Cerebral glucose metabolism of Parkinson's disease patients with mild cognitive impairment.
Half of Parkinson's disease (PD) patients with mild cognitive impairment (MCI) develop dementia. We studied topographic distribution of cerebral hypometabolism in PD with different types of MCI. This study included 61 nondemented PD patients and 14 age-matched controls. PD patients were grouped into normal cognition (PD-NC, n = 20), single amnestic (PD-SA, n = 12), single nonamnestic (PD-SN, n = 11), and multidomain MCI (PD-MD, n = 18). Using [(18)F]-fluorodeoxy-glucose PET, cerebral glucose metabolism of MCI groups was compared with that of controls and the PD-NC group. In comparison with controls, PD-NC and PD-SA groups showed no hypometabolic brain areas. However, the PD-SN group showed hypometabolism in parieto-temporo-occipital cortices. The PD-MD group showed widespread hypometabolism that predominantly involved parieto-occipital cortices. In comparison with the PD-NC group, only the PD-MD group showed hypometabolism in lateral frontal, cingulate, and parieto-temporo-occipital cortices. The distribution of hypometabolic brain areas of the PD-MD group suggests that PD-MD seems to be caused by a common pathology with PD dementia. PD-SA and PD-SN seem to be caused by very mild or topographically heterogeneous cerebral dysfunction. Longitudinal clinical and neuroimaging studies are needed to define whether PD patients with single domain MCI progress to PD-MD and finally to dementia.


Toward Totally Defined Nanocatalysis: Deep Learning Reveals the Extraordinary Activity of Single Pd/C Particles.
Homogeneous catalysis is typically considered "well-defined" from the standpoint of catalyst structure unambiguity. In contrast, heterogeneous nanocatalysis often falls into the realm of "poorly defined" systems. Supported catalysts are difficult to characterize due to their heterogeneity, variety of morphologies, and large size at the nanoscale. Furthermore, an assortment of active metal nanoparticles examined on the support are negligible compared to those in the bulk catalyst used. To solve these challenges, we studied individual particles of the supported catalyst. We made a significant step forward to fully characterize individual catalyst particles. Combining a nanomanipulation technique inside a field-emission scanning electron microscope with neural network analysis of selected individual particles unexpectedly revealed important aspects of activity for widespread and commercially important Pd/C catalysts. The proposed approach unleashed an unprecedented turnover number of 109 attributed to individual palladium on a nanoglobular carbon particle. Offered in the present study is the Totally Defined Catalysis concept that has tremendous potential for the mechanistic research and development of high-performance catalysts.


Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B.
ATP7A and ATP7B are copper-transporting P(1B)-type ATPases (Cu-ATPases) that are critical for regulating intracellular copper homeostasis. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and copper toxicity disorders, Menkes and Wilson diseases, respectively. Clusterin and COMMD1 were previously identified as interacting partners of these Cu-ATPases. In this study, we confirmed that clusterin and COMMD1 interact to down-regulate both ATP7A and ATP7B. Overexpression and knockdown of clusterin/COMMD1 decreased and increased, respectively, endogenous levels of ATP7A and ATP7B, consistent with a role in facilitating Cu-ATPase degradation. We demonstrate that whereas the clusterin/ATP7B interaction was enhanced by oxidative stress or mutation of ATP7B, the COMMD1/ATP7B interaction did not change under oxidative stress conditions, and only increased with ATP7B mutations that led to its misfolding. Clusterin and COMMD1 facilitated the degradation of ATP7B containing the same Wilson disease-causing C-terminal mutations via different degradation pathways, clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway. Furthermore, endogenous ATP7B existed in a complex with clusterin and COMMD1, but these interactions were neither competitive nor cooperative and occurred independently of each other. Together these data indicate that clusterin and COMMD1 represent alternative and independent systems regulating Cu-ATPase quality control, and consequently contributing to the maintenance of copper homeostasis.


N-acetylhistidine, a novel osmolyte in the lens of Atlantic salmon (Salmo salar L.).
Volume homeostasis is essential for the preservation of lens transparency and this is of particular significance to anadromous fish species where migration from freshwater to seawater presents severe osmotic challenges. In Atlantic salmon (Salmo salar L.), aqueous humor (AH) osmolality is greater in fish acclimated to seawater compared with young freshwater fish, and levels of lens N-acetylhistidine (NAH) are much higher in seawater fish. Here we investigate NAH as an osmolyte in the lenses of salmon receiving diets either with or without histidine supplementation. In the histidine-supplemented diet (HD) histidine content was 14.2 g/kg, and in the control diet (CD) histidine content was 8.9 g/kg. A transient increase in AH osmolality of 20 mmol/kg was observed in fish transferred from freshwater to seawater. In a lens culture model, temporary decreases in volume and transparency were observed when lenses were exposed to hyperosmotic conditions. A positive linear relationship between extracellular osmolality and lens NAH content was also observed, whereas there was no change in lens histidine content. Hypoosmotic exposure stimulated [(14)C]-histidine efflux by 9.2- and 2.6-fold in CD and HD lenses, respectively. NAH efflux, measured by HPLC, was stimulated by hypoosmotic exposure to a much greater extent in HD lenses. In vivo, lens NAH increased in response to elevated AH osmolality in HD but not CD fish. In conclusion, NAH has an important and novel role as a compatible osmolyte in salmon lens. Furthermore, it is the major osmolyte that balances increases in AH osmolality when fish move from freshwater to seawater. A deficiency in NAH would lead to a dysfunction of the normal osmoregulatory processes in the lens, and we propose that this would contribute to cataract formation in fish deficient in histidine.


Tolerance to Dose Escalation in Minibeam Radiation Therapy Applied to Normal Rat Brain: Long-Term Clinical, Radiological and Histopathological Analysis.
The major limitation to reaching a curative radiation dose in radioresistant tumors such as malignant gliomas is the high sensitivity to radiation and subsequent damage of the surrounding normal tissues. Novel dose delivery methods such as minibeam radiation therapy (MBRT) may help to overcome this limitation. MBRT utilizes a combination of spatial fractionation of the dose and submillimetric (600 μm) field sizes with an array ("comb") of parallel thin beams ("teeth"). The dose profiles in MBRT consist of peaks and valleys. In contrast, the seamless irradiations of the several squared centimeter field sizes employed in standard radiotherapy result in homogeneous dose distributions (and consequently, flat dose profiles). The innovative dose delivery methods employed in MBRT, unlike standard radiation therapy, have demonstrated remarkable normal tissue sparing. In this pilot work, we investigated the tolerance of the rat brain after whole-brain MBRT irradiation. A dose escalation was used to study the tissue response as a function of dose, so that a threshold could be established: doses as high as 100 Gy in one fraction were still well tolerated by the rat brain. This finding suggests that MBRT may be used to deliver higher and potentially curative radiation doses in clinical practice.


Serotonergic mechanisms involved in the discriminative stimulus, reinforcing and subjective effects of cocaine.
The purpose of the present manuscript is to review the current status of the role of serotonin (5-hydroxytryptamine; 5-HT) systems in the stimulus and reinforcing properties of cocaine in non-humans and the subjective effects of cocaine in humans. Review of the current literature suggests that general enhancement (via precursor administration) or depletion of brain 5-HT content (via neurotoxin administration or tryptophan depletion) impact the reinforcing effects of cocaine in non-humans and its subjective effects in humans. Selective 5-HT reuptake inhibitors (SSRIs) enhance the discriminability of cocaine and decrease cocaine self-administration in animals, although data to the contrary also exist. Studies in humans suggest that SSRIs attenuate the subjective effects of cocaine in humans. Although few drugs with selectivity for 5-HT2 receptors have been studied systematically, a 5-HT2 agonist and several antagonists show some efficacy in enhancing and reducing, respectively, the reinforcing effects of cocaine in non-humans. Limited data from humans suggest that a 5-HT2 antagonist may also decrease the subjective effects of cocaine; thus, 5-HT2 compounds deserve further attention. The majority of studies evaluating the 5-HT3 antagonists have reported negative results across all paradigms. In summary, while the functional significance of 5-HT receptors has not been fully elucidated, these data suggest that changes in serotonergic activity can modulate the effects of cocaine in both animals and humans under a variety of experimental conditions. One commonality among the studies with positive findings is that cocaine effects are only partially modified by 5-HT agents regardless of the direction of change.


