Pre- and postsynaptic modulation of the electrical activity of rat supraoptic neurones.
The release of vasopressin and oxytocin is regulated by the electrical activity of magnocellular neurosecretory cells in the supraoptic and paraventricular nuclei, which is under the control of a great variety of neurotransmitters and neuromodulators. The major neural signals to the supraoptic nucleus are from excitatory glutamate inputs and inhibitory GABA inputs. In recent studies, the voltage-clamp mode of the whole-cell patch-clamp technique has been applied to slice preparations from rat hypothalamus to monitor synaptic inputs to supraoptic neurones. Spontaneous excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) are abolished by CNQX and picrotoxin, respectively, but are insensitive to tetrodotoxin, indicating that they represent quantal release of glutamate and GABA, respectively, from nerve terminals of presynaptic neurones. GABA and glutamate show remarkable suppressive effects on both EPSCs and IPSCs via presynaptic GABA(B) and mGlu receptors, respectively. Noradrenaline, which excites supraoptic neurones via postsynaptic alpha1-receptors, also suppresses IPSCs and potentiates EPSCs. On the other hand, prostaglandin E2, which excites supraoptic neurones via postsynaptic prostaglandin E2 (EP) receptors of the EP4 subclass, also suppresses IPSCs via EP3 receptors but has little effect on EPSCs. Thus pre- and postsynaptic mechanisms may act cooperatively to excite supraoptic neurones. Nitric oxide, which inhibits supraoptic neurones, potentiates IPSCs without affecting EPSCs. This provides another example for the preferential modulation of IPSCs of supraoptic neurones. On the other hand, PACAP, which causes a long-lasting increase in the firing frequency via the postsynaptic receptors, has no effect on EPSCs and IPSCs, suggesting that some ligands act only at postsynaptic receptors. Thus multiple patterns for pre- and postsynaptic modulation are present in the supraoptic nucleus, and the electrical activity of supraoptic neurones is regulated via complex mechanisms at both pre- and postsynaptic sites.


Toothbrush abrasion of surface softened enamel studied with tapping mode AFM and AFM nanoindentation.
The aim of the present in vitro study was to investigate the toothbrush abrasion of surface softened enamel using tapping mode atomic force microscopy (TM-AFM) and AFM nanoindentation. TM-AFM investigations showed that the typical prismatic pattern as observed after demineralisation was retained after toothbrushing. The exposure to artificial saliva resulted in the deposition of a 'sausage-shape' material with random orientation. Brushing of these samples did not lead to a complete removal of this deposited material. Enamel mineral loss increased with increasing demineralisation time and increased further, although only to a small extent, due to subsequent toothbrushing. Exposure to artificial saliva did not alter the amount of enamel mineral lost due to the brushing treatment. AFM nanoindentation investigations showed that the three different demineralisation treatments caused three statistically different reductions in both surface hardness and reduced elastic modulus values, with the shortest exposure time having the least effect on the nanomechanical properties of the enamel samples. Toothbrushing did result only in a small increase in hardness and reduced elastic modulus. The present study has shown that toothbrushing of surface softened enamel leads to minor changes in the surface morphology and nanomechanical properties. The amount of enamel lost due to toothbrushing was independent of the demineralisation time and was lower compared to the mineral loss caused by the demineralisation treatments. Furthermore, the exposure to artificial saliva offers minimal protective effect to the softened enamel surface against toothbrushing.


Formation of Escherichia coli Hfr strains by integrative suppression with the P group plasmid RP1.
Hfr strains of Escherichia coli were obtained by integrative suppression of a dnaA(Ts) mutation by the Inc P-1 plasmid RP1 without prior creation of an unnatural homology between the plasmid and the E. coli chromosome. Unmodified RP1 mobilized the polarized transfer of the chromosome in a counterclock-wise direction from a distinct origin between 81 min (pyrE) and 82 min (dnaA) with pyrE as a leading marker. Inheritance of RP1-Hfr chromosomal and antibiotic resistance genes was due to recombination with the recipient chromosome, as shown by the need for a functional recA system. The acquisition of temperature resistance and donor ability was accompanied by the disappearance of free plasmid when the selection pressure for integration was maintained (growth at 41 degrees C); the loss of temperature resistance and donor ability was accompanied by the reappearance of autonomous RP1 when the selection pressure was removed (growth at 30 degrees C).


Clinicopathological correlates of Gli1 expression in a population-based cohort of patients with newly diagnosed bladder cancer.
Dysregulation of the hedgehog signaling pathway has been linked to the development and progression of a variety of different human tumors including cancers of the skin, brain, colon, prostate, blood, and pancreas. We assessed the clinicopathological factors that are potentially related to expression of Gli1, the transcription factor that is thought to be the most reliable marker of hedgehog pathway activation in bladder cancer. Bladder cancer cases were identified from the New Hampshire State Cancer Registry as histologically confirmed primary bladder cancer diagnosed between January 1, 2002, and July 31, 2004. Immunohistochemical analysis was performed on a tissue microarray to detect Gli1 and p53 expression in these bladder tumors. We computed odds ratios (ORs) and their 95% CIs for Gli1 positivity for pathological category using T category (from TNM), invasiveness, and grade with both the World Health Organization 1973 and World Health Organization International Society of Urological Pathology criteria. We calculated hazard ratios and their 95% CI for Gli1 positivity and recurrence for both Ta-category and invasive bladder tumors (T1+). A total of 194 men and 67 women, whose tumors were assessable for Gli1 staining, were included in the study. No appreciable differences in Gli1 staining were noted by sex, age, smoking status, or high-risk occupation. Ta-category tumors were more likely to stain for Gli1 as compared with T1-category tumors (adjusted OR = 0.38, CI: 0.17-0.87). Similarly, low-grade (grades 1-2) tumors were more likely to stain for Gli1 as compared with high-grade tumors (grade 3) (adjusted OR = 0.44, CI: 0.21-0.93). In a Cox proportional hazards regression analysis, non-muscle-invasive bladder tumors expressing Gli1 were less likely to recur (adjusted hazard ratio = 0.48; CI: 0.28-0.82; P<0.05) than those in which Gli1 was absent. Our findings indicate that Gli1 expression may be a marker of low-stage, low-grade bladder tumors and an indicator of a reduced risk of recurrence in this group.


Quantification of disease progression of several microbial pathogens on Arabidopsis thaliana using real-time fluorescence PCR.
An accurate monitoring of disease progression is important to evaluate disease susceptibility phenotypes. Over the years, Arabidopsis thaliana has become the model species to serve as a host in plant-pathogen interactions. Despite the efforts to study genetic mechanisms of host defense, little efforts are made for a thorough pathogen assessment, often still depending on symptomology. This manuscript describes the use of real-time polymerase chain reaction (PCR) to assess pathogen growth in the host Arabidopsis for a number of frequently studied pathogens. A wide range of correlations between pathogen biomass and fluorescence is demonstrated, demonstrating the theoretical sensitivity of the technique. It is also demonstrated that host DNA does not interfere with the quantification of pathogen DNA over a wide range. Finally, quantification of pathogen biomass in different plant genotypes with a varying degree of resistance shows the capability of this technique to be used for assessment of pathogen development in disease progression.


Effectiveness of steroid/antibiotic treatment in primates administered LD100 Escherichia coli.
Early aggressive therapy with maintenance infusions of methylprednisolone sodium succinate and gentamicin sulfate significantly increases the probability for survival of baboons given LD100 Escherichia coli. The present study was designed to determine if baboons would recover when initiation of treatment was delayed until they had sustained E. coli-induced systemic hypotension for a period of approximately three hours. Sixteen adult baboons were each administered a two-hour infusion of LD100 E. coli. All eight untreated animals died within 42 hours. Five of the eight baboons treated after approximately three hours of hypotension with methylprednisolone sodium succinate and gentamicin sulfate survived. Treated animals had significantly higher blood glucose and insulin levels and lower blood urea nitrogen concentrations than baboons receiving E. coli alone. E. coli blood concentrations were lower in the treated than in the untreated baboon group by the sixth hour (less than 0.02). Heart rates increased in all animals but were not as high in the treated baboons. Both groups experienced similar decreases in mean systemic arterial pressure, PCO2, base excess, leukocyte, lymphocyte, and platelet concentrations, and increases in creatinine and lactate concentrations. Data from the present study indicate that the probability of recovery from shock is significantly increased even when initiation of steroid/antibiotic therapy is postponed until baboons have experienced sustained systemic hypotension.


Modifiers of Response to Treatment With Fesoterodine for Urgency-Predominant Urinary Incontinence in a Randomized Controlled Trial.
The aim of this study was to identify clinical and demographic characteristics that moderate response to treatment with fesoterodine among women with a diagnosis of urgency-predominant urinary incontinence. A multicenter, double-blinded, 12-week randomized controlled trial of pharmacologic therapy for urgency-predominant urinary incontinence in community-dwelling women diagnosed by the 3-item Incontinence Questionnaire (3IQ) was previously performed. Participants (N = 645) were randomized to fesoterodine therapy (4-8 mg daily; n = 322) or placebo (n = 323). Urinary incontinence was assessed by 3-day voiding diaries. In this secondary analysis, a "responder" was defined as reduction of 50% or greater in overall incontinence episode frequency compared with baseline. Clinical and demographic characteristics that may moderate treatment response were assessed by testing for interaction between characteristics and intervention in logit models of responders, adjusting for clinical site. Participants' ages were a mean of 56 (SD, 14) years, 68% were white race, and they had a mean of 3.9 (SD, 3.0) urgency incontinence episodes per day. There were no baseline differences in demographic, clinical, or incontinence characteristics between treatment and placebo groups or between responders and nonresponders. There was an increase in the proportion of responders to fesoterodine with increasing age (P = 0.04) and parity (0.04) and among married women (P = 0.03), but no effect modification was observed by race/ethnicity, body mass index, education, employment status, or alcohol or tobacco use. In ambulatory women with urgency-predominant urinary incontinence, older age, being married, and higher parity significantly moderated and potentiated the effects of pharmacologic therapy on incontinence frequency. This study identifies certain populations who may have increased responsiveness to treatment with antimuscarinic therapy and may be used to inform and guide future therapy.


