differentially associated with adulthood body size.


Technology-Facilitated Gender-Based Violence, Hate Speech, and Terrorism: A Risk Assessment on the Rise of the Incel Rebellion in Canada.
With the proliferation of the internet, emerging groups such as the men's rights movement involuntary celibate (incel) community have new ways to reproduce real-world harm and gender-based violence (GBV) against women. This study conducts a critical discourse and semantic analysis of the incels.co webpage and the Alek Minassian van attack using the Violent Extremism Risk Assessment and the Cyber Extremism Risk Assessment tool. It reveals that Canadian violent extremism frameworks minimize online GBV as a form of extremism. GBV, which extends from online to offline realities, is not captured in theoretical frameworks for terrorism and hate speech.


Biological and functional relevance of CASP predictions.
Our goal is to answer the question: compared with experimental structures, how useful are predicted models for functional annotation? We assessed the functional utility of predicted models by comparing the performances of a suite of methods for functional characterization on the predictions and the experimental structures. We identified 28 sites in 25 protein targets to perform functional assessment. These 28 sites included nine sites with known ligand binding (holo-sites), nine sites that are expected or suggested by experimental authors for small molecule binding (apo-sites), and Ten sites containing important motifs, loops, or key residues with important disease-associated mutations. We evaluated the utility of the predictions by comparing their microenvironments to the experimental structures. Overall structural quality correlates with functional utility. However, the best-ranked predictions (global) may not have the best functional quality (local). Our assessment provides an ability to discriminate between predictions with high structural quality. When assessing ligand-binding sites, most prediction methods have higher performance on apo-sites than holo-sites. Some servers show consistently high performance for certain types of functional sites. Finally, many functional sites are associated with protein-protein interaction. We also analyzed biologically relevant features from the protein assemblies of two targets where the active site spanned the protein-protein interface. For the assembly targets, we find that the features in the models are mainly determined by the choice of template.


Safety and Efficacy of Ombitasvir, Paritaprevir With Ritonavir ± Dasabuvir With or Without Ribavirin in Patients With Human Immunodeficiency Virus-1 and Hepatitis C Virus Genotype 1 or Genotype 4 Coinfection: TURQUOISE-I Part 2.
Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis. TURQUOISE-I, Part 2 is a phase 3 multicenter study. Patients with or without cirrhosis were HCV treatment-naive or -experienced, on an HIV-1 antiretroviral regimen containing atazanavir, raltegravir, dolutegravir, or darunavir (for genotype 4 only), and had plasma HIV-1 ribonucleic acid <40 copies/mL at screening. Patients received OBV/PTV/r ± DSV ±RBV for 12 or 24 weeks. In total, 228 patients were treated according to guidelines. Sustained virologic response at posttreatment week 12 (SVR12) was achieved by 194 of 200 (97%) and 27 of 28 (96%) patients with HCV genotype 1 and genotype 4 infection, respectively. There were 2 virologic failures: 1 breakthrough and 1 relapse in a cirrhotic and a noncirrhotic patient with genotype 1b and 1a infection, respectively. One reinfection occurred at posttreatment week 12 in a genotype 1a-infected patient. Excluding nonvirologic failures, the SVR12 rates were 98% (genotype 1) and 100% (genotype 4). Adverse events were mostly mild in severity and did not lead to discontinuation. Laboratory abnormalities were rare. The OBV/PTV/r ±DSV was well tolerated and yielded high SVR12 rates in patients with HCV genotype 1 or genotype 4/HIV-1 coinfection. The OBV/PTV/r ± DSV ±RBV is a potent HCV treatment option for patients with HIV-1 coinfection, regardless of treatment experience.


A new Enpp1 allele, Enpp1(ttw-Ham), identified in an ICR closed colony.
We recently have reported on a novel ankylosis gene that is closely linked to the Enpp1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene on chromosome 10. Here, we have discovered novel mutant mice in a Jcl:ICR closed colony with ankylosis in the toes of the forelimbs at about 3 weeks of age. The mutant mice exhibited rigidity in almost all joints, including the vertebral column, which increased with age. These mice also showed hypogrowth with age after 16 weeks due to a loss of visceral fat, which may have been caused by poor nutrition. Histological examination and soft X-ray imaging demonstrated the ectopic ossification of various joints in the mutant mice. In particular, increased calcium deposits were observed in the joints of the toes, the carpal bones and the vertebral column. We sequenced all exons and exon/intron boundaries of Enpp1 in the normal and mutant mice, and identified a G-to-T substitution (c.259+1G>T) in the 5' splice donor site of intron 2 in the Enpp1 gene of the mutant mice. This substitution led to the skipping of exon 2 (73 bp), which generated a stop codon at position 354 bp (amino acid 62) of the cDNA (p.V63Xfs). Nucleotide pyrophosphohydrolase (NPPH) activity of ENPP1 in the mutant mice was also decreased, suggesting that Enpp1 gene function is disrupted in this novel mutant. The mutant mice reported in this study will be a valuable animal model for future studies of human osteochondral diseases and malnutrition.