Differential regulation of corticotropin-releasing factor mRNA in rat brain regions by glucocorticoids and stress.
The regulation of corticotropin-releasing factor (CRF) mRNA expression in the rat brain by glucocorticoids and stress was examined by Northern blot analysis and in situ hybridization histochemistry. Rats either were exposed to a single electrical footshock session and killed 2, 4, 12, or 24 hr later (acute stress), or were subjected to the same regimen twice daily for 3 or 7 d and killed on the day following the last session (chronic stress). Rats placed in the experimental chamber but not administered shock comprised a "sham-handling" group. Chronic (7 d) intermittent footshock stress resulted in an 84 +/- 26% (P less than 0.05) increase in CRF mRNA levels in the whole hypothalamus as detected by Northern blot analysis and a 97 +/- 29% (P less than 0.05) increase in the paraventricular nucleus (PVN) as detected using in situ hybridization. No significant change in CRF mRNA levels was observed in the hypothalamus at any time up to 24 hr after a single exposure to footshock stress. A different pattern of results was obtained in other CRF-expressing cell groups. In Barrington's nucleus (a pontine micturition center), both acute and chronic stress produced significant increases in CRF mRNA, while in the olfactory bulb, both paradigms resulted in decreased levels. By Northern blot analysis, CRF mRNA in the olfactory bulb declined steadily, beginning at 4 hr after acute stress, and reached significance at 24 hr (69.2 +/- 1.9% of control, P less than 0.05). Levels from chronically (7 d) stressed animals declined to 54.1 +/- 5.1% of control value (P less than 0.05). Analysis of hybridization histochemical material revealed that both the number of positively hybridized cells and the number of silver grains per cell in the mitral and external plexiform layers of the bulb decreased following acute and chronic stress. However, CRF mRNA levels in the olfactory bulb were decreased to a comparable extent in the sham-handling group, suggesting that exposure to a novel environment can effect a decrease in CRF mRNA levels in the olfactory bulb. To provide comparisons with the effects of manipulation of glucocorticoid status, comparable analyses were carried out in separate groups of animals following adrenalectomy (ADX) with and without corticosteroid replacement. After ADX, CRF mRNA levels in the whole hypothalamus increased 60 +/- 5% (P less than 0.05) and were normalized following dexamethasone replacement. In contrast to the hypothalamus, no effects of steroid manipulation on CRF mRNA levels in the olfactory bulb, midbrain, cerebral cortex, or brain stem were detected.(ABSTRACT TRUNCATED AT 400 WORDS)


Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models.
A diverse array of infectious agents, including prions and certain neurotropic viruses, bind to the laminin receptor (LR), and this determines tropism to the CNS. Bacterial meningitis in childhood is almost exclusively caused by the respiratory tract pathogens Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, but the mechanism by which they initiate contact with the vascular endothelium of the blood brain barrier (BBB) is unknown. We hypothesized that an interaction with LR might underlie their CNS tropism. Using affinity chromatography, coimmunoprecipitation, retagging, and in vivo imaging approaches, we identified 37/67-kDa LR as a common receptor for all 3 bacteria on the surface of rodent and human brain microvascular endothelial cells. Mutagenesis studies indicated that the corresponding bacterial LR-binding adhesins were pneumococcal CbpA, meningococcal PilQ and PorA, and OmpP2 of H. influenzae. The results of competitive binding experiments suggest that a common adhesin recognition site is present in the carboxyl terminus of LR. Together, these findings suggest that disruption or modulation of the interaction of bacterial adhesins with LR might engender unexpectedly broad protection against bacterial meningitis and may provide a therapeutic target for the prevention and treatment of disease.


Morphologic analysis of BMP-9 gene therapy-induced osteogenesis.
The present study was performed to determine the histological, ultrastructural, and radiographic changes that occur over time at intramuscular BMP-9 gene therapy treatment sites. Several members of the bone morphogenetic protein (BMP) family have the potential to induce osteochondrogenesis when the protein is delivered to rodents, canines, rabbits, and nonhuman primates. Previous studies have also demonstrated that BMP gene therapy utilizing adenoviral vectors can also stimulate orthotopic and heterotopic bone formation in rodents and rabbits. Athymic nude and Sprague-Dawley rats were injected with Ad-BMP-9 or Ad-beta-Gal (3.75 x 10(9) particles) in their thigh musculature and light microscopic, electron microscopic, and computerized tomography analysis was performed 3, 6, 9, 12, 15, 18, 21, and 100 days later. To assess early mesenchymal cell proliferation, a bromodeoxyuridine (BrdU) immunohistochemical analysis was also performed 48, 60, and 72 hr postinjection in athymic nude rats. All animals demonstrated extensive endochondral bone formation at the Ad-BMP-9 treatment sites within 3 weeks. The Sprague-Dawley rats also exhibited a massive, acute inflammatory infiltrate during the first week. Proliferating mesenchymal stem cells were clearly evident as early as 2 days after treatment, which differentiated into small or hypertrophied chondrocytes during the next week. During the third week, the cartilaginous matrix mineralized and formed woven bone, which converted to lamellar bone by 3 months. No evidence of bone formation was demonstrated at the Ad-beta-Gal injection sites in the athymic nude or Sprague-Dawley rats. In addition, no cellular proliferation was seen at the Ad-beta-Gal treatment sites in the athymic nude animals as assessed by light microscopy and BrdU immunohistochemistry. The extensive bone formation induced by Ad-BMP-9 suggests that BMP gene therapy may have potential utility in the treatment of degenerative, rheumatic, or traumatic bone pathology.


Dynamic visual perception and reading development in Chinese school children.
The development of reading skills may depend to a certain extent on the development of basic visual perception. The magnocellular theory of developmental dyslexia assumes that deficits in the magnocellular pathway, indicated by less sensitivity in perceiving dynamic sensory stimuli, are responsible for a proportion of reading difficulties experienced by dyslexics. Using a task that measures coherent motion detection threshold, this study examined the relationship between dynamic visual perception and reading development in Chinese children. Experiment 1 compared the performance of 27 dyslexics and their age- and IQ-matched controls in the coherent motion detection task and in a static pattern perception task. Results showed that only in the former task did the dyslexics have a significantly higher threshold than the controls, suggesting that Chinese dyslexics, like some of their Western counterparts, may have deficits in magnocellular pathway. Experiment 2 examined whether dynamic visual processing affects specific cognitive processes in reading. One hundred fifth-grade children were tested on visual perception and reading-related tasks. Regression analyses found that the motion detection threshold accounted for 11% and 12%, respectively, variance in the speed of orthographic similarity judgment and in the accuracy of picture naming after IQ and vocabulary size were controlled. The static pattern detection threshold could not account for any variance. It is concluded that reading development in Chinese depends to a certain extent on the development of dynamic visual perception and its underlying neural pathway and that the impact of visual development can be specifically related to orthographic processing in reading Chinese.


Kids becoming less alike: A behavioral genetic analysis of developmental increases in personality variance from childhood to adolescence.
Recent work in personality development has indicated that the magnitude of individual differences in personality increases over child development. Do such patterns reflect the differentiation of individuals by genotype, an increasing influence of environmental factors, or some (interactive) combination of the two? Using a population-based sample of over 2,500 twins and multiples from the Texas Twin Project, we estimated age trends in the variances in self- and parent-reported measures of the Big Five personality traits between Ages 8 and 18 years. We then estimated age trends in the genetic and environmental components of variance in each measure. Individual differences in personality increased in magnitude from childhood through mid-adolescence. This pattern emerged using both children's self-reports and ratings provided by their parents, and was primarily attributable to increases in the magnitude of genetic influences. Most of the increasing genetic variance appeared nonadditive, pointing to the possibility that developmental processes tend to make genetically similar individuals disproportionately more alike in their personality traits over time. These findings could reflect increasing or accumulating effects of trait-by-trait interactions; person-by-environment transactions, whereby genetically similar people are disproportionally likely to experience similar environments; the activation of dominant genes across developmental transitions (e.g., puberty); or some combination of these three processes, among other factors. Theories of personality development will need to accommodate these descriptive findings, and longitudinal, genetically informed designs are needed to test some of the specific hypotheses springing from this study. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Advances in functional magnetic resonance imaging of the human brainstem.
The brainstem is of tremendous importance for our daily survival, and yet the functional relationships between various nuclei, their projection targets, and afferent regulatory areas remain poorly characterized. The main reason for this lies in the sub-optimal performance of standard neuroimaging methods in this area. In particular, fMRI signals are much harder to detect in the brainstem region compared to cortical areas. Here we describe and validate a new approach to measure activation of brainstem nuclei in humans using standard fMRI sequences and widely available tools for statistical image processing. By spatially restricting an independent component analysis to an anatomically defined brainstem mask, we excluded those areas from the analysis that were strongly affected by physiological noise. This allowed us to identify for the first time intrinsic connectivity networks in the human brainstem and to map brainstem-cortical connectivity purely based on functionally defined regions of interest.