Crown-to-implant ratios of short-length implants.
Excessive crown-implant ratios have been cited in the literature as being detrimental to long-term implant survival. However, unfavorable crown-implant ratios have not yet been established. The primary aim of this study was to determine the crown-implant ratios of single-tooth implant-supported restorations on short-length implants in a clinical practice, and to evaluate the health of these implants via mesial and distal first bone-to-implant contact levels. Additionally, the relationship between crown-implant ratios and proximal first bone-to-implant contact levels will be evaluated. In this retrospective cohort study, the cohort was composed of 194 patients who possessed at least 1 single 5.7 mm or 6 mm length plateau design implant-supported restoration that had been surgically placed between February 1997 and December 2005. A chart review was performed to acquire the most recent radiographs in which both the entire crown and the implant were visible. The length of the crown and implant was measured directly from the radiographs using consistent magnification to calculate the crown-implant ratio. Mesial and distal first bone-to-implant contact levels were measured using 3 times magnification and were mathematically corrected for distortion. The last available radiograph was used to measure bone levels. Follow-up time was calculated from the day of implant placement to the date of the last available radiograph. Statistical analyses with analysis of variance mixed models were used. Data from 309 single implant-supported fixed restorations were tabulated and included in the study. The mean (SD) follow-up time was 20.9 (23.2) months, with a range of 15.6 to 122.8 months. The mean crown length (SD) was 13.4 (2.6) mm, with a range of 6.2 to 21.7 mm. The mean (SD) crown-implant ratio was 2.0 (0.4) and ranged from 0.9 to 3.2. The average mesial and distal first bone-to-implant contact levels (SD) measured from the radiographs were -0.2 (0.7) mm and -0.2 (0.9) mm, respectively. No statistically significant relationship was observed between increasing crown-implant ratios and decreasing mesial and distal first bone-to-implant contact levels around the implant with P values of .94 and .57, respectively. In this investigation, mesial and distal first bone-to-implant contact levels on short-length implants fall within the established guidelines for success. Also, there are no associations between crown-implant ratios and first bone-to-implant contact levels.


Paraquat tolerance of transgenic Nicotiana tabacum with enhanced activities of glutathione reductase and superoxide dismutase.
Transgenic tobacco with enhanced cytosolic activities of glutathione reductase and superoxide dismutase were generated by cross-fertilization. Leaves of the hybrids exhibited further increased tolerance to a O2-.-generating herbicide paraquat than those of their parents. This result indicates the efficiency of manipulating more than one gene in improving resistance of plants to photooxidative stress.


Effects of high nutrient supply on the growth of seven bamboo species.
Over the last decade, bamboo has emerged as an interesting plant for the treatment of various polluted waters using plant-based wastewater treatment systems. In these systems, nitrogen and phosphorous concentrations in wastewater can exceed plant requirements and potentially limit plant growth. The effects of two nutrient rates on the growth of seven bamboo species were assessed in a one-year experiment: Dendrocalamus strictus, Thyrsostachys siamensis, Bambusa tuldoides, Gigantochloa wrayi, Bambusa oldhamii, Bambusa multiplex and Bambusa vulgaris. Nutrient rates were applied with a 20:20:20 NPK fertilizer as 2.6 and 13.2 t.ha.yr(-1) NPK to three-year-old bamboo planted in 70 L containers. Morphological characters, photosynthetic responses, and NPK content in bamboo tissues were investigated. Under high-nutrient supply rate, the main trend observed was an increase of culm production but the culms' diameters were reduced. For the seven species, the above ground biomass yield tended to increase with high-nutrient rate. Increasing in nutrient rates also improved the photosynthetic activity which is consistent with the increase of nitrogen and phosphorus contents measured in plant tissues. All the bamboo species tested appears suitable for wastewater treatment purposes, but the species Bambusa oldhamii and Gigantochloa wrayi showed the higher biomass yield and nutrient removaL


[Depression following intracerebral hemorrhage and the evaluation of cerebral blood flow by single photon emission tomography].
The authors studied patients who presented depression and apathy following intracerebral hemorrhage (ICH). Twelve patients who were admitted in our hospital were divided into two groups according to the presence of post-stroke depression (PSD). Five patients with PSD are in group A, and another seven patients without PSD are in group B. Zung-self depression scale (SDS) and apathy scale were used for screening of depression and apathy. PSD was recognized in 5 (42%) of patients following ICH. Single photon emission tomography (SPECT) suggested the reduction of cerebral blood flow (CBF) in the frontal lobe in all patients of the group A (100%), whereas only 29% of patients of the group B. The reduction of CBF in the frontal lobe might be involved in the mechanism of depression following ICH in subacute stage.


Transport of PEGylated-PLA nanoparticles across a blood brain barrier model, entry into neuronal cells and in vivo brain bioavailability.
Treatments of neurodegenerative diseases (NDDs) are severely hampered by the presence of the blood-brain barrier (BBB) precluding efficient brain drug delivery. The development of drug nanocarriers aims at increasing the brain therapeutic index would represent a real progress in brain disease management. PEGylated polyester nanoparticles (NPs) are intensively tested in clinical trials for improved drug delivery. Our working hypothesis was that some surface parameters and size of NPs could favor their penetration across the BBB and their neuronal uptake. Polymeric material PEG-b-PLA diblocks were synthesized by ring opening polymerisation (ROP) with PEG2000 or PEG5000. A library of polymeric PEG-b-PLA diblocks NPs with different physicochemical properties was produced. The toxicity, endocytosis and transcytosis through the brain microvascular endothelial cells were monitored as well as the neuronal cells uptake. In vitro results lead to the identification of favourable surface parameters for the NPs endocytosis into vascular endothelial cells. NPs endocytosis took place mainly by macropinocytosis while transcytosis was partially controlled by their surface chemistry and size. In vivo assays on a zebrafish model showed that the kinetic of NPs in circulation is dependent on PEG coating properties. In vivo findings also showed a low but similar translocation of PEG-b-PLA diblocks NPs to the CNS, regardless of their properties. In conclusion, modulation of surface PEG chain length and NPs size impact the endocytosis rate of NPs but have little influence on cell barriers translocation; while in vivo biodistribution is influenced by surface PEG chain density.


Plantar calcaneal spurs in older people: longitudinal traction or vertical compression?
Plantar calcaneal spurs are common, however their pathophysiology is poorly understood. This study aimed to evaluate the prevalence and correlates of plantar calcaneal spurs in a large sample of older people. Weightbearing lateral foot radiographs of 216 people (140 women and 76 men) aged 62 to 94 years (mean age 75.9, SD 6.6) were examined for plantar calcaneal and Achilles tendon spurs. Associations between the presence of spurs and sex, body mass index, radiographic measures of foot posture, self-reported co-morbidities and current or previous heel pain were then explored. Of the 216 participants, 119 (55%) had at least one plantar calcaneal spur and 103 (48%) had at least one Achilles tendon spur. Those with plantar calcaneal spurs were more likely to have Achilles tendon spurs (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.2 to 3.5). Prevalence of spurs did not differ according to sex. Participants with plantar calcaneal spurs were more likely to be obese (OR = 7.9, 95% CI 3.6 to 17.0), report osteoarthritis (OR = 2.6, 95% CI 1.6 to 4.8) and have current or previous heel pain (OR = 4.6, 95% CI 2.3 to 9.4). No relationship was found between the presence of calcaneal spurs and radiographic measures of foot posture. Calcaneal spurs are common in older men and women and are related to obesity, osteoarthritis and current or previous heel pain, but are unrelated to radiographic measurements of foot posture. These findings support the theory that plantar calcaneal spurs may be an adaptive response to vertical compression of the heel rather than longitudinal traction at the calcaneal enthesis.


GABAergic control of depression-related brain states.
The GABAergic deficit hypothesis of major depressive disorders (MDDs) posits that reduced γ-aminobutyric acid (GABA) concentration in brain, impaired function of GABAergic interneurons, altered expression and function of GABA(A) receptors, and changes in GABAergic transmission dictated by altered chloride homeostasis can contribute to the etiology of MDD. Conversely, the hypothesis posits that the efficacy of currently used antidepressants is determined by their ability to enhance GABAergic neurotransmission. We here provide an update for corresponding evidence from studies of patients and preclinical animal models of depression. In addition, we propose an explanation for the continued lack of genetic evidence that explains the considerable heritability of MDD. Lastly, we discuss how alterations in GABAergic transmission are integral to other hypotheses of MDD that emphasize (i) the role of monoaminergic deficits, (ii) stress-based etiologies, (iii) neurotrophic deficits, and (iv) the neurotoxic and neural circuit-impairing consequences of chronic excesses of glutamate. We propose that altered GABAergic transmission serves as a common denominator of MDD that can account for all these other hypotheses and that plays a causal and common role in diverse mechanistic etiologies of depressive brain states and in the mechanism of action of current antidepressant drug therapies.


Exploring Language Development Support for Foster Children: A Scoping Review of Interventions for Foster Care Families.
Children in foster care are at an increased risk for language delays and disorders, and foster parents can play a significant role in preventing delays in early language development. This scoping review explored empirical studies that included foster parent training programs for families with foster children under the age of 5 years. Using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews), multiple databases were searched, and resulting article titles and abstracts were screened for inclusion in the review. Each study that met inclusion criteria was then coded for the training methods used to teach foster parents intervention strategies and the targeted outcomes of the intervention. A total of 24 studies were identified. Of the 24 studies reviewed, all included interventions focused on increasing parent-child relationships and decreasing child challenging behaviors, but few included opportunities for foster parents to practice using intervention strategies with their foster child. None of the studies focused specifically on strategies for promoting children's language development. When outcomes across the studies were reviewed, only two focused on children's language. The results of this review point to the need for more research on language interventions that can be implemented by foster parents. The discussion focuses on the important role speech-language pathologists can play in the prevention of early language delays or disorders in young foster children. https://doi.org/10.23641/asha.21714311.