[Effect of potassium ions on electrogenesis and contraction of ureter smooth muscle].
In the ureter smooth muscle cells, high--K solution produced a depolarization at the onset of which the action potentials (AP) and contraction occur; the latter consists of an initial phasic (Ph) and subsequent tonic (T) components. Ph component is initiated by the AP, T component--by a stable potassium depolarization. In Ca--free solution the AP, Ph and T components are blocked, although a sustained potassium depolarization is preserved. Basing on these results it is suggested that: 1) phasic contraction is initiated by calcium ions influxed via fast potential--dependent calcium channels participating in the AP generation; 2) tonic contraction is also initiated mainly by extracellular calcium influx through slow potential--dependent calcium channels of plasmatic membrane that appear to be similar to calcium channels of sarcoplasmic reticulum membrane in skeletal muscles and of the membrane of presinaptic nerve terminals.


Mutants of Streptomyces roseosporus that express enhanced recombination within partially homologous genes.
Streptomyces roseosporus mutants that express enhanced recombination between partially homologous (homeologous) sequences were isolated by selection for recombination between the bacteriophage phi C31 derivative KC570 containing the Streptomyces coelicolor glucose kinase (glk) gene and the S. roseosporus chromosome. The frequencies of homeologous recombination in the ehr mutants were determined by measuring the chromosomal insertion frequencies of plasmids containing S. coelicolor glnA or whiG genes. S. roseosporus ehr mutants showed 10(2)- to 10(4)-fold increases in homeologous recombination relative to Ehr+ strains, but no increase in homologous recombination. Southern hybridization analysis revealed single unique sites for the insertion of each of the plasmids, and the crossovers occurred in frame and in proper translational register, yielding functional chimeric glnA and whiG genes.


Exploring drug users' attitudes and decisions regarding hepatitis C (HCV) treatment in the U.S.
Individuals with a history of injecting drugs are at the highest risk of becoming infected with the hepatitis C virus (HCV), with studies of patients in methadone maintenance treatment programmes (MMTPs) reporting that 60-90 percent of intravenous drug users (IDUs) have the virus. Fortunately, HCV therapy has been shown to be effective in 42-82 percent of all patients with chronic HCV infection, including IDUs. While the decision to start HCV therapy requires significant consideration, little research exists that explores the attitudes of drug users toward HCV therapy. Therefore, this paper examines how drug users perceive the treatment, as well as the processes by which HCV-positive individuals examined the advantages and disadvantages of starting the HCV medications. Interviews were conducted with 164 patients from 14 drug treatment programmes throughout the United States, and both uninfected and HCV-positive drug users described a pipeline of communication among their peers that conveys largely negative messages about the medications that are available to treat HCV. Although many of the HCV-positive individuals said that these messages heightened their anxiety about the side effects and difficulties of treatment, some patients said that their peers helped them to consider, initiate HCV treatment or both. Gaining a better understanding of drug users' perceptions of HCV treatment is important, because so many of them, particularly IDUs, are already infected with HCV and may benefit from support in addressing their HCV treatment needs. In addition, currently uninfected drug users will likely remain at high risk for contracting HCV and may need to make decisions about whether or not to start the HCV medical regimen in the future.


Development of insulin-sensitivity at weaning in the rat. Role of the nutritional transition.
This study was undertaken to determine the factors involved in the development of insulin-sensitivity at weaning. Glucose kinetics were studied in suckling rats and in rats weaned on to a high-carbohydrate (HC) or a high-fat (HF) diet, in the basal state and during euglycaemic-hyperinsulinaemic-clamp studies. These studies were coupled with the 2-deoxyglucose technique, allowing a measure of glucose utilization by individual tissues. In the basal state, the glycaemia was higher in HF-weaned rats (124 +/- 4 mg/dl) than in suckling (109 +/- 1 mg/dl) and HC-weaned rats (101 +/- 3 mg/dl). Glucose turnover rates were similar in the three groups of animals (14 mg/min per kg). Nevertheless, basal metabolic glucose clearance rate was 20% lower in HF-weaned rats than in the other groups. During the euglycaemic-hyperinsulinaemic experiments, hepatic glucose production was suppressed by 90% in HC-weaned rats, whereas it remained at 40% of basal value in suckling and HF-weaned rats, indicating an insulin resistance of liver of these animals. Glucose clearance rate during the clamp was 18.3 +/- 0.9 ml/min per kg in suckling rats, whereas it was 35.3 +/- 1.2 ml/min per kg in HC-weaned rats and 27.8 +/- 1.1 ml/min per kg in HF-weaned rats, indicating an insulin resistance of glucose utilization in suckling, and to a lower extent, in HF-weaned rats. The deoxyglucose technique showed that peripheral insulin resistance was localized in muscles and white adipose tissue of suckling and HF-weaned rats. These results indicate that the switch from milk to a HC diet is an important determinant of the development of insulin-sensitivity at weaning in the rat.


Members of the AP-1 family, c-Jun and c-Fos, functionally interact with JC virus early regulatory protein large T antigen.
The activating protein 1 (AP-1) family of regulatory proteins is characterized as immediate-early inducible transcription factors which were shown to be activated by a variety of stress-related stimuli and to be involved in numerous biological processes, including cellular and viral gene expression, cell proliferation, differentiation, and tumorigenesis. We have recently demonstrated the involvement of the AP-1 family members c-Jun and c-Fos in transcriptional regulation of the human polyomavirus, JC virus (JCV), genome. Here, we further examined their role in JCV gene regulation and replication through their physical and functional interaction with JCV early regulatory protein large T antigen (T-Ag). Transfection and replication studies indicated that c-Jun and c-Fos can significantly diminish T-Ag-mediated JCV gene transcription and replication. Affinity chromatography and coimmunoprecipitation assays demonstrated that c-Jun and T-Ag physically interact with each other. Results from band shift assays showed that the binding efficiency of c-Jun to the AP-1 site was reduced in the presence of T-Ag. In addition, we have mapped, through the use of a series of deletion mutants, the regions of these proteins which are important for their interaction. While the c-Jun interaction domain of T-Ag is localized to the middle portion of the protein, the T-Ag interacting domain of c-Jun maps to its basic-DNA binding region. Results of transient-transfection assays with various c-Jun mutants and T-Ag expression constructs further confirm the specificity of the functional interaction between c-Jun and T-Ag. Taken together, these data demonstrate that immediate-early inducible transcription factors c-Jun and c-Fos physically and functionally interact with JCV major early regulatory protein large T-Ag and that this interaction modulates JCV transcription and replication in glial cells.