"Merging Yoga and Occupational Therapy (MY-OT): A feasibility and pilot study".
To examine the feasibility and benefits of the Merging Yoga and Occupational Therapy (MY-OT) intervention. This is the primary analysis of a non-controlled pretest-posttest pilot study to understand the feasibility and impact of MY-OT on balance, balance self-efficacy, and fall risk factor management in people with chronic stroke. University research laboratory. People with chronic stroke were included in the study if they: had sustained a fall or had fear of falling, were able to stand, and hand impaired balance and were at risk for falls (≤46 on the Berg Balance Scale (BBS)). Individuals completed an 8 week intervention that included 16 sessions of both yoga and group occupational therapy (OT). Yoga included physical postures, breathing exercises, and meditation. OT focused on post-stroke fall risk factor management. The BBS was used to assess balance, the Activities-specific Balance Confidence Scale (ABC) was used to measure balance self-efficacy. Five fall risk factor management scales were used. Overall, the intervention was considered feasible, as individuals were able to safely complete the intervention with little attrition and high attendance. Balance improved by 30% (p=0.002). Balance self-efficacy improved by 15% (p=0.034). Each of the five fall risk factor management scales improved, but only two significantly improved (Fall Prevention and Management Questionnaire, 29%, p=0.004 and Fall Prevention Strategy Survey, 42%, p=0.032). The results demonstrate that MY-OT is a potential intervention to improve multiple fall related outcomes for people with stroke. Therapists may consider these interventions for people with stroke, but additional research is warranted.


Deficiency in repair of the mitochondrial genome sensitizes proliferating myoblasts to oxidative damage.
Reactive oxygen species (ROS), generated as a by-product of mitochondrial oxidative phosphorylation, are particularly damaging to the genome of skeletal muscle because of their high oxygen consumption. Proliferating myoblasts play a key role during muscle regeneration by undergoing myogenic differentiation to fuse and restore damaged muscle. This process is severely impaired during aging and in muscular dystrophies. In this study, we investigated the role of oxidatively damaged DNA and its repair in the mitochondrial genome of proliferating skeletal muscle progenitor myoblasts cells and their terminally differentiated product, myotubes. Using the C2C12 cell line as a well-established model for skeletal muscle differentiation, we show that myoblasts are highly sensitive to ROS-mediated DNA damage, particularly in the mitochondrial genome, due to deficiency in 5' end processing at the DNA strand breaks. Ectopic expression of the mitochondrial-specific 5' exonuclease, EXOG, a key DNA base excision/single strand break repair (BER/SSBR) enzyme, in myoblasts but not in myotubes, improves the cell's resistance to oxidative challenge. We linked loss of myoblast viability by activation of apoptosis with deficiency in the repair of the mitochondrial genome. Moreover, the process of myoblast differentiation increases mitochondrial biogenesis and the level of total glutathione. We speculate that our data may provide a mechanistic explanation for depletion of proliferating muscle precursor cells during the development of sarcopenia, and skeletal muscle dystrophies.


In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells.
A rare set of hematopoietic stem cells (HSC) must undergo a massive expansion to produce mature blood cells. The phenotypic isolation of HSC from mice offers the opportunity to determine directly their proliferation kinetics. We analyzed the proliferation and cell cycle kinetics of long-term self-renewing HSC (LT-HSC) in normal adult mice. At any one time, approximately 5% of LT-HSC were in S/G2/M phases of the cell cycle and another 20% were in G1 phase. BrdUrd incorporation was used to determine the rate at which different cohorts of HSC entered the cell cycle over time. About 50% of LT-HSC incorporated BrdUrd by 6 days and >90% incorporated BrdUrd by 30 days. By 6 months, 99% of LT-HSC had incorporated BrdUrd. We calculated that approximately 8% of LT-HSC asynchronously entered the cell cycle per day. Nested reverse transcription-PCR analysis revealed cyclin D2 expression in a high proportion of LT-HSC. Although approximately 75% of LT-HSC are quiescent in G0 at any one time, all HSC are recruited into cycle regularly such that 99% of LT-HSC divide on average every 57 days.


Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension.
Bone morphogenic protein (BMP)4 can stimulate superoxide production and exert proinflammatory effects on the endothelium. The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain elusive. To elucidate the cellular pathways by which BMP4-induced endothelial dysfunction is mediated through oxidative stress-dependent upregulation of cyclooxygenase (COX)-2. Impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4-treated mouse aortae, which were prevented by the BMP4 antagonist noggin. Pharmacological inhibition with thromboxane prostanoid receptor antagonist or COX-2 but not COX-1 inhibitor prevented BMP4-induced endothelial dysfunction, which was further confirmed with the use of COX-1(-/-) or COX-2(-/-) mice. Noggin and knockdown of BMP receptor 1A abolished endothelium-dependent contractions and COX-2 upregulation in BMP4-treated aortae. Apocynin and tempol treatment were effective in restoring endothelium-dependent relaxations, preventing endothelium-dependent contractions and eliminating ROS overproduction and COX-2 overexpression in BMP4-treated aortae. BMP4 increased p38 mitogen-activated protein kinase (MAPK) activity through a ROS-sensitive mechanism and p38 MAPK inhibitor prevented BMP4-induced endothelial dysfunction. COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS overproduction and COX-2 upregulation. Importantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction. We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 upregulation in endothelial cells, leading to endothelial dysfunction through ROS-dependent p38 MAPK activation. This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension.


Differential potentiation of mitogen-stimulated phosphoinositide hydrolysis in protein kinase C-depleted Swiss 3T3 cells.
In Swiss 3T3 cells, depletion of protein kinase C (PKC) by prolonged incubation with phorbol esters potentiates the formation of total inositol phosphates in response to bombesin or vasopressin [Blakeley, Corps & Brown (1989) Biochem. J. 258, 177-185]. The characteristics of the accumulation of inositol phosphates in control and PKC-depleted cells stimulated by bombesin, vasopressin or prostaglandin F2 alpha (PGF2 alpha) have now been compared. The potentiation of the PGF2 alpha response was greater than that of the vasopressin response which was, in turn, greater than that of the bombesin response. The time courses of the responses to all three agonists were biphasic, and both phases of the response were amplified in the PKC-depleted cells. These results provide further evidence for the involvement of a PKC-mediated negative-feedback loop regulating phosphoinositide hydrolysis in response to several 3T3 cell mitogens. The differential potentiation of the response to these agonists suggests that PKC might act at multiple sites within the signal transduction pathway.


Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults.
Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine. To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults. We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010. We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm. Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. Ten studies (2769 participants, 4062 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12, 5.2 and 5.0 for 2-hour pain-free and 1- and 2-hour headache relief, respectively, when medication was taken for moderate to severe pain. Nausea, photophobia and phonophobia were reduced more with paracetamol than with placebo at 2 hours (NNTs of 7 to 11); more individuals were free of any functional disability at 2 hours with paracetamol (NNT 10); and fewer participants needed rescue medication over 6 hours (NNT 6).Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan 100 mg for 2-hour headache relief; there were no 2-hour pain-free data. There was no significant difference between the paracetamol plus metoclopramide combination and sumatriptan for relief of "light/noise sensitivity" at 2 hours, but slightly more individuals needed rescue medication over 24 hours with the combination therapy (NNT 17).Adverse event rates were similar between paracetamol and placebo, and between paracetamol plus metoclopramide and sumatriptan. No serious adverse events occurred with paracetamol alone, but more "major" adverse events occurred with sumatriptan than with the combination therapy (NNH 32). Paracetamol 1000 mg alone is an effective treatment for acute migraine headaches, and the addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg. Adverse events with paracetamol did not differ from placebo; "major" adverse events were slightly more common with sumatriptan than with paracetamol plus metoclopramide.


Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain.
Inflammation with expression of interleukin 6 (IL-6) in the brain occurs in many neurodegenerative disorders. To better understand the role of IL-6 in such disorders, we examined performance in a learning task in conjunction with molecular and cellular neuropathology in transgenic mice that express IL-6 chronically from astrocytes in the brain. Transgenic mice exhibited dose- and age-related deficits in avoidance learning that closely corresponded with specific progressive neuropathological changes. These results establish a link between the central nervous system expression of IL-6, inflammatory neurodegeneration, and a learning impairment in transgenic mice. They suggest a critical role for a proinflammatory cytokine in the cognitive deficits and associated neuroinflammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.


The peaked audiometric configuration in Meniere's disease: disease related?
A retrospective analysis of audiograms was completed for persons from 3 different patient groups. These 3 groups were (1) persons with unilateral Meniere's disease, (2) persons with unilateral acoustic tumor, and (3) persons from the general clinical population of an audiology clinic in a major medical center. As Paparella, McDermott, Luiz, and de Sousa (1982) also report, the most common audiometric configuration in the Meniere's disease group was peaked, a condition in which poorer hearing is reported in the low and high frequencies, and an island of better hearing sensitivity occurs at either 1.0 or 2.0 kHz. Some of the peaked audiograms from persons in our Meniere's disease group could be a result of a low-frequency hearing loss caused by Meniere's disease combined with a high-frequency hearing loss due to aging or other environmental factors. However, 27% (13/48) of the peaked audiograms in ears with Meniere's disease were found in persons with no hearing loss in the high frequencies of their nondiseased ear. Thus, the peaked audiometric configuration is associated with Meniere's disease, as suggested by research results from animals with experimentally induced endolymphatic hydrops. Peaked audiometric configurations were also observed in roughly 9% of the general clinical population and in 12.5% of ears of persons with acoustic tumors. A rule--based on the audiometric configurations that maximized identification of patients with Meniere's disease--using the general clinical population as a control did not fare as well when the tumor group was used as a control. This finding provides further evidence that peaked audiograms, although common to Meniere's disease, are not pathognomonic of this disease. Furthermore, these results indicate that the diagnosis of Meniere's disease from audiometric profiles is risky, at best.


Mechanisms for removal of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) from drinking water by conventional and enhanced coagulation.
Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are persistent organic pollutants that have been found to be ubiquitous in the environment. This article, for the first time, delineates removal areas of these polar compounds on a coagulation diagram that associates chemical conditions with different coagulation mechanisms. Variables considered were solution pH, coagulant dosage, coagulants (alum and ferric chloride), natural organic matter (NOM), initial turbidity, and flocculation time. The jar-test results show that conventional coagulation (alum dosage of 10-60 mg/L and final pH of 6.5-8.0) removed ≤20% of PFOS and PFOA. These chemicals tended to be removed better by enhanced coagulation at higher coagulant dosages (>60 mg/L) and (thus) lower final pH (4.5-6.5). A coagulation diagram was developed to define the coagulant dosage and solution pH for PFOS/PFOA removal. The results suggest that the primary PFOS/PFOA removal mechanism is adsorption to fine Al hydroxide flocs freshly formed during the initial stage of coagulation; increasing flocculation time from 2 to 90 min could not further improve PFOS and PFOA removals. Furthermore, the effect of NOM on PFOS/PFOA removal by coagulation was examined, and possible removal mechanisms were discussed.


Structural studies by X-ray diffraction on metal substituted desulforedoxin, a rubredoxin-type protein.
Desulforedoxin (Dx), isolated from the sulfate reducing bacterium Desulfovibrio gigas, is a small homodimeric (2 x 36 amino acids) protein. Each subunit contains a high-spin iron atom tetrahedrally bound to four cysteinyl sulfur atoms, a metal center similar to that found in rubredoxin (Rd) type proteins. The simplicity of the active center in Dx and the possibility of replacing the iron by other metals make this protein an attractive case for the crystallographic analysis of metal-substituted derivatives. This study extends the relevance of Dx to the bioinorganic chemistry field and is important to obtain model compounds that can mimic the four sulfur coordination of metals in biology. Metal replacement experiments were carried out by reconstituting the apoprotein with In3+, Ga3+, Cd2+, Hg2+, and Ni2+ salts. The In3+ and Ga3+ derivatives are isomorphous with the iron native protein; whereas Cd2+, Hg2+, and Ni2+ substituted Dx crystallized under different experimental conditions, yielding two additional crystal morphologies; their structures were determined by the molecular replacement method. A comparison of the three-dimensional structures for all metal derivatives shows that the overall secondary and tertiary structures are maintained, while some differences in metal coordination geometry occur, namely, bond lengths and angles of the metal with the sulfur ligands. These data are discussed in terms of the entatic state theory.


Advanced practice in nursing: conceptual issues.
The issue of defining advanced practice nursing roles is increasingly a subject of national discussion and debate. Central to this discussion has been the issue of merging nurse practitioner (NP) and clinical nurse specialist (CNS) roles and the tendency for the term "nurse practitioner" to replace that of "clinical nurse specialist" in denotation of these roles. The authors note the lack of any attempt to use a broader conceptual approach in these discussions. In this article, the development of each role is reviewed, and the strengths and weaknesses of each role in current practice and education are evaluated. The authors conclude that inadequate justification exists for continuing both roles, but that the answer is not in simply replacing the CNS with the NP. Ongoing careful and thoughtful dialogue should be used to guide the merging of these two roles.


Structural Basis of Intracellular TGF-β Signaling: Receptors and Smads.
Stimulation of the transforming growth factor β (TGF-β) family receptors activates an intracellular phosphorylation-dependent signaling cascade that culminates in Smad transcriptional activation and turnover. Structural studies have identified a number of allosteric mechanisms that control the localization, conformation, and oligomeric state of the receptors and Smads. Such mechanisms dictate the ordered binding of substrate and adaptor proteins that determine the directionality of the signaling process. Activation of the pathway has been illustrated by the various structures of the receptor-activated Smads (R-Smads) with SARA, Smad4, and YAP, respectively, whereas mechanisms of down-regulation have been elucidated by the structural complexes of FKBP12, Ski, and Smurf1. Interesting parallels have emerged between the R-Smads and the Forkhead-associated (FHA) and interferon regulatory factor (IRF)-associated domains, as well as the Hippo pathway. However, important questions remain as to the mechanism of Smad-independent signaling.


Can forest management be used to sustain water-based ecosystem services in the face of climate change?
Forested watersheds, an important provider of ecosystems services related to water supply, can have their structure, function, and resulting streamflow substantially altered by land use and land cover. Using a retrospective analysis and synthesis of long-term climate and streamfiow data (75 years) from six watersheds differing in management histories we explored whether streamflow responded differently to variation in annual temperature and extreme precipitation than unmanaged watersheds. We show significant increases in temperature and the frequency of extreme wet and dry years since the 1980s. Response models explained almost all streamflow variability (adjusted R2 > 0.99). In all cases, changing land use altered streamflow. Observed watershed responses differed significantly in wet and dry extreme years in all but a stand managed as a coppice forest. Converting deciduous stands to pine altered the streamflow response to extreme annual precipitation the most; the apparent frequency of observed extreme wet years decreased on average by sevenfold. This increased soil water storage may reduce flood risk in wet years, but create conditions that could exacerbate drought. Forest management can potentially mitigate extreme annual precipitation associated with climate change; however, offsetting effects suggest the need for spatially explicit analyses of risk and vulnerability.