The actin-binding protein capulet genetically interacts with the microtubule motor kinesin to maintain neuronal dendrite homeostasis.
Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease.


Gastric nitric oxide synthase expression during endotoxemia: implications in mucosal defense in rats.
This study was performed to examine expression of gastric nitric oxide synthase (NOS) isoforms during endotoxemia in rats and to assess their role(s) in gastric injury from bile and ethanol. Lipopolysaccharide (LPS) enhanced the expression and activity of inducible nitric oxide synthase in gastric mucosa in a dose- and time-dependent manner. Endothelial nitric oxide synthase and neural nitric oxide synthase expression did not significantly change, but constitutive nitric oxide synthase activity decreased over time. LPS alone caused injury to the gastric mucosa and disrupted F-actin filaments in the same cells with enhanced immunostaining for inducible nitric oxide synthase. LPS also exacerbated gastric injury from the mild irritants 5 mmol/L acidified taurocholate and 20% ethanol as did local intra-arterial infusion of the nitric oxide donor S-nitroso-N-acetyl-penicillamine. The selective inducible nitric oxide synthase inhibitor aminoguanidine negated LPS-induced exacerbation of gastric injury from these irritants. The nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester augmented the deleterious effects of LPS, an effect reversed by L-arginine but not D-arginine. Aminoguanidine, but not N(G)-nitro-L-arginine methyl ester, negated LPS-induced accumulation of gastric luminal nitrates. These data suggest that increased inducible NOS activity and decreased constitutive nitric oxide synthase activity are primarily responsible for exacerbating gastric injury from luminal irritants during endotoxemia. Moreover, septic patients may be more susceptible to gastric injury from bile during gastrointestinal ileus.


Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: 2014 updates.
The Saudi Association for Pulmonary Hypertension (previously called Saudi Advisory Group for Pulmonary Hypertension) has published the first Saudi Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension back in 2008.[1] That guideline was very detailed and extensive and reviewed most aspects of pulmonary hypertension (PH). One of the disadvantages of such detailed guidelines is the difficulty that some of the readers who just want to get a quick guidance or looking for a specific piece of information might face. All efforts were made to develop this guideline in an easy-to-read form, making it very handy and helpful to clinicians dealing with PH patients to select the best management strategies for the typical patient suffering from a specific condition. This Guideline was designed to provide recommendations for problems frequently encountered by practicing clinicians involved in management of PH. This publication targets mainly adult and pediatric PH-treating physicians, but can also be used by other physicians interested in PH.


Verification of target position in the post-prostatectomy cancer patient using cone beam CT.
We present the results of a pilot study designed to investigate methods that may be applied to develop a patient position correction protocol for the post-prostatectomy patient receiving radiotherapy. Imaging was carried out with cone beam CT (CBCT) to investigate its suitability for detecting changes in rectal and bladder volumes and movements of these organs relative to the treatment planning CT. Eligible patients were imaged daily during the first week of treatment and weekly thereafter. Surrogate explanatory variables, including distance from the isocentre to the anterior rectum and bladder length, were tested for their potential to substitute for contouring entire organs and predict for changes in coverage of the planning treatment volume (PTV) by the 95% isodose (PTV95) and the maximum dose delivered to 50% of the rectal volume (RECTD50). The PTV defined on the CBCT images was larger than that defined on the planning CT and resulted in a decrease in the PTV95. Bladder length correlated with bladder volume and changes in bladder volume were associated with a decrease in PTV95. Rectal volumes changed randomly during treatment. There was a trend for the rectum to move anteriorly as treatment progressed. CBCT may be used to define the PTV, rectum and bladder though the reason for an apparent increase in PTV on CBCT requires further investigation. The bladder length and distance to the anterior rectal wall are potential surrogate explanatory variables. Further studies will be designed to test values of these surrogates that predict the need for a change in isocentre position.


Selection in Hereford cattle. I. Selection intensity, generation interval and indexes in retrospect.
Selection intensity and generation interval were evaluated in a Hereford cattle herd made up of 14 inbred lines and 14 linecross groups corresponding to the lines of inbred sires at the Suan Juan Basin Research Center, Hesperus, Colorado. Selection indexes practiced were calculated in retrospect. Analyses of the records collected from 1946 through 1973 involved weaning weight (WW) and postweaning traits in males and females. Analyses by line were performed for the inbreds, while pooled analyses were done on the inbred and linecross populations. From records of 1,239 calves weaned, age of sire averaged 3.75 yr compared with 4.52 yr for age of dam, showing faster generation turnover for sires than for dams. Generation interval determined as actual age of midparent was 4.13 yr. Selection applied for WW, evaluated as annual selection differentials within inbred lines and then pooled over all lines, averaged .55 standard deviations (sigma)/generation for sires. For females, selection was much less intense. Midparent selection differential amounted to .33 sigma/generation. For sires, pooled standardized selection differentials per generation over all lines during the postweaning gain period were .49 sigma, .46 sigma, .40 sigma, -.20 sigma, -.10 sigma and .69 sigma, respectively, for initial weight, final weight, feed consumed, feed efficiency (FE, unadjusted and adjusted) and average daily gain (ADG). Selection of females for postweaning traits was not intense. Selection index actually practiced in retrospect for sires was: IS = .4461 (WW) - .0092 (FE) + .6126 (ADG). The indexes for dams included WW, 12-mo weight (12W), 18-mo weight (18W), mature spring weight (SPW) and mature fall weight (FAW) and were: for inbred dams, ID = .1824 (WW) - .0284 (12W) + .0736 (18W) - .1097 (SPW) - .1097 (FAW); for linecross dams, ID = .2693 (WW) - .2960 (12W) + .0147 (18W) + .1185 (SPW) - .0354 (FAW). The corresponding index selection differentials were .818, .203 and .209. Sire index selection differentials represent about 79% of the total selection differentials.


Comparison of Potent Odorants in Raw and Ripened Pu-Erh Tea Infusions Based on Odor Activity Value Calculation and Multivariate Analysis: Understanding the Role of Pile Fermentation.
Infusions prepared from raw pu-erh tea (RAPT) and ripened pu-erh tea (RIPT) showed remarkable aroma differences. Predominant odorants in RAPT and RIPT infusions were identified and compared by the combined use of gas chromatography-olfactometry, aroma extract dilution analysis, odor activity values (OAVs), and multivariate analysis. A total of 35 and 19 odorants (OAV > 1) were detected in RIPT and RAPT, respectively. Odorants in RAPT and RIPT are significantly different in both odor properties and aroma compound intensities. Overall, RAPT contained a complex variety of chemical classes with diverse odors and moderate odor intensities, while RIPT is dominated by structurally and organoleptically similar compounds with high potency. Specifically, stale and musty smelling methoxybenzenes contributed the most to RIPT, while floral-, sweet-, and woody-smelling terpene alcohols, terpene ketones, and phenolic compounds were the predominant odorants in RAPT. Orthogonal partial least squares discriminant analysis revealed that linalool, α-ionone, 1,2,4-trimethoxybenzene, 1,2,3-trimethoxy-5-methylbenzene, 1,2,3,4-tetramethoxybenzene, and 1,2,3-trimethoxybenzene underwent remarkable changes during pile fermentation and could be used as potential odor-active markers for RIPT and RAPT discrimination. The comprehensive aroma characterization of pu-erh tea and determination of the effect of pile fermentation on odorant alteration herein will provide guidance for pu-erh tea flavor quality control and evaluation.


Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones.
A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.


Perineal nodular induration: a trauma-induced mass in a female equestrian.
A 55-year-old female equestrian presented with a 3.5 cm painful left perineal mass. Histologic examination of the excised mass showed a poorly circumscribed mesenchymal proliferation involving fibroadipose and fibrous tissue. The lesion consisted of a bland spindle cell proliferation with areas of fat necrosis, hemosiderin-laden macrophages, multinucleated histiocytes, and extracellular hyalinization with degenerative features. Immunohistochemical studies showed vimentin positivity and no staining for actin, desmin, and CD34. On the basis of clinical, morphologic, and immunostaining findings, the lesion was consistent with a diagnosis of perineal nodular induration. This lesion has been described almost exclusively in avid male cyclists with repetitive perineal trauma. A similar etiology of longstanding and repetitive perineal trauma from horseback riding is postulated for this case. Perineal nodular induration should be considered in the differential diagnosis of perineal masses in women with persistent perineal trauma, such as equestrianism, as well as other similar sport activities.


The Nup358-RanGAP complex is required for efficient importin alpha/beta-dependent nuclear import.
In vertebrate cells, the nucleoporin Nup358/RanBP2 is a major component of the filaments that emanate from the nuclear pore complex into the cytoplasm. Nup358 forms a complex with SUMOylated RanGAP1, the GTPase activating protein for Ran. RanGAP1 plays a pivotal role in the establishment of a RanGTP gradient across the nuclear envelope and, hence, in the majority of nucleocytoplasmic transport pathways. Here, we investigate the roles of the Nup358-RanGAP1 complex and of soluble RanGAP1 in nuclear protein transport, combining in vivo and in vitro approaches. Depletion of Nup358 by RNA interference led to a clear reduction of importin alpha/beta-dependent nuclear import of various reporter proteins. In vitro, transport could be partially restored by the addition of importin beta, RanBP1, and/or RanGAP1 to the transport reaction. In intact Nup358-depleted cells, overexpression of importin beta strongly stimulated nuclear import, demonstrating that the transport receptor is the most rate-limiting factor at reduced Nup358-concentrations. As an alternative approach, we used antibody-inhibition experiments. Antibodies against RanGAP1 inhibited the enzymatic activity of soluble and nuclear pore-associated RanGAP1, as well as nuclear import and export. Although export could be fully restored by soluble RanGAP, import was only partially rescued. Together, these data suggest a dual function of the Nup358-RanGAP1 complex as a coordinator of importin beta recycling and reformation of novel import complexes.