Several new considerations in mitral valve repair.
A retrospective evaluation was made of a small personal series of patients undergoing mitral valve repair in order to address four contemporary questions: (i) What is the best method of achieving a stable repair in mitral valve prolapse?; (ii) How should patients with pure annular dilatation without prolapse or antecedent ischemia be categorized?; (iii) Are valve procedures in ischemic mitral regurgitation (MR) still associated with less satisfactory early and late outcomes?; and (iv) Is prophylactic amiodarone therapy safe and effective in reducing postoperative arrhythmias? Between 1993 and 2002, a total of 118 patients with non-rheumatic MR undergoing isolated mitral valve repair with or without coronary bypass was analyzed retrospectively: of these patients, 66 had prolapse (Group I), 21 had pure annular dilatation (Group II), and 31 had ischemic MR (Group III). All three groups routinely underwent Carpentier ring annuloplasty. Twenty-three patients in Group I were managed with leaflet resection and reconstruction (LRR), but in 1996 the technique for Group I was changed to uniform artificial chordal replacement (ACR) and no leaflet resection (n = 43). Also in 1996, prophylactic amiodarone therapy was first used routinely, and postoperative arrhythmia data were compared to those from prior patients. Baseline and outcome variables were assessed for each group and compared between the three groups. Survival data were evaluated using the Cox proportional hazards model. Significant differences in baseline characteristics were observed: Group II was predominantly female; Group III more often experienced acute presentation; and Groups II and III had more comorbid disorders and left ventricular dysfunction (all p < 0.01). ACR was highly successful for repair of prolapse, and no ACR patient exhibited significant residual MR or outflow tract obstruction. Operative mortality and morbidity were low in all groups, and ischemic etiology failed to be an independent predictor of early or late adverse outcome (p > 0.10). Cox model analysis to nine years of follow up (median 4 years) identified only advanced age and number of comorbidities as influencing late mortality (both p < 0.03). Over the follow up period, 8.7% of LRR patients required reoperation for valve failure due to late chordal rupture, whereas none of the ACR patients failed. Finally, prophylactic amiodarone significantly reduced postoperative arrhythmias (p = 0.03) with no observed complications, and also eliminated death due to arrhythmia. Ischemic etiology may be diminishing as an independent risk factor in Group III, at least partially because of uniform valve repair. Group II comprised a distinct entity of females with higher comorbidity, and prophylactic amiodarone therapy seemed useful as a routine measure. Finally, ACR appeared to produce a stable repair in virtually all Group I patients, suggesting that prolapse might be appropriately managed with ring annuloplasty and uniform ACR. However, future studies are suggested for further consideration of these hypotheses.


[Prevention of secondary neurotic and other mental disorders in traumatic epilepsy].
A study was made of the effect of risk factors and the clinical picture of the prodromal period in 184 patients with traumatic epilepsy, of the efficacy of nootropic and long-acting psychotropic drugs in combined treatment. The risk factors were brain contusions, open cranial injuries, particularly in frontotemporal areas, comatose states after injury lasting over 6 hours, successive fits in the acute period of injury, episodic disorders of dull consciousness. Administration of nootropic and long-acting drugs brought about a reduction of the cerebral asthenic symptomatology and stabilization of emotional disturbances which promoted prevention of secondary neurotic and other mental disorders in patients with traumatic epilepsy.


Thyroid storm--a nursing crisis.
A 48-year-old woman with a known history of hypothyroidism was admitted to the intensive care unit with a diagnosis of thyroid storm secondary to acute thyroid hormone poisoning and the possible hyperfunction of a singular thyroid nodule. Her clinical manifestations included pyrexia, tachycardia, tachypnea, hypertension, RUQ abdominal pain, psychotic behavior, and pharyngitis. She was successfully treated with sodium iodide, PTU, propranolol, antibiotics, and a hypothermia mattress, with her serum T4 level returning to normal range prior to discharge. The patient was discharged 9 days after admission in good medical health with no medication. This article clearly shows that the functions of the endocrine system remain a frontier in today's medicine. With research, perhaps one day we might fully understand the intricate pathophysiology that results in thyroid storm. The potential problem format has been utilized in the development of the nursing care plan to assist the nurse with identifying and defining her patient's problems, as well as directing her assessment and nursing intervention. As more is learned about thyroid storm, nurses should update their knowledge so that they will be prepared to care for the patient with these difficult nursing problems.