What is the role of portion control in weight management?
Systematic studies have shown that providing individuals with larger portions of foods and beverages leads to substantial increases in energy intake. The effect is sustained over weeks, supporting the possibility that large portions have a role in the development of obesity. The challenge is to find strategies to effectively manage the effects of portion size. One approach involves teaching people to select appropriate portions and to use tools that facilitate portion control. Although tools such as portion-control plates have been shown in several randomized trials to improve weight loss, limited data are available on whether education and tools lead to long-term changes in eating behavior and body weight. Another approach is to use preportioned foods (PPFs) to add structure to meals and minimize decisions about the amount of food to eat. A number of randomized controlled trials have demonstrated the efficacy of both liquid meal replacements and solid PPFs for weight loss and weight loss maintenance, but it is not known if they lead to better understanding of appropriate portions. Although portion control is important for weight management, urging people simply to 'eat less' of all foods may not be the best approach as high-energy-dense foods disproportionately increase energy intake compared with those lower in energy density. A more effective strategy may be to encourage people to increase the proportion of foods low in energy density in their diets while limiting portions of high-energy-dense foods. If people lower the energy density of their diet, they can eat satisfying portions while managing their body weight.


IMI - Clinical Myopia Control Trials and Instrumentation Report.
The evidence-basis based on existing myopia control trials along with the supporting academic literature were reviewed; this informed recommendations on the outcomes suggested from clinical trials aimed at slowing myopia progression to show the effectiveness of treatments and the impact on patients. These outcomes were classified as primary (refractive error and/or axial length), secondary (patient reported outcomes and treatment compliance), and exploratory (peripheral refraction, accommodative changes, ocular alignment, pupil size, outdoor activity/lighting levels, anterior and posterior segment imaging, and tissue biomechanics). The currently available instrumentation, which the literature has shown to best achieve the primary and secondary outcomes, was reviewed and critiqued. Issues relating to study design and patient selection were also identified. These findings and consensus from the International Myopia Institute members led to final recommendations to inform future instrumentation development and to guide clinical trial protocols.


Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study.
Hepatitis C virus (HCV) infection increases the risk of B-cell non-Hodgkin lymphomas (B-NHL). Antiviral treatment (AT) can induce hematological responses in patients with marginal zone lymphomas (MZL). The ANRS HC-13 Lympho-C study aimed at a better understanding of the impact of AT on HCV associated B-NHL. This multicentric study enrolled 116 HCV-positive patients with B-NHL between 2006 and 2012. Cytological and histological samples were collected for centralized review. At lymphoma diagnosis, median age was 61 years and gender ratio M/F was 1. Cytohistological distribution was marginal zone lymphoma (MZL) n = 45 (39%), diffuse large B-cell lymphoma (DLBCL) n = 45 (39%), and other types n = 26 (22%). MZL patients had more frequent detection of rheumatoid factor (68% vs. 35%; P = 0.001) and more frequently mixed cryoglobulinemia (74% vs. 44%; P = 0.021) than patients with DLBCL. Among patients receiving AT, a sustained virologic response was achieved in 23 of 38 (61%) patients with MZL and in 9 of 17 (53%) with DLBCL (P = 0.42). Three-year overall survival (OS) and progression-free survival were 78% 95%CI [63-88] and 64% [48-76], respectively, without difference between cytohistological groups. Outcome analysis showed a favorable association between OS and AT in all patients (P = 0.05) and in the subgroup of MZL patients only (P = 0.04). Our data support that AT improves the outcomes of HCV-associated NHLs. The impact of new AT regimen with protease inhibitor needs to be investigated in this setting. [clinicalTrials.gov Identification number NCT01545544]


NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C23, 43% Chlorine) (CAS No. 108171-27-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Toxicology and carcinogenesis studies of chlorinated paraffins (C23, 43% chlorine), an extreme-pressure lubricant and flame retardant, were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Additional groups of 10 rats per sex and dose were examined at 6 and at 12 months. Male rats received doses of 0, 1,875, or 3,750 mg/kg body weight; female rats were given 0, 100, 300, or 900 mg/kg. Male and female mice received 0, 2,500, or 5,000 mg/kg. Doses selected for the 2-year studies were based on the results from 13-week studies in which rats of each sex received 0 to 3,750 mg/kg, and mice of each sex, 0 to 7,500 mg/kg. No toxicity of chlorinated paraffins (C23, 43% chlorine) was observed in male rats or in male or female mice in the 13-week studies. A dose-related inflammation of the liver was observed in female rats in the 13-week studies and in male and female rats in the 13-week studies and in male and female rats at 6 and 12 months in the 2-year studies. Chlorinated paraffins (C23, 43% chlorine) administration did not influence mean body weights of rats during the 2-year studies, but both male and female low dose mice gained less weight than did vehicle controls or the high dose groups. Survival of dosed and vehicle control groups was similar for each sex and species (male rats: vehicle control, 30/50; low dose, 32/50; high dose, 27/50; female rats: 34/50; 30/50; 33/50; 31/50; male mice: 29/50; 36/50; 28/50; female mice: 21/50; 22/50; 20/50). For female mice, 60%-70% of the early deaths in each group were attributed to utero-ovarian infection. The lower survival for female mice may have decreased the sensitivity of this study to detect a carcinogenic effect. Pheochromocytomas of the adrenal gland medulla occurred with an increased incidence in female rats exposed to chlorinated paraffins (C23, 43% chlorine) (vehicle control, 1/50; low dose, 4/50; mid dose, 6/50; high dose, 7/50). However, adrenal gland medullary hyperplasia was not increased (6/50; 3/50; 1/50; 6/50). Malignant lymphomas were increased in dosed male mice (6/50; 12/50; 16/50). High dose female mice showed a marginal increase in the incidence of hepatocellular carcinomas (1/50; 1/49; 6/50) and in the incidence of adenomas or carcinomas (combined) (4/50; 3/49; 10/50). The primary nonneoplastic lesion associated with chlorinated paraffins (C23, 43% chlorine) administration was a diffuse lymphohistiocytic inflammation in the liver and in the pancreatic and mesenteric lymph nodes of male and female rats. Splenic congestion was a secondary effect. These lesions occurred earlier and at lower doses in female rats than in male rats. No significant nonneoplastic lesions were considered compound related in mice. Chlorinated paraffins (C23, 43% chlorine) was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when assayed according to the preincubation protocol. An audit of the experimental data was conducted for these 2-year studies of chlorinated paraffins (C23, 43% chlorine). No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male F344/N rats given 1,875 or 3,750 mg/kg per day. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female F344/N rats as shown by an increased incidence of adrenal gland medullary pheochromocytomas. There was clear evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male B6C3F1 mice as shown by an increase in the incidence of malignant lymphomas. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female B6C3F1 mice as shown by a marginal increase in the incidence of hepatocellular neoplasms. *The Chemical Abstract Service Seal increase in the incidence of hepatocellular neoplasms. *The Chemical Abstract Service Service (CAS) number that appeared on this technical report at the time of publication (63449-39-8) reflects the generic CAS number for chlorinated paraffins. This number has been replaced in the NTP Chemtrack chemical tracking system with the more appropriate number.


Induced pluripotent stem cell derived macrophages as a cellular system to study salmonella and other pathogens.
A number of pathogens, including several human-restricted organisms, persist and replicate within macrophages (Mφs) as a key step in pathogenesis. The mechanisms underpinning such host-restricted intracellular adaptations are poorly understood, in part, due to a lack of appropriate model systems. Here we explore the potential of human induced pluripotent stem cell derived macrophages (iPSDMs) to study such pathogen interactions. We show iPSDMs express a panel of established Mφ-specific markers, produce cytokines, and polarise into classical and alternative activation states in response to IFN-γ and IL-4 stimulation, respectively. iPSDMs also efficiently phagocytosed inactivated bacterial particles as well as live Salmonella Typhi and S. Typhimurium and were able to kill these pathogens. We conclude that iPSDMs can support productive Salmonella infection and propose this as a flexible system to study host/pathogen interactions. Furthermore, iPSDMs can provide a flexible and practical cellular platform for assessing host responses in multiple genetic backgrounds.