Changes in serum potassium following succinylcholine in patients with infections.
Changes in serum potassium level in 21 control patients and 21 patients with infections of varying severity were measured after administration of succinylcholine. Serum potassium levels increased significantly in patients with infections, but not in the normal control patients. The magnitude of the increase in serum potassium was related to the severity and duration of infection.


Resource-constrained rate control for Motion JPEG2000.
With the increasing importance of heterogeneous networks and time-varying communication channels, fine scalability has become a highly desirable feature in both image and video coders. A single highly scalable bitstream can provide precise rate control for constant bitrate (CBR) traffic and accurate quality control for variable bitrate (VBR) traffic. We first propose two leaky-bucket rate allocation methods that provide constant quality video under buffer constraints. These methods can be used with all scalable coders. Moreover, we make use of one of these methods (DBRC) and extend it so that it can be used when multiple sequences are multiplexed over a single communications channel. The goal is to allocate the capacity of the channel between sequences to achieve constant quality across all sequences. Experimental results using Motion JPEG2000 demonstrate substantial benefits.


Body mass index in obsessive-compulsive disorder.
Psychiatric disorders are associated with overweight/obesity. Obsessive-compulsive disorder (OCD) may be an exception, as anecdotal evidence suggests lower BMI in OCD. Additionally, depression is associated with elevated BMI, but effects of comorbid secondary depression are unknown. The aim of the present study was to assess BMI and risk for overweight/obesity in OCD and to assess the effect of comorbid depression on BMI. BMI, demographics, and clinical status were assessed in large samples of individuals with OCD, anxiety disorders, depressive disorders, comorbid anxiety/depressive disorders, and non-clinical controls (NCC). Although no initial differences were found between the samples on BMI, the non-depressed OCD subsample had significantly lower BMI and risk for overweight/obesity compared to all other clinical samples. NCC were nearly twice as likely to be overweight compared to non-depressed OCD. Eating disorders were excluded in the OCD sample, but BMI < 17 was used as an exclusion criterion in the clinical control groups in lieu of screening for Anorexia. Group differences on demographics were controlled for. Recruitment methodology differed between samples. OCD is associated with significantly lower rates of obesity and overweight, but this relationship was not found when comorbid depression was present. This suggests that the purer the phenotype of OCD, the more substantial protective factor against overweight/obesity emerges compared to other clinical samples and NCC. An OCD-specific reward/anhedonia model, previously offered to elucidate lower smoking rates in OCD, may account for lower BMI in OCD. These results warrant careful clinical attention to the negative impact of comorbid depression on OCD that spans from increasing risk for obesity and cigarette smoking, to hindering treatment response.


Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors.
Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) with the E7 oncoprotein from HPV-16 (gDE7). Two subcutaneous doses of gDE7, admixed with poly (I:C), conferred complete and long-lasting therapeutic antitumor protection on mice previously challenged with tumor cells expressing the HPV-16 oncoproteins. The vaccine induced multifunctional E7-specific CD8+ T cells with cytotoxic activity and effector memory phenotype (CD44+ CD62Llow). In addition, gDE7 admixed with poly (I:C) vaccination controlled the expansion of tumor-induced regulatory T cells and myeloid-derived suppressor cells. More importantly, gDE7 activated mouse CD11c+ CD8α+ and human BDCA3+ dendritic cells (DC), specialized in antigen cross-presentation to CD8+ T cells, under in vitro conditions. These results indicated that the activation of a specific DC population, mediated by gD, improved the antigen-specific immune responses and the therapeutic performance induced by antitumor vaccines. These results open perspectives for the clinical testing of gDE7-based vaccines under the concept of active immunization as a tool for the therapeutic control of cancer. Mol Cancer Ther; 16(9); 1922-33. ©2017 AACR.


Non-uniformity of projection distributions attenuates resolution in Cryo-EM.
Virtually all single-particle cryo-EM experiments currently suffer from specimen adherence to the air-water interface, leading to a non-uniform distribution in the set of projection views. Whereas it is well accepted that uniform projection distributions can lead to high-resolution reconstructions, non-uniform (anisotropic) distributions can negatively affect map quality, elongate structural features, and in some cases, prohibit interpretation altogether. Although some consequences of non-uniform sampling have been described qualitatively, we know little about how sampling quantitatively affects resolution in cryo-EM. Here, we show how inhomogeneity in any projection distribution scheme attenuates the global Fourier Shell Correlation (FSC) in relation to the number of particles and a single geometrical parameter, which we term the sampling compensation factor (SCF). The reciprocal of the SCF is defined as the average over Fourier shells of the reciprocal of the per-particle sampling and normalized to unity for uniform distributions. The SCF therefore ranges from one to zero, with values close to the latter implying large regions of poorly sampled or completely missing data in Fourier space. Using two synthetic test cases, influenza hemagglutinin and human apoferritin, we demonstrate how any amount of sampling inhomogeneity always attenuates the FSC compared to a uniform distribution. We advocate quantitative evaluation of the SCF criterion to approximate the effect of non-uniform sampling on resolution within experimental single-particle cryo-EM reconstructions.


Factor V deficiency in Philadelphia-positive chronic myelogenous leukemia.
Factor V deficiency has been identified in 8 of 8 patients 7--20 yr of age, with Philadelphia-positive (Ph1+) chronic myelogenous leukemia (CML). In these 8 patients, factor V deficiency was not due to hepatic dysfunction, factor V inhibitors, or disseminated intravascular coagulation. In 3 patients, factor V activity rose 10%--12% (0.10--0.12 U/ml) after the infusion of 28--31 ml/kg body weight of fresh frozen plasma (FFP). The rise persisted less than 14 hr. The mean measured postinfusion rise in factor V was 18% of the expected rise calculated from the volume of FFP infused in the patients' plasma volume. In 4 patients, a small transient rise in factor V activity occurred after splenectomy or plateletpheresis. Factor V deficiency was completely corrected after a marked reduction in bone marrow cellularity in 2 patients with Ph1+ CML treated with extensive chemotherapy, total body irradiation, and bone marrow transplantation. Factor V deficiency was retrospectively observed in 6 of 20 patients, ages 20--80 yr, with Ph1+ CML and 3 of 6 patients with other myeloproliferative disorders. The factor V deficiency appears to be associated with the large myeloid-megakaryocytic cell mass characteristic of CML and other myeloproliferative disorders.


Influence of meal intake on liver stiffness in patients with chronic hepatitis B and C.
Transient elastography (TE) is a non-invasive test for evaluation of fibrosis in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Meal intake has been found to affect liver stiffness (LS) values in CHC patients, but there is still lack of data in CHB patients. Evaluate the influence of meal intake on LS values by TE in non-cirrhotic CHB patients and compare its effect with non-cirrhotic CHC patients. Forty-five CHB patients and 37 CHC patients were included LS measurements by TE were done at three different times including 4-hour fasting immediately, and 60 minutes after finishing 500 kcal meal. Mean fasting LS values in CHB patients were 5.40--1.7 kPa. LS values in CHB patients significantly increased at both immediately and 60 minutes after finishing meal by 0.31?0.1 kPa (p = 0.035) and 0.33 +/- 0.1 kPa (p = 0.018), respectively Difference in the peak changes of LS values after meal were not significant between CHB and CHC patients (CHB 0.72 +/- 0.1 vs. CHC 1.16 +/- 0.1, p = 0.076). No other variables associated with the changes ofLS values after meal in either CHB patients or CHC patients. Meal intake significantly increases LS values in CHB and CHC patients. It was considered to be a confounding factor in LS measurements. An appropriate time offasting should be done before LS measurement in both CHB and CHC patients.


Ataxia-telangiectasia and T-cell leukemias: no evidence for somatic ATM mutation in sporadic T-ALL or for hypermethylation of the ATM-NPAT/E14 bidirectional promoter in T-PLL.
The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-cell prolymphocytic leukemia (T-PLL), which is often associated with cytogenetic aberrations of chromosome 14. The ATM gene was shown to sustain frequent loss-of-function mutations in T-PLL tumor cells, consistent with functioning as a tumor suppressor gene in this leukemia. To investigate the possibility of nonmutational or nonrecombinational mechanisms of T-PLL development, we have used bisulfite genomic sequencing to analyze DNA methylation in the putative bidirectional promoter region of the closely linked ATM and NPAT/E14 genes within the CpG island at 11q22-q23. We show that this region is completely demethylated in lymphocytes expressing ATM; however, no extensive hypermethylation was found in 9 T-PLL tumor DNA samples without evidence of ATM/p53 mutations. Because acute T-cell lymphoblastic leukemias (T-ALL) were also observed in ataxia-telangiectasia patients and T-ALL tumor cells contain chromosome 14 abnormalities, 19 presentation samples of T-ALL patients were analyzed for ATM mutations. Although T-ALL patients exhibited rare nucleotide substitutions not previously found in ATM, all were identified in the germ-line, indicating constitutional polymorphisms, potentially confined to ethnic subpopulations. The absence of somatic nucleotide changes in ATM in T-ALL as compared with T-PLL suggests a distinct pattern of genetic events in the development of the two leukemias.


Microbial involvement in chronic wound malodour.
The role of specific micro-organisms in producing chronic wound malodour was investigated by directly comparing odour severity and microbiology in infected and non-infected leg ulcers. Malodour was most frequently associated with infected wounds involving mixed aerobic and anaerobic, Gram-positive and Gram-negative microbial populations. Infected ulcers that were not characterised by an offensive odour were rarely colonised with anaerobic bacteria. A reduced incidence of pigmented and non-pigmented Gram-negative anaerobes (Bacteriodes spp, Prevotella spp, Porphyromonas spp) was evident in non-infected, non-malodorous leg ulcers. These observations emphasise the significance of specific anaerobic bacteria in the generation of wound malodour, and it is probable that their effect is potentiated by coexistence with mixed facultative micro-organisms.