The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial.
QT interval prolongation is associated with torsade de pointes but remains a poor predictor of drug torsadogenicity. Increased transmural dispersion of myocardial repolarization (TDR), measured as the time interval between the peak and end of the T wave (Tp-e), is a more reliable predictor. Carbetocin is recommended as an uterotonic in patients undergoing cesarean delivery (CD), but its effect on Tp-e is unknown. We evaluated the effect of carbetocin dose on Tp-e and Bazett-corrected QT intervals (QTc) during elective CD under spinal anesthesia. On patient consent, 50 healthy parturients undergoing elective CD with a standardized spinal anesthetic and phenylephrine infusion were randomized to receive an intravenous (IV) bolus of carbetocin 50 µg (C50) or 100 µg (C100) via an infusion pump over 1 minute. A 12-lead electrocardiogram (ECG) was obtained at baseline, 5 minutes after spinal anesthesia, then 5 and 10 minutes after carbetocin administration. A cardiologist blinded to group and timing of ECGs measured QTc and Tp-e using Emori's criteria. Primary outcome was the change in Tp-e at 5 minutes after carbetocin administration between the C50 and C100 groups and within each group compared to baseline values. Secondary outcomes included occurrence of arrhythmias, changes in QTc at 5 and 10 minutes after carbetocin, changes in both QTc and Tp-e after spinal anesthesia compared to baseline between and within groups. Data from 41 parturients with a mean (standard deviation [SD]) age of 39.0 (0.7) years and weight of 75.0 (12.0) kg were analyzed. Between groups, at 5 minutes after carbetocin administration, Tp-e in C100 was 4.1 milliseconds longer compared to C50 (95% confidence interval [CI], 0.8-7.5; P = .01). Within groups, at 5 minutes after carbetocin administration, C50 did not significantly increase Tp-e compared to baseline (mean difference [MD] 1.9 milliseconds; 95% CI, -0.95 to 4.81 milliseconds; P = .42) but C100 did (MD 5.1 milliseconds; 95% CI, 2.1-8.1; P = .003). QTc increased significantly within C50 and C100 groups at 5 and 10 minutes after carbetocin administration (all P < .001), with no between-group differences. There were no arrhythmias. Tp-e was unaffected by C50 IV given after CD in healthy parturients under spinal anesthesia, but minimally prolonged by C100. The increase in QTc after carbetocin administration was statistically significant, but with no apparent dose-dependent effect. The minimal Tp-e prolongation at the higher dose is unlikely to have any clinically significant impact on TDR and therefore the risk of inducing torsade de pointes is low.


Thyroxine-binding globulin: specificity for the hormonally active conformation of triiodothyronine.
The conformational requirements for binding of triiodothyronine to thyroxine-binding globulin were investigated with triiodothyronine analogs having restricted rotation at the ether bond. Although it has been reported that the predominant conformation of triiodothyronine carries the 3' iodine in a position proximal to the phenylalanine ring, the analog for the distal, hormonally active orientation of the 3' iodine is more effective in displacing triiodothyronine and thyroxine from thyroxine-binding globulin. The lower binding affinity of thyroxine-binding globulin for triiodothyronine as compared to thyroxine may be explained by specificity of the binding site for the less abundant conformation of triiodothyronine.


Effects of diltiazem on smooth muscles and neuromuscular junction in the mesenteric artery.
Effects of diltiazem on membrane properties, neuromuscular transmissions, and mechanical responses were investigated in intact and skinned muscles of the guinea pig mesenteric artery. Diltiazem (greater than 10(-6) M) depolarized the membrane, increased the membrane resistance, and suppressed the spike evoked by either electrical depolarization or summation of excitatory junction potentials (EJPs). This drug also suppressed the facilitation process of amplitudes of EJPs produced by repetitive perivascular nerve stimulations. These suppressions of EJPs were not caused by a reduced number of active nerves contributing to the generation of EJP but but rather to a reduction in the release of chemical transmitters. Norepinephrine (NE)-induced and K-induced contractions were suppressed by diltiazem noncompetitively, but the contraction evoked in Na-deficient solution was not suppressed, i.e., diltiazem is not a nonselective inhibitor of the Ca influx. In the saponin-treated skinned muscles diltiazem did not suppress the release from or the accumulation into the Ca store site, nor did it suppress activation of the Ca receptor in contractile proteins. These results indicate that diltiazem acts on the surface membrane and nerve terminal as a Ca antagonist or Ca-channel blocker.


Detection of arbuscular mycorrhizal fungi associated with pecan (Caryaillinoinensis) trees by molecular and morphological approaches.
Arbuscular mycorrhizal (AM) fungal community associated with pecan (Caryaillinoinensis) roots and rhizospheric soils was assessed by spore isolation and morphological characterisation and by pyrosequencing of AM molecular markers. The AM fungal community associated with pecan growing in the field, was always more diverse than that associated with pecan growing in containers. This was not observed when AM richness was studied, suggesting that soil disturbance by a reduction in host plant richness leads to a less equitable distribution of AM fungal species, in contrast to natural soils. The chosen primers (AMV4.5F/AMDGR) for pyrosequencing showed high AM fungal specificity. Based on 97% sequence similarity, 49 operational taxonomic units (MOTUs) were obtained and, amongst these, 41 MOTUs corresponded to the Glomeromycotaphylum. The number of obtained AM sequences ranged from 2164, associated with field samples, to 5572 obtained from pecan trap pot culture samples, defining 30 and 29 MOTUs, respectively. Richness estimated by conventional species identification was 6 and 9 AM fungal species in soil and pot samples, respectively. Claroideoglomuslamellosum, Funneliformismosseae and Entrophosporainfrequens were the only taxa detected using both techniques. Predominant sequences in the pecan rhizosphere samples, such as Rhizoglomusirregulare and other less abundant (Dominikiairanica, Dominikiaindica, Sclerocystissinuosa, Paraglomuslaccatum), were detected only by pyrosequencing. Detection of AM fungal species based on spore morphology, in combination with molecular approaches, provides a more comprehensive estimate of fungal community composition.