Age Effects on Hypocotyl Mechanics.
Numerous studies deal with composition and molecular processes involved in primary cell wall formation and alteration in Arabidopsis. However, it still remains difficult to assess the relation between physiological properties and mechanical function at the cell wall level. The thin and fragile structure of primary cell walls and their large biological variability, partly related to structural changes during growth, make mechanical experiments challenging. Since, to the best of our knowledge, there is no reliable data in the literature about how the properties of the fully elongated zone of hypocotyls change with age. We studied in a series of experiments on two different seed batches the tensile properties the region below the growth zone of 4 to 7 day old etiolated Arabidopsis hypocotyls. Additionally, we analysed geometrical parameters, hypocotyl density and cellulose content as individual traits and their relation to tissue mechanics. No significant differences of the mechanical parameters of the non-growing region between 5-7 day old plants could be found whereas in 4 day old plants both tensile stiffness and ultimate tensile stress were significantly lower than in the older plants. Furthermore hypocotyl diameters and densities remain almost the same for 5, 6 and 7 day old seedlings. Naturally, hypocotyl lengths increase with age. The evaluation whether the choice-age or length-influences the mechanical properties showed that both are equally applicable sampling parameters. Additionally, our detailed study allows for the estimation of biological variability, connections between mechanics and hypocotyl age could be established and complement the knowledge on biochemistry and genetics affecting primary plant cell wall growth. The application of two different micromechanical devices for testing living Arabidopsis hypocotyls allows for emphasizing and discussing experimental limitations and for presenting a wide range of possibilities to address current and future questions related to plant cell wall mechanics, synthesis and growth in combination with molecular biology methodologies.


Analysis of global gene expression changes in human bronchial epithelial cells exposed to spores of the allergenic fungus, Alternaria alternata.
Exposure and sensitivity to ubiquitous airborne fungi such as Alternaria alternata have long been implicated in the development, onset, and exacerbation of chronic allergic airway disorders. This present study is the first to investigate global changes in host gene expression during the interaction of cultured human bronchial epithelial cells and live Alternaria spores. In in vitro experiments human bronchial epithelial cells (BEAS-2B) were exposed to spores or media alone for 24 h. RNA was collected from three biological replicates per treatment and was used to assess changes in gene expression patterns using Affymetrix Human Genome U133 Plus 2.0 Arrays. In cells treated with Alternaria spores compared to controls, 613 probe sets representing 460 individual genes were found differentially expressed (p ≤ 0.05). In this set of 460 statistically significant, differentially expressed genes, 397 genes were found to be up-regulated and 63 were down-regulated. Of these 397 up-regulated genes, 156 genes were found to be up-regulated ≥2 fold. Interestingly, none of the 63 down-regulated genes were found differentially expressed at ≤-2 fold. Differentially expressed genes were identified following statistical analysis and subsequently used for pathway and network evaluation. Interestingly, many cytokine and chemokine immune response genes were up-regulated with a particular emphasis on interferon-inducible genes. Genes involved in cell death, retinoic acid signaling, and TLR3 response pathways were also significantly up-regulated. Many of the differentially up-regulated genes have been shown in other systems to be associated with innate immunity, inflammation and/or allergic airway diseases. This study now provides substantial information for further investigating specific genes and innate immune system pathways activated by Alternaria in the context of allergic airway diseases.


Bound to supine sleep: Parkinson's disease and the impact of nocturnal immobility.
Impaired nocturnal mobility is a well-known problem in Parkinson's disease (PD), and clinical experience suggests a predominance of supine body position during sleep. However, this assumption - and potential consequences - still awaits objective validation by a polysomnography-based and adequately controlled study. Clinical and polysomnographical analysis of 80 consecutive PD patients and 80 control subjects carefully matched for age, sex, body mass index and apnea-hypopnea index. PD patients slept twice as much in supine position than control subjects (62.2 ± 32.9% vs. 34.2 ± 28.5%, p < 0.001). In PD, but not in control subjects, more supine sleep correlated with fewer changes in body position (rho = -0.434, p < 0.001). Longer PD disease duration was an independent predictor of more supine sleep in multiple linear regression analysis (β = 0.389, p < 0.001); conversely, more supine sleep was associated with higher apnea-hypopnea index and daytime sleepiness. We confirmed that supine sleep is common in PD, and increases with longer disease duration. Our findings indicate that supine sleep may contribute to the overall disease burden by deteriorating sleep-disordered breathing and daytime vigilance.


Crop prices, farm incomes, and food security during the COVID-19 pandemic in India: Phone-based producer survey evidence from Haryana State.
In March 2020, India declared a nationwide lockdown in response to the COVID-19 pandemic. Such restrictions on mobility interrupted the normal functioning of agricultural value chains. For a sample of 1767 tomato and wheat producers in the state of Haryana, we study to what extent the lockdown limited access to inputs, labor, machinery, and markets to produce, harvest, and sell their crops. We quantify crop income reductions during the first months of the lockdown and analyze to what extent these are associated with borrowing and food insecurity. We find that wheat producers, for whom state-led procurement guaranteed market access at fixed prices, suffered minimal declines in income. For tomato producers-an already more vulnerable population-income fell by 50% relative to their expected income in a normal year, largely due to a steep fall of tomato prices as they shifted from wholesale markets to local retail markets, resulting in a sharp increase in local supply. Relative to wheat producers affected by the lockdown, reduced income for tomato producers was associated with an increase in borrowing and reduced food security. We conclude that targeting producers of crops that face substantial price risk and introducing policies that stabilize market prices are important in efforts to aid recovery and build resilience of smallholder farmers.


Unintended consequences of a quality measure for acute bronchitis.
To determine whether diagnostic coding shifts might undermine apparent improvements resulting from the 2007 Healthcare Effectiveness Data and Information Set (HEDIS) measure on avoidance of antibiotics for the treatment of adults with acute bronchitis (International Classification of Diseases, Ninth Revision, Clinical Modification code 466.0). Time series analysis within a primary care network for 3 successive winter seasons from 2006 to 2009. All initial adult visits with a primary diagnosis code of 466.0 or 490 (bronchitis, not otherwise specified) were analyzed. Multivariable analysis accounted for clustering of observations by physician. The percentage of visits treated with antibiotics declined significantly for code 466.0 (76.8% to 74.4% to 27.0% of visits over the 3-year study period; P <.0001 for trend) but did not decline for code 490 (86.6% to 87.6% to 82.1% of visits; P = .33 for trend). Use of the 490 code rose significantly over the study period, from 1.5% of total bronchitis visits in year 1 to 84.6% of total bronchitis visits in year 3. As a result, the odds of an antibiotic prescription for codes 466 and 490 combined decreased slightly in year 3 compared with year 1 (odds ratio 0.88; 95% confidence interval 0.78-0.99). While performance on the specific HEDIS measure improved dramatically during this study period, overall antibiotic prescribing did not decline substantially. Quality measures that assess performance on specific diagnosis codes are imperfect and do not account for shifts in diagnosis coding.


The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence.
We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.


Morphological characterization of cherry rootstock candidates selected from Central and East Black Sea Regions in Turkey.
The use of rootstocks particularly for sweet cherry cultivars is of great importance for successful and sustainable production. Choosing the right cherry rootstocks is just as important as choosing the right cultivar. In this study, 110 sweet cherry, 30 sour cherry, and 41 mahaleb types displaying rootstock potential for sweet cherry cultivars were selected from Central and East Black Sea Regions in Turkey. The morphologic characteristics of the studied genotypes were compared with the standard clonal rootstocks PHL-A, MaxMa 14, Montmorency, Weiroot 158, Gisela 5, Gisela 6, and SL 64. A total of 42 morphological UPOV characteristics were evaluated in the selected genotypes and clonal rootstocks. The obtained data were analyzed by using principal component analysis and it revealed that eigenvalues of the first 3 components were able to represent 36.43% of total variance. The most significant positive correlations of the plant vigor were determined with leaf blade length and petiole thickness. According to the diversity analysis of coefficients, the 05 C 002 and 08 C 039 genotypes were identified as being similar (6.66), while the 05 C 002 and 55 S 012 genotypes were determined as the most distant genotypes (325.84) in terms of morphology.