Non-pharmacological therapy for chemotherapy-induced peripheral neurotoxicity: a network meta-analysis of randomized controlled trials.
Chemotherapy-induced peripheral neurotoxicity (CIPN) is the most common adverse effect in patients undergoing chemotherapy, and no effective interventions are currently available for its prevention and treatment. Non-pharmacological therapies appear to be beneficial for the prevention and treatment of CIPN, but it remains unclear which therapy is most effective. The aim of this study was to identify the most effective non-pharmacological therapy for CIPN patients. PubMed, Web of Science, Embase, and Cochrane Library were searched for randomized controlled trials on non-pharmacological therapies for CIPN. The primary outcomes included pain and peripheral neuropathological symptoms, and the secondary outcomes included quality of life, sensory and motor symptoms. The pairwise analysis and a network meta-analysis were performed using a random effects model. A total of 46 articles were included in this study, involving 2,878 participants. Our study showed that massage was more effective in pain-alleviating compared with acupuncture [SMD = 0.81, 95%CI (0.04, 1.57)], vitamin and gabapentin [SMD = 2.56, 95%CI (1.39, 3.74)], and usual care and placebo [SMD = 0.9, 95%CI (0.31, 1.49)]. As for attenuating peripheral neuropathological symptoms, massage was more effective than usual care and placebo [SMD = 0.75, 95%CI (0.33, 1.17)], sensorimotor training [SMD = 1.17, 95%CI (0.24, 2.10)], electrostimulation [SMD=-1.18, 95%CI (-2.14, -0.21)], multimodal exercise [SMD=-0.82, 95%CI (-1.57, -0.08)], and resistance training [SMD = 1.03, 95%CI (0.11, 1.95)]. Massage was also more effective than other non-pharmacological therapies in improving quality of life, sensory and motor symptoms. According to our study, massage has advantages in alleviating pain, improving quality of life, and improving peripheral neuropathological symptoms and has better effect than other non-pharmacological interventions, representing certain clinical significance. However, the results of this study should be interpreted with caution due to the limitations of the included studies. In the future, more high-quality multi arm randomized controlled trials can be attempted to provide direct comparisons of the relative effects of non-pharmacological interventions.


Evolutionary changes in the capsid P2 region of Australian strains of the norovirus GII.Pe_GII.4.
The protruding (P) 2 region of the norovirus capsid is thought to include hypervariable sites involved in receptor binding. This study examines the changes that occurred in the P2 region of GII.Pe_GII.4 norovirus in the course of its evolution from a precursor phase (2008-2009), to an intermediate phase (2010) and finally to an epidemic phase (2012-2015). Twenty-two P2 region amino acid (aa) sequences (166 aa long) from all phases of the evolution of the virus were compared and the changes analysed.Results/key findings. Twenty sites in the P2 region underwent aa change and of these, 10 corresponded to previously proposed hypervariable sites and 10 to novel hypervariable sites. It was notable that aa changes at two sites, X and Y, only emerged as the epidemic phase progressed. 3D computer modelling of the P2 region indicated that neither X nor Y were in the uppermost 'crown', but further down in the 'neck' portion. The location of X and Y and the nature of aa change at Y suggest these sites were important in enhancing the structural integrity of the capsid, which in turn may have facilitated the longer term viability of the virus. The current study helps establish the validity of previously proposed hypervariable sites in the P2 region as well as indicating new ones. It also provides quantitative and qualitative data on how these sites changed over the evolutionary history of a particular norovirus strain.


Self-management in diabetes: training implications for professional carers.
A workshop was convened to examine factors determining patient self-management and implications for those providing care. It was attended by 15 doctors and 15 nurses with considerable expertise in education for those with diabetes. Discussion included: the experience of training programmes to date; factors determining effective patient self-management; the implications for training of professionals, skills required, their current availability and proposals for their development. The conclusions were that training and experience of these skills are both inadequate. Programmes of training, which are equally applicable to the management of other chronic diseases, should be embedded in the system of care and delivered at local level. Regional or national programmes are required to develop trainers in all districts able to deliver and maintain local programmes. This critical element of care in diabetes must be adequately funded if self-care standards are to be improved and expensive complications prevented.


"Isolated long thoracic nerve palsy": More than meets the eye.
Two main hypotheses have been proposed for the pathophysiology of long thoracic nerve (LTN) palsy: nerve compression and nerve inflammation. We hypothesized that critical reinterpretation of electrodiagnostic (EDX) studies and MRIs of patients with a diagnosis of non-traumatic isolated LTN palsy could provide insight into the pathophysiology and, potentially, the treatment. A retrospective review was performed of all patients with a diagnosis of non-traumatic isolated LTN palsy and an EDX and brachial plexus or shoulder MRI studies performed at our institution. The original EDX studies and MR examinations were reinterpreted by a neuromuscular neurologist and musculoskeletal radiologist, respectively, both blinded to our hypothesis. Seven patients met the inclusion criteria as having a non-traumatic isolated LTN palsy. Upon reinterpretation, all of them were found to have findings not consistent with an isolated LTN. On physical examination, three of them (43%) presented with weakness in muscles not innervated by the LTN. Four of them (57%) had additional EDX abnormalities beyond the distribution of the LTN. Five of them (71%) had MRI evidence of enlargement of nerves or denervation atrophy of muscles outside the innervation of the LNT, without evidence of compression of the LTN in the middle scalene muscle. In our series, all 7 patients, originally diagnosed as having an isolated LTN, on reinterpretation, were found to have a more diffuse muscle/nerve involvement pattern, without MR findings to suggest nerve compression. These data strongly support an inflammatory pathophysiology.


Structural basis for substrate specificity of alphavirus nsP2 proteases.
The alphavirus nsP2 protease is essential for correct processing of the alphavirus nonstructural polyprotein (nsP1234) and replication of the viral genome. We have combined molecular dynamics simulations with our structural studies to reveal features of the nsP2 protease catalytic site and S1'-S4 subsites that regulate the specificity of the protease. The catalytic mechanism of the nsP2 protease appears similar to the papain-like cysteine proteases, with the conserved catalytic dyad forming a thiolate-imidazolium ion pair in the nsP2-activated state. Substrate binding likely stabilizes this ion pair. Analysis of bimolecular complexes of Venezuelan equine encephalitis virus (VEEV) nsP2 protease with each of the nsP1234 cleavage sites identified protease residues His(510), Ser(511), His(546) and Lys(706) as critical for cleavage site recognition. Homology modelling and molecular dynamics simulations of diverse alphaviruses and their cognate cleavage site sequences revealed general features of substrate recognition that operate across alphavirus strains as well as strain specific covariance between binding site and cleavage site residues. For instance, compensatory changes occurred in the P3 and S3 subsite residues to maintain energetically favourable complementary binding surfaces. These results help explain how alphavirus nsP2 proteases recognize different cleavage sites within the nonstructural polyprotein and discriminate between closely related cleavage targets.


Beta-catenin in the race to fracture repair: in it to Wnt.
The Wnt/beta-catenin pathway regulates multiple biological events during embryonic development, including bone formation. Fracture repair recapitulates some of the processes of normal bone development, such as the formation of bone from a cartilaginous template, and many cell-signaling pathways that underlie bone development are activated during the repair process. The Wnt/beta-catenin signaling pathway is activated during fracture repair, and dysregulation of this pathway alters the normal bone-healing response. In early pluripotent mesenchymal stem cells, Wnt/beta-catenin signaling needs to be precisely regulated to facilitate the differentiation of osteoblasts; by contrast, beta-catenin is not needed for chondrocyte differentiation. Once mesenchymal stem cells are committed to the osteoblast lineage, activation of Wnt/beta-catenin signaling enhances bone formation. This activity suggests that the Wnt/beta-catenin pathway is a therapeutic target during bone repair. Indeed, treatments that activate Wnt/beta-catenin signaling, such as lithium, increase bone density and also enhance healing.


Reported and Recorded Sleepiness in Obesity and Depression.
Obesity and depression are both associated with changes in sleep/wake regulation, with potential implications for individualized treatment especially in comorbid individuals suffering from both. However, the associations between obesity, depression, and subjective, questionnaire-based and objective, EEG-based measurements of sleepiness used to assess disturbed sleep/wake regulation in clinical practice are not well known. The study investigates associations between sleep/wake regulation measures based on self-reported subjective questionnaires and EEG-derived measurements of sleep/wake regulation patterns with depression and obesity and how/whether depression and/or obesity affect associations between such self-reported subjective questionnaires and EEG-derived measurements. Healthy controls (HC, NHC = 66), normal-weighted depressed (DEP, NDEP = 16), non-depressed obese (OB, NOB = 68), and obese depressed patients (OBDEP, NOBDEP = 43) were included from the OBDEP (Obesity and Depression, University Leipzig, Germany) study. All subjects completed standardized questionnaires related to daytime sleepiness (ESS), sleep quality and sleep duration once as well as questionnaires related to situational sleepiness (KSS, SSS, VAS) before and after a 20 min resting state EEG in eyes-closed condition. EEG-based measurements of objective sleepiness were extracted by the VIGALL algorithm. Associations of subjective sleepiness with objective sleepiness and moderating effects of obesity, depression, and additional confounders were investigated by correlation analyses and regression analyses. Depressed and non-depressed subgroups differed significantly in most subjective sleepiness measures, while obese and non-obese subgroups only differed significantly in few. Objective sleepiness measures did not differ significantly between the subgroups. Moderating effects of obesity and/or depression on the associations between subjective and objective measures of sleepiness were rarely significant, but associations between subjective and objective measures of sleepiness in the depressed subgroup were systematically weaker when patients comorbidly suffered from obesity than when they did not. This study provides some evidence that both depression and obesity can affect the association between objective and subjective sleepiness. If confirmed, this insight may have implications for individualized diagnosis and treatment approaches in comorbid depression and obesity.


The nature of the landers-mojave earthquake line.
The Landers, California, earthquake of 28 June 1992 (magnitude = 7.3) is the latest of six significant earthquakes in the past 60 years whose epicenters and slip directions define a 100-kilometer alignment running approximately N15 degrees W across the central Mojave region. This pattern may indicate a geologically young throughgoing fault that replaces numerous older strike-slip faults by obliquely cutting across them. These older faults, and perhaps also the bend in the San Andreas fault, may be losing their ability to accommodate upper crustal deformation because they have become unfavorably oriented with respect to the regional stress field.