Acrylic acid induces the glutathione-independent mitochondrial permeability transition in vitro.
Acrylic acid (AA) is used widely in the synthesis of esters essential in the production of paints, adhesives, plastics, and coatings. The minimal systemic toxicity of AA is attributed to its rapid oxidation to acetyl-CoA and CO2 via the vitamin B12-independent beta-oxidation pathway. This oxidation is localized to the mitochondria and preliminary evidence suggests a possible inhibition of mitochondrial metabolism by acrylic acid. The purpose of this investigation was to evaluate whether AA interferes with mitochondrial bioenergetics in vitro. Incubation of isolated rat liver mitochondrial with AA resulted in a dose-dependent induction of the mitochondrial permeability transition (MPT). This was evidenced by an increased sensitivity to calcium-induced stimulation of state 4 oxygen consumption, depolarization of membrane potential, and swelling, all of which were prevented by preincubating the mitochondrial with cyclosporine A, a potent and specific inhibitor of the mitochondrial permeability transition pore. Both N-ethylmaleimide (NEM) and dithiothreitol (DTT) showed only partial protection against induction of the MPT by AA. Associated with the induction of the MPT by AA was the loss of mitochondrial glutathione (GSH), which was due to efflux from the matrix rather than oxidation to GSSG. Cyclosporine A, by inhibiting the permeability transition, prevented the AA-induced loss of mitochondrial GSH. In conclusion, AA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the MPT. Although the molecular mechanism has yet to be defined, it does not appear to be related to the oxidation of critical thiols.


[Influence of sexual maturity and gonadectomy on cardiac electrical activity in male and female rabbits].
Sex-associated differences in cardiac electrical activity have already been document noted. Even though these differences are usually associated with the effect of maturity and sex hormones, there are still some controversial points to this respect. The aim of this study was to evaluate the effects of maturity and gonadectomy on the different parameters of surface electrocardiogram and the duration of the action potential in young and adult rabbits. The differences obtained in females were observed in late repolarization, whereas in males took place in early repolarization. There was a relationship between the differences observed in the duration from the peak to the end of the T wave and those observed in the duration of the action potential to 90% of repolarization in females, whereas in males the relationship exists between the duration from the point J to the peak of the T wave and the duration of the action potential at 30 and 50% of repolarization. Differences could be related to hormonal or non-hormonal factors.


Does Signal Degradation Affect Top-Down Processing of Speech?
Speech perception is formed based on both the acoustic signal and listeners' knowledge of the world and semantic context. Access to semantic information can facilitate interpretation of degraded speech, such as speech in background noise or the speech signal transmitted via cochlear implants (CIs). This paper focuses on the latter, and investigates the time course of understanding words, and how sentential context reduces listeners' dependency on the acoustic signal for natural and degraded speech via an acoustic CI simulation.In an eye-tracking experiment we combined recordings of listeners' gaze fixations with pupillometry, to capture effects of semantic information on both the time course and effort of speech processing. Normal-hearing listeners were presented with sentences with or without a semantically constraining verb (e.g., crawl) preceding the target (baby), and their ocular responses were recorded to four pictures, including the target, a phonological (bay) competitor and a semantic (worm) and an unrelated distractor.The results show that in natural speech, listeners' gazes reflect their uptake of acoustic information, and integration of preceding semantic context. Degradation of the signal leads to a later disambiguation of phonologically similar words, and to a delay in integration of semantic information. Complementary to this, the pupil dilation data show that early semantic integration reduces the effort in disambiguating phonologically similar words. Processing degraded speech comes with increased effort due to the impoverished nature of the signal. Delayed integration of semantic information further constrains listeners' ability to compensate for inaudible signals.


Test-retest reliability of a questionnaire to assess physical environmental factors pertaining to physical activity.
Despite the documented benefits of physical activity, many adults do not obtain the recommended amounts. Barriers to physical activity occur at multiple levels, including at the individual, interpersonal, and environmental levels. Only until more recently has there been a concerted focus on how the physical environment might affect physical activity behavior. With this new area of study, self-report measures should be psychometrically tested before use in research studies. Therefore the objective of this study was to document the test-retest reliability of a questionnaire designed to assess physical environmental factors that might be associated with physical activity in a diverse adult population. Test and retest surveys were conducted over the telephone with 106 African American and White women and men living in either Forsyth County, North Carolina or Jackson, Mississippi. Reliability of self-reported environmental factors across four domains (e.g., access to facilities and destinations, functionality and safety, aesthetics, natural environment) was determined using intraclass correlation coefficients (ICC) overall and separately by gender and race. Generally items displayed moderate and sometimes substantial reliability (ICC between 0.4 to 0.8), with a few differences by gender or race, across each of the domains. This study provides some psychometric evidence for the use of many of these questions in studies examining the effect of self-reported physical environmental measures on physical activity behaviors, among African American and White women and men.


Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data.
This study was conducted to assess the utility of unbound brain EC50 (EC50,u) as a measure of in vivo potency for centrally active drugs. Seven mu-opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as model central nervous system drugs because they elicit a readily measurable central effect (antinociception) and their clinical pharmacokinetics/pharmacodynamics are well understood. Mice received an equipotent subcutaneous dose of one of the model opioids. The time course of antinociception and the serum and brain concentrations were determined. A pharmacokinetic/pharmacodynamic model was used to estimate relevant parameters. In vitro measures of opioid binding affinity (Ki) and functional activity [EC50 for agonist stimulated guanosine 5'-O-(3-[35S]thio)triphosphate binding] and relevant clinical parameters were obtained to construct in vitro-to-preclinical and preclinical-to-clinical correlations. The strongest in vitro-to-in vivo correlation was observed between Ki and unbound brain EC50,u (r2 approximately 0.8). A strong correlation between mouse serum and human plasma EC50 was observed (r2 = 0.949); the correlation was improved when corrected for protein binding (r2 = 0.995). Clinical equipotent i.v. dose was only moderately related to Ki. However, estimates of ED50 and EC50 (total serum, unbound serum, total brain, and unbound brain) were significant predictors of clinical equipotent i.v. dose; the best correlation was observed for brain EC50,u (r2 = 0.982). For each opioid, brain equilibration half-life in mice was almost identical to the plasma effect-site equilibration half-life measured clinically. These results indicate that the mouse is a good model for opioid human brain disposition and clinical pharmacology and that superior in vitro-to-preclinical and preclinical-to-clinical correlations can be achieved with relevant unbound concentrations.


Quantum Simulation of Molecular Response Properties in the NISQ Era.
Accurate modeling of the response of molecular systems to an external electromagnetic field is challenging on classical computers, especially in the regime of strong electronic correlation. In this article, we develop a quantum linear response (qLR) theory to calculate molecular response properties on near-term quantum computers. Inspired by the recently developed variants of the quantum counterpart of equation of motion (qEOM) theory, the qLR formalism employs "killer condition" satisfying excitation operator manifolds that offer a number of theoretical advantages along with reduced quantum resource requirements. We also used the qEOM framework in this work to calculate the state-specific response properties. Further, through noiseless quantum simulations, we show that response properties calculated using the qLR approach are more accurate than the ones obtained from the classical coupled-cluster-based linear response models due to the improved quality of the ground-state wave function obtained using the ADAPT-VQE algorithm.


The Effect of the Yingyangbao Complementary Food Supplement on the Nutritional Status of Infants and Children: A Systematic Review and Meta-Analysis.
Yingyangbao (YYB) is a nutrient-dense complementary food supplement for infants and young children in China. There has been considerable interest and research on the potential effects of YYB on hematological and anthropometric outcomes in China, but limited effort has been made to consolidate and synthesize the evidence to inform the research and policy agendas. Eight English databases and three Chinese databases were searched from January 2001 to June 2019 to identify YYB intervention studies. A total of 32 quasi-experimental, post-only, concurrent-control studies or pre-post studies were identified, and 26 were included in the meta-analyses. A pooled analysis of post-only studies with concurrent-control determined that YYB was associated with an increase of 4.43 g/L (95% confidence interval (CI) 1.55, 7.30) hemoglobin concentration, 2.46 cm (CI 0.96, 3.97) in height, and 0.79 kg (CI 0.25, 1.32) weight in infants and young children. YYB was also associated with reductions in the prevalence of anemia (risk ratio (RR) = 0.55; 95% CI: 0.45, 0.67), stunting (RR = 0.60; 95% CI: 0.44, 0.81), and underweight (RR = 0.51; 95% CI: 0.39, 0.65). Overall, YYB was found to be associated with improved hematological and anthropometric indicators among infants and young children in China; however, randomized trials are needed to causally assess the efficacy of YYB due to the inherent risk of bias in existing quasi-experimental studies; rigorous implementation and cost-effectiveness evaluations are also needed.


Hemolytic anemia in hereditary pyrimidine 5'-nucleotidase deficiency: nucleotide inhibition of G6PD and the pentose phosphate shunt.
We evaluated the erythrocytes of two patients with hereditary pyrimidine 5'-nucleotidase deficiency. Significant findings included an increased reduced glutathione content, increased incubated Heinz body formation, a positive ascorbate cyanide test, and decreased intraerythrocytic pH. The pentose phosphate shunt activity of the patients' red cells as measured by the release of 14CO2 from 14C-1-glucose was decreased compared to high reticulocyte controls. Glucose-6-phosphate dehydrogenase (G6PD) activity in hemolysates from control erythrocytes was inhibited 43% by 5.5 mM cytidine 5'-triphosphate (CTP) and 50% by 5.5 mM in uridine 5'-triphosphate (UTP) at pH 7.1. CTP was a competitive inhibitor for G6P (Ki = 1.7 mM) and a noncompetitive inhibitor for NADP+ (Ki = 7.8 mM). Glutathione peroxidase, glutathione reductase, and 6-phosphogluconate dehydrogenase were not affected by these compounds. Pentose phosphate shunt activity in control red cell hemolysate at pH 7.1 was inhibited to a similar degree by 5.5 mM CTP or UTP. Since the intracellular concentrations of G6P and NADP+ are below their KmS for G6PD, these data suggest that high concentrations of pyrimidine 5'-nucleotides depress pentose phosphate shunt activity in pyrimidin 5'-nucleotidase deficiency. Thus, this impairment of the pentose phosphate pathway appears to contribute to the pathogenesis of hemolysis in pyrimidine 5'-nucleotidase deficiency hemolytic anemia.