Pore-forming toxins and cellular non-immune defenses (CNIDs).
Pore-forming toxins (PFTs) are the most common class of bacterial protein toxin and are important for bacterial pathogenesis. Recent studies have shown that the previous model stating that epithelial cells lyse in response to these toxins and have no defenses against these pores is oversimplified. Rather, it appears that cells have sophisticated mechanisms and signal-transduction pathways with which to respond to such an attack. There is a growing body of knowledge about how cells respond to and protect themselves against PFTs; this protection against PFTs is likely to be important in host survival to attack by bacterial pathogens, but does not neatly fit into current concepts of adaptive or innate immunity. Therefore, it is proposed that the terminology cellular non-immune defenses (CNIDs) be used to describe defenses that are employed by non-immune cells to protect against bacterial attack.


Doing without learning: stimulation of the frontal eye fields and floccular complex does not instruct motor learning in smooth pursuit eye movements.
Under natural conditions, motor learning is instructed by sensory feedback. We have asked whether sensory signals that indicate motor errors are necessary to instruct learning or if the motor signals related to movements normally driven by sensory error signals would be sufficient. We measured eye movements in trained rhesus monkeys while employing electrical microstimulation of the floccular complex of the cerebellum and the smooth eye movement region of the frontal eye fields to alter ongoing pursuit eye movements. Repeated electrical stimulation at fixed times after the onset of target motion and pursuit failed to cause any learning that was retained beyond the time period used to instruct learning. Learning was not uncovered when the target was stabilized with respect to the moving eye to prevent competition between instructive signals created by electrical stimulation and visual image motion signals evoked when stimulation drove the eye away from the tracking target. We suggest that signals emanating from motor-related structures in the pursuit circuit do not instruct learning. Instead, instructive sensory error signals seem to be necessary.


Impairments in working memory associated with naturalistic dieting in women: no relationship between task performance and urinary 5-HIAA levels.
The present study investigated the question of whether the previously observed impairments of working memory characteristic of dieting to lose weight can be explained in terms of preoccupying cognitions relating to body shape or to alterations in serotonergic function resulting from a low dietary intake of tryptophan. The population comprised female non-dieting, lower restrained eaters (N=23), non-dieting higher restrained eaters (N=11) and current dieters (N=19). Each participant completed three tasks, each of which selectively loaded on to a different sub-component of working memory. The tasks comprised the Tower of London task, a letter string recall task and a mental rotation task. In addition, all participants completed self-report measures of body shape concern and affective state. Serotonin turnover was assessed by means of 24 h urine sample collection for each participant on their day of testing. This was analysed (via HPLC) for levels of the main serotonin metabolite 5-HIAA.The results of the present study broadly replicated previous findings of a Central Executive and Phonological Loop (but not Visuo-Spatial Sketchpad) deficit in those subjects who reported themselves to be currently dieting. Tower of London task performance also significantly correlated with self-reported feelings of fatness and body shape disparagement. There were no group differences in 5-HIAA levels nor did 5-HIAA levels correlate with task performance. However, there was a significant negative correlation between 5-HIAA levels and self-reported depression. These results support the hypothesis that the variables mediating this deficit are preoccupying cognitions concerning body shape. They do not support the hypothesis that the serotonergic function of dieters is compromised, although this conclusion is tentative.


How close are we to incorporating measurable residual disease into clinical practice for acute myeloid leukemia?
Assessment of measurable residual disease, also called "minimal residual disease," in patients with acute myeloid leukemia in morphological remission provides powerful prognostic information and complements pretreatment factors such as cytogenetics and genomic alterations. Based on data that low levels of persistent or recurrent residual leukemia are consistently associated with an increased risk of relapse and worse long-term outcomes, its routine assessment has been recommended by some experts and consensus guidelines. In addition to providing important prognostic information, the detection of measurable residual disease may also theoretically help to determine the optimal post-remission strategy for an individual patient. However, the full therapeutic implications of measurable residual disease are uncertain and thus controversy exists as to whether it should be routinely incorporated into clinical practice. While some evidence supports the use of allogeneic stem cell transplantation or hypomethylating agents for some subgroups of patients in morphological remission but with detectable residual leukemia, the appropriate use of this information in making clinical decisions remains largely speculative at present. To resolve this pressing clinical issue, several ongoing studies are evaluating measurable residual disease-directed treatments in acute myeloid leukemia and may lead to new, effective strategies for patients in these circumstances. This review examines the common technologies used in clinical practice and in the research setting to detect residual leukemia, the major clinical studies establishing the prognostic impact of measurable residual disease in acute myeloid leukemia, and the potential ways, both now and in the future, that such testing may rationally guide therapeutic decision-making.


Buckling instabilities and spatio-temporal dynamics of active elastic filaments.
Biological filaments driven by molecular motors tend to experience tangential propulsive forces also known as active follower forces. When such a filament encounters an obstacle, it deforms, which reorients its follower forces and alters its entire motion. If the filament pushes a cargo, the friction on the cargo can be enough to deform the filament, thus affecting the transport properties of the cargo. Motivated by cytoskeletal filament motility assays, we study the dynamic buckling instabilities of a two-dimensional slender elastic filament driven through a dissipative medium by tangential propulsive forces in the presence of obstacles or cargo. We observe two distinct instabilities. When the filament's head is pinned or experiences significant translational but little rotational drag from its cargo, it buckles into a steadily rotating coiled state. When it is clamped or experiences both significant translational and rotational drag from its cargo, it buckles into a periodically beating, overall translating state. Using minimal analytically tractable models, linear stability theory and fully nonlinear computations, we study the onset of each buckling instability, characterize each buckled state, and map out the phase diagram of the system. Finally, we use particle-based Brownian dynamics simulations to show our main results are robust to moderate noise and steric repulsion. Overall, our results provide a unified framework to understand the dynamics of tangentially propelled filaments and filament-cargo assemblies.


Biogeography and biodiversity in sulfide structures of active and inactive vents at deep-sea hydrothermal fields of the Southern Mariana Trough.
The abundance, diversity, activity, and composition of microbial communities in sulfide structures both of active and inactive vents were investigated by culture-independent methods. These sulfide structures were collected at four hydrothermal fields, both on- and off-axis of the back-arc spreading center of the Southern Mariana Trough. The microbial abundance and activity in the samples were determined by analyzing total organic content, enzymatic activity, and copy number of the 16S rRNA gene. To assess the diversity and composition of the microbial communities, 16S rRNA gene clone libraries including bacterial and archaeal phylotypes were constructed from the sulfide structures. Despite the differences in the geological settings among the sampling points, phylotypes related to the Epsilonproteobacteria and cultured hyperthermophilic archaea were abundant in the libraries from the samples of active vents. In contrast, the relative abundance of these phylotypes was extremely low in the libraries from the samples of inactive vents. These results suggest that the composition of microbial communities within sulfide structures dramatically changes depending on the degree of hydrothermal activity, which was supported by statistical analyses. Comparative analyses suggest that the abundance, activity and diversity of microbial communities within sulfide structures of inactive vents are likely to be comparable to or higher than those in active vent structures, even though the microbial community composition is different between these two types of vents. The microbial community compositions in the sulfide structures of inactive vents were similar to those in seafloor basaltic rocks rather than those in marine sediments or the sulfide structures of active vents, suggesting that the microbial community compositions on the seafloor may be constrained by the available energy sources. Our findings provide helpful information for understanding the biogeography, biodiversity and microbial ecosystems in marine environments.