Mosquito feeding modulates Th1 and Th2 cytokines in flavivirus susceptible mice: an effect mimicked by injection of sialokinins, but not demonstrated in flavivirus resistant mice.
Culex pipiens and Aedes aegypti mosquitoes were fed on C3H/HeJ mice and systemic cytokine production was quantified from stimulated lymphocytes harvested four to ten days after feeding. Mosquito feeding on C3H/HeJ mice significantly down regulated IFN gamma production seven to ten days post feeding by Cx. pipiens and seven days after Ae aegypti feeding. Th2 cytokines, IL-4 and IL-10, were significantly up regulated 4-7 days after Cx. pipiens and Ae. aegypti feeding. The immunosuppressive effect of Cx. pipiens feeding on systemic cytokine production was not evident in congenic flavivirus resistant (C3H/RV) mice, as systemic IFN gamma and IL-2 were significantly up regulated at days 7 and 10, correlating with a significant decrease in IL-4 10 days after feeding by Cx. pipiens mosquitoes. Inoculation of 5-1000 ng of sialokinin-I into C3H/HeJ mice mimicked the effect of Ae. aegypti feeding by down regulating Th1 cytokines and significantly up regulating Th2 cytokines four days post inoculation. Injections of sialokinin-II resulted in only moderate effects on IFN gamma and IL-4 production seven and ten days after injection. Thus natural feeding by two arbovirus vectors had a profound T cell modulatory effect in vivo in virus susceptible animals which was not demonstrated in the flavivirus resistant host. Moreover, sialokinin-I and sialokinin-II mimicked the effect of mosquito feeding by modulating the host T cell response. These results may lend new insight into specific aspects of the role of the mosquito vector in potentiating virus transmission in the mammalian host.


[Human and Influenza - an Overview].
Influenza is an acute viral disease with involvement of the respiratory tract. It can be life-threatening. New types of influenza viruses can spread globally and cause influenza pandemics with exalted case numbers. The knowledge about epidemiology, preventive hygiene and vaccination, diagnostic, therapy and clinics are essential for the general practitioner as well as the specialist. This article gives an overview with focus on seasonal influenza in adults. In addition, molecular pathological characteristics of influenza viruses are explained and current problems in influenza management are named. The course consists of 10 multiple-choice questions to consolidate the acquired knowledge.


Integrated 18F-FDG PET/MRI in breast cancer: early prediction of response to neoadjuvant chemotherapy.
To explore whether integrated 18F-FDG PET/MRI can be used to predict pathological response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Between November 2014 and April 2016, 26 patients with breast cancer who had received NAC and subsequent surgery were prospectively enrolled. Each patient underwent 18F-FDG PET/MRI examination before and after the first cycle of NAC. Qualitative MRI parameters, including morphological descriptors and the presence of peritumoral oedema were assessed. Quantitatively, PET parameters, including maximum standardized uptake value, metabolic tumour volume and total lesion glycolysis (TLG), and MRI parameters, including washout proportion and signal enhancement ratio (SER), were measured. The performance of the imaging parameters singly and in combination in predicting a pathological incomplete response (non-pCR) was assessed. Of the 26 patients, 7 (26.9%) exhibited a pathological complete response (pCR), and 19 (73.1%) exhibited a non-pCR. No significant differences were found between the pCR and non-pCR groups in the qualitative MRI parameters. The mean percentage reductions in TLG30% on PET and SER on MRI were significantly greater in the pCR group than in the non-pCR group (TLG30% -64.8 ± 15.5% vs. -25.4 ± 48.7%, P = 0.005; SER -34.6 ± 19.7% vs. -8.7 ± 29.0%, P = 0.040). The area under the receiver operating characteristic curve for the percentage change in TLG30% (0.789, 95% CI 0.614 to 0.965) was similar to that for the percentage change in SER (0.789, 95% CI 0.552 to 1.000; P = 1.000).The specificity of TLG30% in predicting pCR) was 100% (7/7) and that of SER was 71.4% (5/7). The sensitivity of TLG30% in predicting non-pCR was 63.2% (12/19) and that of SER was 84.2% (16/19). When the combined TLG30% and SER criterion was applied, sensitivity was 100% (19/19), and specificity was 71.4% (5/7). 18F-FDG PET/MRI can be used to predict non-pCR after the first cycle of NAC in patients with breast cancer and has the potential to improve sensitivity by the addition of MRI parameters to the PET parameters.


Short- and long-term outcome in an intensive treatment program for adult stutterers.
A three week intensive treatment program for adult stutterers is described. This treatment has evolved from an original program developed by Ingham and Andrews (1973) using speech prolongation techniques, gradual shaping of speech rate to normal, and systematic transfer of skills acquired in the clinic to real life situations. Immediately after intensive treatment, stuttering was virtually eliminated and speech rate and attitudes toward communication were normalized. There was no substantial deterioration in these treatment effects when clients were evaluated in the clinic after two months in the Maintenance Phase of treatment. Speech and attitude measures collected outside the clinic 12--18 months after intensive treatment showed lasting overall improvement in most clients, although some deterioration in fluency from immediate post-intensive treatment levels had occurred in 40% of clients. Covertly collected data supported this finding. Possible causes of relapse and likely solutions are discussed.


Localization of nitric oxide synthase isoforms (I, II and III) in the endolymphatic sac of the guinea pig.
The localization of nitric oxide (NO) synthase (NOS) isoforms was examined in the endolymphatic sac (ES) of the pigmented guinea pig by indirect immunohistochemistry. The cytoplasm of the epithelial cells in the ES showed both NOS-I and -III immunoreactivity, whereas their nuclei appeared negative. NOS-III staining was also observed in the endothelial lining of the blood vessels. These findings support the hypothesis that NO in the epithelial cells may play an important role for the active intracellular transport of the endolymph and ion. NO may also be crucially involved in the regulation of ES blood flow. Immunostaining for NOS II revealed no reactivity in general, while in lipopolysaccharide-inoculated animals, intense reactivity was found in the cytoplasm of the ES epithelial cells as well as macrophages in the lumen. Thus it has been indicated that NO also may play an important role in the immunodefensive mechanisms in the ES.


A novel noncontact method to assess the biomechanical properties of wound tissue.
A novel noncontact optical coherence tomography based air-jet indentation system was developed for characterizing the biomechanical properties of soft tissue in a noncontact way. This study aimed to measure the stiffness of diabetic foot ulcer tissues by using this air-jet indentation system, and examining the test/retest reliability. Eight subjects with diabetes (seven males, one female), with a total of 10 foot ulcers between them, participated in the study. A total of 20 measuring sites located at the central wound bed (n=10) or peri-ulcer areas (n=10), respectively, were evaluated with the air-jet indentation system. Four cycles of loading and unloading, each with a duration of approximately 36 seconds at an indentation rate of 0.08 mm/s, were carried out for each indentation trial. The test/retest reliability was examined at all measuring points. The average stiffness coefficient of the peri-ulcer area (mean ± SD: 0.47 ± 0.15 N/mm) was significantly larger than that of the central wound bed area (mean ± SD: 0.35 ± 0.23 N/mm; p=0.042). A high value for test/retest reliability was shown (intraclass correlation coefficient: 0.986; Pearson's correlation: r=0.972, p<0.001). Our preliminary findings showed that the peri-ulcer area had greater stiffness than the central wound bed. This greater magnitude of hardness and inelasticity at the peri-ulcer region may scatter part of the contractile forces for wound contraction during the healing process. We found the novel air-jet system to be a reliable tool for characterizing the stiffness of soft tissues around the wound in a noncontact way.


Induction of cyclobutane pyrimidine dimer photolyase in cultured fish cells by UVA and blue light.
The cyclobutane pyrimidine dimer (CPD) photolyase in fish cells is known to be regulated by environmental factors, such as light, hydrogen peroxide and growth inhibition. The induction of CPD photolyase by light in cultured goldfish cells was dependent on the wavelength of the light, and UVA and blue light had high inductive activity. The spectrum for CPD photolyase activity was different from that for the induction. Treatment with blue or yellow light for a short time, which did not induce any CPD photolyase, induced high CPD photolyase activity in the presence of the photosensitizers, TPPS (monosulfonated meso-tetraphenyl porphine) and ALPS (aluminum phthalocyanine tetrasulfonate), respectively. These results suggest that the induction of CPD photolyase might be triggered by active oxygen produced by light and cellular photosensitizers. We also found that immediately after treatment with UVA, blue light or a photosensitizer in combination with light, cellular attachment to the substratum was enhanced, as was the CPD photolyase activity. Pretreatment with a flavonoid, quercetin, inhibited both photoinduction of CPD photolyase and enhancement of cellular attachment. Vitamin E inhibited only photoinduction of CPD photolyase activity. Treatment with H7, a strong inhibitor for protein kinase C, after light treatment inhibited photoinduction of CPD photolyase activity, but an analogue of H7, Ha1004, which is a weak inhibitor of protein kinase C, did not have such an effect.


Ethnic differences in HIV risk perceptions and behaviors among Black 18-39 year-old residents of Broward County, Florida.
The study assessed ethnic differences in the perceived risks of HIV infection, sexual experiences, and HIV-antibody testing histories among Black populations in Broward County, Florida. Data were analyzed for 2,731 well-characterized survey respondents 18-39 years old who indicated they were African Americans, Caribbean Islanders, English-speaking, or Creole-speaking Haitians. Creole-speaking Haitians were least likely to consider themselves at risk of HIV infection, report using condoms in the last 12 months, and indicate that they had ever been tested for HIV. English-speaking Haitians were more likely than African Americans to report never engaging in sexual intercourse and were less likely to have ever been tested for HIV. English-speaking Caribbean Islanders reported preventive behaviors similar to those of African Americans, but had lower perceptions of HIV risk and were less likely to have ever been tested. Health promotion programs designed to improve HIV prevention practices must appreciate social and cultural differences among Black populations.