Understanding resolution of deliberate self harm: qualitative interview study of patients' experiences.
To explore the accounts of those with a history of deliberate self harm but who no longer do so, to understand how they perceive this resolution and to identify potential implications for provision of health services. Qualitative in-depth interview study. Interviews in a community setting. 20 participants selected from a representative cohort identified in 1997 after an episode of deliberate self poisoning that resulted in hospital treatment. Participants were included if they had no further episodes for at least two years before interview. We identified three recurrent themes: the resolution of adolescent distress; the recognition of the role of alcohol as a precipitating and maintaining factor in self harm; and the understanding of deliberate self harm as a symptom of untreated or unrecognised illness. Patients with a history of deliberate self harm who no longer harm themselves talk about their experiences in terms of lack of control over their lives, either through alcohol dependence, untreated depression, or, in adolescents, uncertainty within their family relationships. Hospital management of deliberate self harm has a role in the identification and treatment of depression and alcohol misuse, although in adolescents such interventions may be less appropriate.


[Retroperitoneal paraganglioma incidentally detected by health examination: a case report].
We report a case of non-functioning retroperitoneal paraganglioma detected incidentally by health examination in a 60-year-old female without any clinical manifestation. She was admitted to our hospital for the purpose of evaluation of a renal mass detected by ultrasound sonography. Computed tomography, magnetic resonance imaging and angiography revealed the heterogeneously-enhanced 10 x 10 cm mass in the left retroperitoneal space without any distant metastasis. It was suspected to be a renal cell carcinoma. All laboratory data, including those from endocrinological examinations, were within normal ranges. Radical nephrectomy was performed to resect en bloc the mass and the left kidney. The pathological and immunohistochemical examinations of the mass which was completely separated from the kidney and the adrenal gland, showed characteristic features of paraganglioma with vascular and capsular invasion, with a final clinical diagnosis of the pathologically-malignant non-functioning paraganglioma occurring between the left kidney and the adrenal gland.


[Hand metastases--a rare metastatic form of colorectal carcinoma].
24 years after the diagnosis of ulcerative colitis had been made a now 77-year-old man was found to have carcinoma of the rectum. One year after its resection lung metastases and a sacral recurrence became apparent. Two years later swelling of the left hand was at first diagnosed as Sudeck's atrophy, but subsequent tests revealed a metastasis of the known adenocarcinoma to the hand. Palliative telecobalt radiation quickly brought about symptomatic relief.


Study of Langerhans cells after allogeneic bone marrow transplantation.
We assessed the number of Langerhans cells (LC) before and after bone marrow transplantation (BMT) in 27 patients in order to study the fate and behavior of these dendritic antigen-presenting cells following allogeneic BMT. LC were identified using monoclonal antibody OKT6 on skin biopsies performed on days - 10, 0, 11, 25, 39, 120, and 365. In a control group composed of 15 healthy adults aged 20-37 yr, the mean number of LC (+/- SEM) was 25.6 +/- 1.17/0.1 sq mm of epidermal surface. Our study shows that pretransplant, the number of LC in patients with aplastic anemia or leukemia was lower than that of controls. The finding of low numbers of LC in patients with untreated aplastic anemia is suggestive of a medullary origin of LC in man. Moreover, during the early posttransplant period, nearly all patients present a severe deficit in LC. This deficit may delay the maturation of their immune system. The number of LC reaches nearly normal levels 4-12 mo after BMT. Finally, we have noted a significant impairment of LC reconstitution in patients with acute graft-versus-host disease (GVHD), providing evidence that this defect may be an important mechanism involved in acute GVHD-related immunodeficiency.


CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis.
Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe-/- background developed increased aortic lipid-rich plaques compared to control Apoe-/- mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe-/- mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe-/- marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow-derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.


Multiscale Surface-Attached Hydrogel Thin Films with Tailored Architecture.
A facile route for the fabrication of surface-attached hydrogel thin films with well-controlled chemistry and tailored architecture on wide range of thickness from nanometers to micrometers is reported. The synthesis, which consists in cross-linking and grafting the preformed and ene-reactive polymer chains through thiol-ene click chemistry, has the main advantage of being well-controlled without the addition of initiators. As thiol-ene click reaction can be selectively activated by UV-irradiation (in addition to thermal heating), micropatterned hydrogel films are easily synthesized. The versatility of our approach is illustrated by the possibility to fabricate various chemical polymer networks, like stimuli-responsive hydrogels, on various solid substrates, such as silicon wafers, glass, and gold surfaces. Another attractive feature is the development of new complex hydrogel films with targeted architecture. The fabrication of various architectures for polymer films is demonstrated: multilayer hydrogel films in which single-networks are stacked one onto the other, interpenetrating networks films with mixture of two networks in the same layer, and nanocomposite hydrogel films where nanoparticles are stably trapped inside the mesh of the network. Thanks to its simplicity and its versatility this novel approach to surface-attached hydrogel films should have a strong impact in the area of polymer coatings.


Medication adherence and patient outcomes: part 2: interventions and resources to overcome low health literacy.
This article explores the influence of health literacy on medication adherence. With health literacy skills nearly flat for over a decade and an aging population receiving multiple and complex medication regimens, literacy is becoming a more important factor in nursing assessment and intervention. Concrete tools are provided to help the clinical nurse specialist (CNS) assess literacy and evaluate written resources for patient education and to improve medication adherence.


Responsive polymer-fluorescent carbon nanoparticle hybrid nanogels for optical temperature sensing, near-infrared light-responsive drug release, and tumor cell imaging.
Fluorescent carbon nanoparticles (FCNPs) have been successfully immobilized into poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)] nanogels based on one-pot precipitation copolymerization of NIPAM monomers with hydrogen bonded FCNP-AAm complex monomers in water. The resultant poly(NIPAM-AAm)-FCNP hybrid nanogels can combine functions from each building block for fluorescent temperature sensing, cell imaging, and near-infrared (NIR) light responsive drug delivery. The FCNPs in the hybrid nanogels not only emit bright and stable photoluminescence (PL) and exhibit up-conversion PL properties, but also increase the loading capacity of the nanogels for curcumin drug molecules. The reversible thermo-responsive swelling/shrinking transition of the poly(NIPAM-AAm) nanogel can not only modify the physicochemical environment of the FCNPs to manipulate the PL intensity for sensing the environmental temperature change, but also regulate the releasing rate of the loaded anticancer drug. In addition, the FCNPs embedded in the nanogels can convert the NIR light to heat, thus an exogenous NIR irradiation can further accelerate the drug release and enhance the therapeutic efficacy. The hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells upon laser excitation. The demonstrated hybrid nanogels with nontoxic and optically active FCNPs immobilized in responsive polymer nanogels are promising for the development of a new generation of multifunctional materials for biomedical applications.


Decreased numbers of platelet alpha-adrenergic binding sites in diabetes mellitus.
Eleven men with diabetes mellitus were compared with 45 male controls for platelet alpha-adrenergic binding sites by using [3H]dihydroergocryptine (DHE) as the radioligand antagonist. There was no difference between the two for binding affinity, but the number of sites was 430 +/- 30 (means +/- SEM) for diabetic subjects and 574 +/- 29 for controls (P = .005). Decreased sites were related to increased glycosylated hemoglobin levels (P = .002). There was no relationship between the decreased sites and catecholamine levels, duration of disease, body weight, or fasting blood sugar. Hence, binding sites were inversely related to control, but further studies are needed to define the pathophysiologic significance of this.


Evidence for a conserved role for CRKII and Rac in engulfment of apoptotic cells.
Apoptosis or programmed cell death occurs in multicellular organisms throughout life. The removal of apoptotic cells by phagocytes prevents secondary necrosis and inflammation and also plays a key role in tissue remodeling and regulating immune responses. The molecular mechanisms that regulate the engulfment of apoptotic cells are just beginning to be elucidated. Recent genetic studies in the nematode Caenorhabditis elegans have implicated at least six genes in the removal of apoptotic cell corpses. The gene products of ced-2, ced-5, and ced-10 are thought to be part of a pathway that regulates the reorganization of the cytoskeleton during engulfment. The adapter proteins CrkII and Dock180 and the small GTPase Rac represent the mammalian orthologues of the ced-2, ced-5 and ced-10 gene products, respectively. It is not known whether CrkII, Dock180, or Rac proteins have any role during engulfment in mammalian cells. Here we show, using stable cell lines and transient transfections, that overexpression of wild-type CrkII or an activated form of Rac1 enhances engulfment. Mutants of CrkII failed to mediate this increased engulfment. The higher CrkII-mediated uptake was inhibited by coexpression of a dominant negative form of Rac1 but not by a dominant a negative Rho protein; this suggested that Rac functions downstream of CrkII in this process, which is consistent with genetic studies in the worm that place ced-10 (rac) downstream of ced-2 (crk) in cell corpse removal. Taken together, these data suggest that CED-2/CrkII and CED-10/Rac are part of an evolutionarily conserved pathway in engulfment of apoptotic cells.


Total Wrist Arthroplasty: An International Perspective.
Concerns about implant durability and technical difficulty continue to make total wrist arthroplasties a specialized procedure with a narrow scope of indications. As a result, more routinely performed total or partial wrist arthrodesis continues to maintain popularity over arthroplasty. However, wrist motion preservation is undoubtedly preferable for patients and current literature is trending to more favorable outcomes for total wrist arthroplasties. In the setting of the evolving role of wrist arthroplasties in clinical practice, it is important to focus on providing hand surgeons a practical approach to incorporating total wrist arthroplasty into the treatment toolbox available to them when treating patients with painful wrist arthritis.


Antisaccade task performance in patients at ultra high risk for developing psychosis.
Patients with schizophrenia consistently perform worse than healthy controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. To our knowledge there is no research yet showing how patients at ultra high risk (UHR) for developing psychosis perform on the antisaccade task. The aim of the present study was to investigate antisaccade task performance in UHR patients. Patients were eligible for the study when they met criteria for one or more of the following groups: Attenuated symptoms or brief limited intermitted psychotic symptoms or a first-degree family member with a psychotic disorder and reduced functioning or basic symptoms. In 35 UHR patients we assessed antisaccades, neuropsychological test performance and symptomatology. Antisaccade task results were compared with those obtained in 42 age- and intelligence-matched patients with recent-onset schizophrenia and 28 matched healthy controls. Antisaccade error rate was significantly higher in the UHR patients than in the controls. Schizophrenia patients performed worse than the UHR patients and the control subjects. We found a trend towards higher antisaccade error rate at baseline in the UHR patients who later made the transition to psychosis compared to the UHR patients who did not make the transition to psychosis. Poor spatial working memory function was related to increased antisaccade errors in the UHR group. Abnormal antisaccade task performance is also present in patients at UHR for developing psychosis. Subsequent research needs to clarify if increased antisaccade error rate is predictive of a psychotic episode. In UHR patients, poor antisaccade performance may reflect working memory dysfunction.