Anti-hyperglycemic and anti-hyperlipidemic effects of guava leaf extract.
Psidium guajava Linn. (guava) is used not only as food but also as folk medicine in subtropical areas around the world because of its pharmacologic activities. In particular, the leaf extract of guava has traditionally been used for the treatment of diabetes in East Asia and other countries. Moreover, the anti-hyperglycemic activity of the extract has been reported in some animal models. However, little is known regarding the therapeutic activity of the extract in human clinical trials as well as its underlying therapeutic mechanisms and safety. In Japan, Guava Leaf Tea (Bansoureicha(R), Yakult Honsha, Tokyo, Japan) containing the aqueous leaf extract from guava has been approved as one of the Foods for Specified Health Uses and is now commercially available. This review describes the active component of the aqueous guava leaf extract and its inhibition of alpha-glucosidase enzymes in vitro, safety of the extract and Guava Leaf Tea, reduction of postprandial blood glucose elevation, and improvement of hyperglycemia, hyperinsulinemia, hypoadiponectinemia, hypertriglycemia and hypercholesterolemia in murine models and several clinical trials. It is suggested that the chronic suppression of postprandial blood glucose elevation is important in preventing type 2 diabetes mellitus, and that Guava Leaf Tea is considered useful as an alimentotherapy for chronic treatment.


Improved understanding of the pathophysiology of atrial fibrillation through the lens of discrete pathological pathways.
Atrial fibrillation (AF) is a common disorder with a complex and incompletely understood pathophysiology. Genetic approaches to understanding the pathophysiology of AF have led to the identification of several biological pathways important in the pathogenesis of the arrhythmia. These include pathways important for cardiac development, generation and propagation of atrial electrical impulses, and atrial remodeling and fibrosis. While common and rare genetic variants in these pathways are associated with increased susceptibility to AF, they differ substantially among patients with lone versus typical AF. Furthermore, how these pathways converge to a final common clinical phenotype of AF is unclear and might also vary among different patient populations. Here, we review the contemporary knowledge of AF pathogenesis and discuss how derangement in cardiac development, ion channel dysfunction, and promotion of atrial fibrosis may contribute to this common and important clinical disorder.


[History of the special surgery department].
The author showed a history of the Special Surgery Department in Val de Grace. The Heads of the Department were celebrated surgeons, otolaryngologists, ophthalmologists and facial-maxillary surgeons.


Elevated admission international normalized ratio strongly predicts mortality in victims of abusive head trauma.
Victims of abusive head trauma have poor outcomes compared with other injured children. There is often a delay in diagnosis because these young patients are unable to communicate with health care providers. These critically injured patients would benefit from early identification and therapy. We performed a retrospective review of our single hospital trauma registry from 2005 to 2014. All Level 1 pediatric (age 0-17 years) trauma patients who sustained abusive head trauma were included. Exclusion criteria included no admission coagulation studies, prehospital product transfusion, preexisting coagulation disorder, or death upon arrival. Primary outcome was mortality; secondary outcomes were early blood transfusion and neurosurgical intervention. Univariate analysis included Fisher's exact and Wilcoxon rank-sum testing; we then performed logistic regression modeling and calculated adjusted odds ratios (AORs) to control for known predictors of poor outcome including hypotension, hypothermia, acidosis, Injury Severity Score (ISS), and head Abbreviated Injury Scale (AIS) score. In 101 total subjects, 35% (n = 35) had international normalized ratio (INR) of 1.3 or greater at admission. On univariate analysis, patients with coagulation dysregulation were more likely to have hypothermia, hypotension, acidosis, high ISS, and low Glasgow Coma Scale (GCS) score (all p < 0.05). There was no difference in age, anemia, and incidence of polytrauma. Overall mortality was 24.8% (n = 25), which varied significantly based at admission INR (60% INR ≥ 1.3 vs. 6% INR > 1.3, p < 0.001). Patients with elevated INR were also more likely to have early packed red blood cell transfusion (p = 0.003) and neurosurgical intervention (p = 0.011). In logistic regression analysis, admission INR was the strongest independent predictor of mortality, with increased odds of 3.65 (p = 0.045). AOR after controlling specifically for hypotension, hypothermia, and acidosis was 6.25 (p = 0.006), and after controlling for head AIS score and admission GCS score, the AOR was 5.27 (p = 0.007). Admission INR of 1.3 or greater strongly predicts mortality in abusive head trauma. These patients should be targeted for early aggressive interventions and monitoring with the goal of improving patient outcomes. Further study is warranted to investigate potential therapeutic targets in trauma-induced coagulation dysregulation. Prognostic and epidemiologic study, level III.


A high-yielding CHO transient system: coexpression of genes encoding EBNA-1 and GS enhances transient protein expression.
An efficient rapid protein expression system is crucial to support early drug development. Transient gene expression is an effective route, and to facilitate the use of the same host cells as for subsequent stable cell line development, we have created a high-yielding Chinese hamster ovary (CHO) transient expression system. Suspension-adapted CHO-K1 host cells were engineered to express the gene encoding Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) with and without the coexpression of the gene for glutamine synthetase (GS). Analysis of the transfectants indicated that coexpression of EBNA-1 and GS enhanced transient expression of a recombinant antibody from a plasmid carrying an OriP DNA element compared to EBNA-1-only transfectants. This was confirmed with the retransfection of an EBNA-1-only cell line with a GS gene. The retransfected cell lines showed an increase in transient expression when compared with that of the EBNA-1-only parent. The transient expression process for the best CHO transient cell line was further developed to enhance protein expression and improve scalability by optimizing the transfection conditions and the cell culture process. This resulted in a scalable CHO transient expression system that is capable of expressing 2 g/L of recombinant proteins such as antibodies. This system can now rapidly provide gram amounts of recombinant antibody to supply preclinical development studies that has comparable product quality to antibody produced from a stably transfected CHO cell line.


Superior long-term outcomes after surgery in child-pugh class a patients with single small hepatocellular carcinoma compared to radiofrequency ablation.
There are insufficient data comparing long-term prognoses after radiofrequency ablation (RFA) and surgery. We compared the baseline characteristics and survival rates of patients (single, ≤3 cm, and Child-Pugh class A) treated surgically (n = 215) and with RFA (n = 255) from January 2000 to December 2007 at our institution. The surgery group was characterized by younger age, higher prevalence of HBsAg, less cirrhosis, and an increased chance of Child-Pugh score of 5 and CLIP score of 1, compared to the RFA group. During the median follow-up period of 42 months (range 1-109), the 3-, 5- and 7-year overall survival rates in the surgery group were 98, 94, and 94%, respectively, which were significantly higher than those in the RFA group (92, 87, and 76%, respectively, P = 0.002). The 3- and 5-year recurrence-free survival rates were 72 and 66%, respectively, in the surgery group, which were significantly higher than those in the RFA group (34 and 24%, respectively, P < 0.001). The superiority of the survival rates in the surgery group persisted in most patients throughout the subgroup analysis, based on the Child-Pugh score and CLIP score. Multivariate analysis showed that age and surgery as a procedure type were the significant predictive factors for both overall survival [HR = 1.04 (CI 1.001-1.08), P = 0.047 for age; HR = 2.97 (CI 1.19-7.45), P = 0.02 for surgery] and recurrence-free survival [HR = 1.02 (CI 1.01-1.04), P = 0.01 for age; HR = 2.44 (CI 1.76-3.37), P < 0.001 for surgery]. The long-term outcome after surgery for Child-Pugh class A and single small HCC is superior to that after RFA.


Changes in activity of the striatum during formation of a motor habit.
To examine experience-dependent plasticity of striatal neurons during habit learning in awake, freely moving animals, single neurons in the dorsolateral striatum (54 neurons related specifically to vertical head movement and 14 unresponsive neurons, i.e. not related to any body movement) were recorded and tracked off-line to assess changes in firing rate over sessions as performance of instrumental head movement became automatic and habitual. Rats were trained to emit operant vertical head movements that triggered water delivery for 14 sessions (2 h per session, one session per day). Rats significantly increased the number and efficiency of head movements over sessions until reaching asymptotic behaviour. Habit formation was indicated by significantly higher levels of instrumental responding exhibited by rats during a late, relative to an early, session in which the reward was devalued. As head movements became habitual across sessions, most head movement-related neurons (89%) exhibited decreased firing rate, while a small population (11%) exhibited increased or maintained firing rate. The rate of decrease in firing by the majority correlated with the rate of improvement in movement efficiency over sessions. All unresponsive neurons, though not apparently related to movement, exhibited decreased firing rate over sessions. Our findings suggest that, during habit learning, the striatum may shift from facilitating acquisition of efficient movement with a large population of neurons to modulating or maintaining habitual movement with stronger firing of fewer movement-related neurons.


Rapid genetic grouping of factor h-binding protein (genome-derived neisserial antigen 1870), a promising group B meningococcal vaccine candidate.
The most important antigen component of a promising multicomponent group B meningococcal recombinant protein vaccine is based on genome-derived neisserial antigen 1870, which recently was renamed factor H-binding protein (FHBP) to reflect one of its critical functions as a complement regulatory protein. Neisseria meningitidis strains can be subdivided into three FHBP variant groups based on divergence of FHBP amino acid sequences. Within each variant group, amino acid sequences are >90% conserved. To develop an FHBP-based group B vaccine, it is important to know the distribution of FHBP variant 1, 2, and 3 strains in different geographic regions, since antibodies against FHBP are bactericidal against strains within the homologous group but show minimal activity against strains from other groups. We have devised a high-throughput, quantitative PCR-based method that allows rapid and precise assignment of FHBP genes into each of the three major variant lineages. Among 48 group B isolates from patients hospitalized in California in 2003 to 2004, 83%, 13%, and 4%, respectively, had variant 1, 2, and 3 genes. Thus, a vaccine based on the variant 1 protein has the potential to prevent the majority of cases of group B disease. The quantitative PCR-based method will be useful for determining and monitoring the prevalence of meningococcal isolates with genes encoding different FHBP variant proteins. The technique also is suitable for monitoring variation of genes encoding other protein antigens targeted for vaccination.


The androgen receptor inhibits transcription of GPER1 by preventing Sp1 and Sp3 from binding to the promoters in prostate cancer cells.
G-1, a GPER1 agonist, was shown to inhibit the growth of castration-resistant mouse xenografts but not their parental androgen-dependent tumors. It is currently unknown how the androgen receptor (AR) represses GPER1 expression. Here, we found that two GPER1 mRNA variants (GPER1v2 and GPER1v4) were transcriptionally repressed, not via transcript destabilization, by the androgen-activated AR. Although no AR binding was found in all active promoters near GPER1, data from promoter assays suggested that both variants' promoters were inhibited by androgen treatment. Site-directed mutagenesis on Sp1/Sp3 binding sites revealed their role in supporting the basal expression of GPER1. Knockdown of Sp1 and Sp3 together but not separately repressed GPER1 expression whereas overexpression of both Sp1 and Sp3 together was required to alleviate AR repression of GPER1. Based on the chromatin immunoprecipitation data, Sp3 was found to bind to the promoters prior to the binding of Sp1 and RNA polymerase II. However, the binding of all three transcription factors was inhibited by DHT treatment. Concordantly, DHT treatment induced nuclear interactions between AR and Sp1 or Sp3. Taken together, these results indicate that AR represses transcription of GPER1 by binding to Sp1 and Sp3 independently to prevent their transactivation of the GPER1 promoters.


Secondary Electron Cloaking with Broadband Plasmonic Resonant Absorbers.
Scanning electron microscopy (SEM) is one of the most powerful tools for nanoscale inspection and imaging. It is broadly used for biomedicine, materials science, and nanotechnology, enabling spatial resolution beyond the optical diffraction limit. In SEM, a high-energy electron beam illuminates a specimen, and the emitted secondary electrons are routed to a positively biased, synchronized detector for image creation. Here, for the first time, we experimentally demonstrate a cloaking of metallic objects from a secondary electron image. We make a metallic disc with a diameter of 300 nm almost invisible to a secondary electron detector with <5 nm spatial resolution. The secondary electron cloaking is based on broadband optical radiation absorption in the near field. Our secondary electron images are in good agreement with full-wave numerical solution of Maxwell's equations at optical frequencies, confirming the concept of secondary electron cloaking based on broadband optical radiation absorption.


Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species-specific conformations.
An assembly of multiprotein complexes achieves chromosomal DNA replication at the replication fork. In eukaryotes, proliferating cell nuclear antigen (PCNA) plays a vital role in the assembly of multiprotein complexes at the replication fork and is essential for cell viability. PCNA from several organisms, including Saccharomyces cerevisiae, has been structurally characterised. However, the structural analyses of PCNA from fungal pathogens are limited. Recently, we have reported that PCNA from the opportunistic fungal pathogen Candida albicans complements the essential functions of ScPCNA in S. cerevisiae. Still, it only partially rescues the loss of ScPCNA when the yeast cells are under genotoxic stress. To understand this further, herein, we have determined the crystal structure of CaPCNA and compared that with the existing structures of other fungal and human PCNA. Our comparative structural and in-solution small-angle X-ray scattering (SAXS) analyses reveal that CaPCNA forms a stable homotrimer, both in crystal and in solution. It displays noticeable structural alterations in the oligomerisation interface, P-loop and hydrophobic pocket regions, suggesting its differential function in a heterologous system and avenues for developing specific therapeutics. DATABASES: The PDB and SASBDB accession codes for CaPCNA are 7BUP and SASDHQ9, respectively.


Ultrasound-induced heart rate decrease: role of the vagus nerve.
The goal of this study is to investigate the role of the vagus nerve (VN) in the ultrasound (US)-induced negative chronotropic effect (deceased heart rate). One of the functions of the VN is to mediate lowering of the heart rate. A previous study showed a decrease of ~20% in the heart rate but the mechanism of the effect was not investigated. Sprague Dawley rats (n = 20) were exposed transthoracically to ultrasonic pulses at an approximate duty factor of 1% with sequentially 2.0, 2.5, and 3.0 MPa peak rarefactional pressure amplitudes (PRPAs). The ultrasonic exposure parameters herein were chosen to match those of the previous study to have confidence that an ultrasound-induced negative chronotropic effect would occur. For each of the three PRPA sequences, the pulse repetition frequency (PRF) started slightly greater than the rat's heart rate and then was decreased sequentially in 1-Hz steps every 10 s (i.e., 6, 5, and 4 Hz for a total duration of 30 s). The experiments were organized in a standard (2 × 2) factorial design with VN (cut versus intact) as one factor and US (on versus off) as another factor. VN (intact/cut) and US (on/off) groups were divided into four groups each consisting of 5 animals: 1) VN intact-US off, 2) VN intact-US on, 3) VN cut-US off, and 4) VN cut-US on. Two-way analysis of variance for repeated measures was used to compare heart rate, cardiac output, systolic volume, ejection fraction, end-diastolic volume, end-systolic volume, respiratory rate, and arterial pressure before and after ultrasound stimulation. In this study, the heart rate decreased ~4% for the non-vagotomy and vagotomy groups. The ultrasound effect was significant for heart rate (p = 0.02) and cardiac output (p = 0.005) at 3 min post US exposure; the vagotomy effect was not significant. For heart rate, the Bonferroni test showed no differences between the four groups. The vagotomy group showed similar ultrasound-induced cardiac effects compared with the non-vagotomy group, suggesting that the vagus nerve is not influenced by the ultrasound exposure procedures. The US application caused a negative chronotropic effect of the rat heart without affecting the hemodynamic conditions. The results at this point are suggestive for an alternative cardiac pacing capability.


Imaging of neuropathic arthropathy.
Neuropathic arthropathy is a chronic, progressive joint degeneration with bone fragmentation, ligamentous instability, and dislocation. Diabetes is the leading cause of neuropathic arthropathy. Conventional radiography is the most commonly used imaging modality for diagnosing neuropathic arthropathy. The disease is mostly the hypertrophic type and is manifested by sclerosis of the bone, fragmentation, joint destruction, swelling, large joint effusion, and large osteophyte formation. Computed tomography, magnetic resonance imaging and radionucleide scintigraphy are helpful for diagnosing the disease and may help in distinguishing neuropathic arthropathy from septic arthritis and osteomyelitis.


High dietary sodium reduces brachial artery flow-mediated dilation in humans with salt-sensitive and salt-resistant blood pressure.
Recent studies demonstrate that high dietary sodium (HS) impairs endothelial function in those with salt-resistant (SR) blood pressure (BP). The effect of HS on endothelial function in those with salt-sensitive (SS) BP is not currently known. We hypothesized that HS would impair brachial artery flow-mediated dilation (FMD) to a greater extent in SS compared with SR adults. Ten SR (age 42 ± 5 yr, 5 men, 5 women) and 10 SS (age 39 ± 5 yr, 5 men, 5 women) healthy, normotensive participants were enrolled in a controlled feeding study consisting of a run-in diet followed by a 7-day low dietary sodium (LS) (20 mmol/day) and a 7-day HS (300 mmol/day) diet in random order. Brachial artery FMD and 24-h BP were assessed on the last day of each diet. SS BP was individually assessed and defined as a change in 24-h mean arterial pressure (MAP) of >5 mmHg between the LS and HS diets (ΔMAP: SR -0.6 ± 1.2, SS 7.7 ± 0.4 mmHg). Brachial artery FMD was lower in both SS and SR individuals during the HS diet (P < 0.001), and did not differ between groups (P > 0.05) (FMD: SR LS 10.6 ± 1.3%, SR HS 7.2 ± 1.5%, SS LS 12.5 ± 1.7%, SS HS 7.8 ± 1.4%). These data indicate that an HS diet impairs brachial artery FMD to a similar extent in adults with SS BP and SR BP.


Effect of host blood source on the gonotrophic cycle of Aedes triseriatus.
Host blood source was found to affect both the fecundity and the duration of te gonotrophic cycle of Aedes triseriatus. Mosquitoes were fed on restrained deer, chipmunks, squirrels, humans and suckling mice. Results showed that mosquitoes fed on chipmunks or squirrels, the major La Crosse virus vertebrate amplifier hosts, had greater fecundity but longer gonotrophic time intervals (approximately 2 more days per ovarian cycle) than mosquitoes fed on deer, which is a non-amplifier species. Results were similar for both first and second mosquito gonotrophic cycles. Application of these data to a model determining differential reproductive capacity showed a 24% reduction in the number of second cycle eggs laid by Ae. triseriatus taking the initial blood meal on amplifier species as compared to those taking the initial blood meal from deer. As only those uninfected mosquitoes that feed on an amplifier species have a chance of becoming orally infected and producing infected eggs, this reduced reproductive capacity reduces correspondingly the potential number of vertical infections that can be established during the amplification process.


Pediatric burns in military hospitals of China from 2001 to 2007: a retrospective study.
Childhood burns are a global health problem. To date, no epidemiological study with a large sample size of hospitalized pediatric burn patients from the Chinese mainland has been conducted. This study retrospectively analyzed pediatric burn cases to identify the characteristics of pediatric burns and their risk factors in China. Data for pediatric burn inpatients younger than 14 years were retrieved from the Chinese Trauma Databank (CTDB). The epidemiological characteristics of pediatric burns and risk factors for mortality were analyzed. A total of 61,068 cases were included in the study. Children under 3 years old were at the highest risk of injury. Scalds were the commonest burns (87.59%). Flame burns occurred more in winter, and electrical burns occurred mainly in July and August. Age, etiology, depth of injury, total body surface area (TBSA), site of injury, and outcome were correlated with length of hospital stay. Risk factors for pediatric burn mortality included being male, having third degree burns, ≥30% TBSA, and having multi-site burns. The results showed the epidemiological characteristics of pediatric burns in China, which differ from those reported for other countries and regions. These characteristics can be used to develop measures to prevent pediatric burns.