Development of a New Growth Standard for Breastfed Chinese Infants: What Is the Difference from the WHO Growth Standards?
The objectives of this longitudinal study were to examine the trajectory of breastfed infants' growth in China to update growth standards for early childhood, and to compare these updated Chinese growth standards with the growth standards recommended by the World Health Organization (WHO) in 2006.This longitudinal cohort study enrolled 1,840 healthy breastfed infants living in an "optimal" environment favorable to growth and followed up until one year of age from 2007 to 2010. The study subjects were recruited from 60 communities in twelve cities in China. A participating infant's birth weight was measured within the first hour of the infant's life, and birth length and head circumference within 24 hours after birth. Repeated weekly and monthly anthropometric measurements were also taken. Multilevel (ML) modelling via MLwiN2.25 was fitted to estimate the growth curves of weight-for-age (WFA), length-for-age (LFA), and head circumference-for-age (HFA) for the study sample as a whole and by child sex, controlling for mode of delivery, the gravidity and parity of the mother, infant's physical measurements at birth, infant's daily food intaking frequency per day, infant's medical conditions, the season when the infant's physical measurement was taken, parents' ages, heights, and attained education, and family structure and income per month. During the first four weeks after birth, breastfed infants showed an increase in weight, length, and head circumference of 1110g, 4.9 cm, and 3.2 cm, respectively, among boys, and 980 g, 4.4 cm, and 2.8 cm, respectively, among girls. Throughout infancy, the total growth for these three was 6930 g, 26.4 cm, and 12.5 cm, respectively, among boys, and 6480 g, 25.5 cm, and 11.7 cm, respectively, among girls. As expected, there was a significant sex difference in growth during the first year. In comparison with the WHO growth standards, breastfed children in our study were heavier in weight, longer in length, and bigger in head circumference, with the exception of a few age points during the first two to four months on the upper two percentile curves.Our data suggested the growth curves for breastfed infants in China were significantly different in comparison with those based on the WHO standards. The adoption of the WHO infant growth standards among Chinese infants, as well as the methods used in the development of such growth standards in China, need careful and coordinated consideration.


The mode of pheromone evolution: evidence from bark beetles.
Sex and aggregation pheromones consist of species-specific blends of chemicals. The way in which different species' blends have evolved has been the subject of some debate. Theoretical predictions suggest that differences between species have arisen not through the accruing of small changes, but through major shifts in chemical composition. Using data on the aggregation pheromones of 34 species of bark beetle from two genera, Dendroctonus and Ips, we investigated how the distributions of the chemical components of their pheromone blends mirror their phylogenetic relationships. We tested whether there were consistent patterns that could be used to help elucidate the mode of pheromone evolution. Although there were obvious differences in pheromone blends between the two genera, the differences between species within each genus followed a less clear phylogenetic pattern. In both genera, closely related species are just as different as more distantly related species. Within Dendroctonus, particularly, most chemical components were distributed randomly across the phylogeny. Indeed, for some chemicals, closely related species may actually be more different than would be expected from a random distribution of chemical components. This argues strongly against the idea of minor shifts in pheromone evolution. Instead, we suggest that, within certain phylogenetic constraints, pheromone evolution in bark beetles is characterized by large saltational shifts, resulting in sibling species being substantially phenotypically (i.e. pheromonally) different from one another, thus agreeing with theoretical predictions.


Monoamine and amino acid content in brain regions of Brattleboro rats.
Monoamine and amino acid content were measured in brain regions from 12 week old male, homozygous Brattleboro (DI, n = 12) and Long-Evans control (LE, n = 12) rats. Norepinephrine (NE) content was significantly elevated (16-25%) in the spinal cord, pons-medulla and anterior hypothalamus of DI rats when compared to LE controls. NE content of the neurointermediate lobe of pituitary in DI rats was almost twice that of LE controls. Serotonin content was also significantly elevated in the spinal cord, pons-medulla, anterior hypothalamus and forebrain of DI rats relative to the LE controls. Taurine content in DI rats was increased (31-42%) above that of LE rats in the anterior hypothalamus, striatum and forebrain. Glutamine content was also greater in DI rats than LE in the spinal cord, pons-medulla, anterior hypothalamus, striatum, hippocampus and forebrain. The changes in monoamine and amino acid content were discussed in relation to the cardiovascular and osmoregulatory deficits that are present in DI rats due to arginine vasopressin (AVP) deficiency. The possible role of AVP in modulating NE turnover was also discussed. The increase in brain TAU content in DI rats may be a physiological response to hypernatremia.


Adaptor heat shock protein complex formation regulates trafficking of the asialoglycoprotein receptor.
In the asialoglycoprotein receptor (ASGPR) endocytic pathway, internalized receptors pass through early, recycling, and sorting endosomal compartments before returning to the cell surface. Sorting motifs in the cytoplasmic domain (CD) and protein interactions with these sequences presumably direct receptor trafficking. Previous studies have shown that association of a potential sorting heat shock protein (HSP) heterocomplex with the ASGPR-CD was regulated by casein kinase 2 (CK2)-mediated phosphorylation. Mass spectrometry and immunoblot analyses identified five of these ASGPR-CD-associated proteins as the molecular chaperones glycoprotein 96, HSP70, HSP90, cyclophilin A, and FK 506 binding protein. The present study was undertaken to determine whether any of the adaptor protein complexes (AP1, AP2, or AP3) were selectivity associated with the ASGPR-CD. In conjunction with molecular chaperones, AP2 and AP1 were recovered from a CK2 phosphorylated agarose-GSH-GST-ASGPR-CD matrix. Binding of AP3 was independent of the phosphorylation status of the CD matrix. Inhibition of CK2-mediated phosphorylation with tetrabromobenzotriazole prevented AP recovery within an immunoadsorbed ASGPR complex. Rapamycin, which dissociates the HSP heterocomplex from ASGPR-CD, thereby altering receptor trafficking also, inhibited AP association. Similar results were obtained with an inhibitor of HSP90 heterocomplex formation, geldanmycin. The data presented provide evidence that recruitment of AP1 and AP2, which is necessary for appropriate receptor trafficking, is mediated by the interaction of AP with the ASGPR-CD-bound HSP complex.


The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.
Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.


Unique physicochemical properties of perfluorinated compounds and their bioconcentration in common carp Cyprinus carpio L.
Carp (Cyprinus carpio L.) was exposed to perfluorinated compounds (PFCs)-perfluoroalkyl carboxylic acids (number of carbon atoms, C = 8, 11, 12, 14, 16, and 18) and perfluorooctane sulfonate (PFOS)-in bioconcentration tests to compare the bioconcentration factors (BCFs) and physicochemical properties of each specific compound. Despite having the same number of carbon atoms (C = 8), the BCFs of perfulorooctanoic acid (PFOA) and PFOS differed by more than two orders of magnitude (PFOA BCF = < 5.1 to 9.4; PFOS BCF = 720 to 1300). The highest BCFs were obtained from perfluorododecanoic acid (BCF = 10,000 to 16,000) and perfluorotetradecanoic acid (BCF = 16,000 to 17,000). The longest observed depuration half-lives were for perfluorohexadecanoic acid (48 to 54 days) and PFOS (45 to 52 days). The concentrations of PFCs were highest in the viscera, followed by the head, integument, and remaining parts of the test fish. PFCs concentrations in the integument, which was in direct contact with the test substances, were relatively greater than that of other lipophilic substance (hexachlorobenzene). It is likely that Clog P would be a better parameter than log K (ow) for the prediction of BCFs for PFCs. Threshold values for PFCs bioaccumulation potential (molecular weight = 700, maximum diameter = 2 nm) seemed to deviate from those generally reported because of the specific steric bulk effect of molecule size.


Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection.
The objective of the present study was to evaluate whether vascular endothelial growth factor (VEGF)-induced penile erection is mediated by activation of endothelial nitric oxide synthase (eNOS) through its phosphorylation. We assessed the role of constitutively activated eNOS in VEGF-induced penile erection using wild-type (WT) and eNOS-knockout (eNOS(-/-)) mice with and without vasculogenic erectile dysfunction. Adult WT and eNOS(-/-) mice were subjected to sham operation or bilateral castration to induce vasculogenic erectile dysfunction. At the time of surgery, animals were injected intracavernosally with a replication-deficient adenovirus expressing human VEGF145 (10(9) particle units) or with empty virus (Ad.Null). After 7 days, erectile function was assessed in response to cavernous nerve electrical stimulation. Total and phosphorylated protein kinase B (Akt) as well as total and phosphorylated eNOS were quantitatively assessed in mice penes using Western immunoblot and immunohistochemistry. In intact WT mice, VEGF145 significantly increased erectile responses, and in WT mice after castration, it completely recovered penile erection. However, VEGF145 failed to increase erectile responses in intact eNOS(-/-) mice and only partially recovered erectile function in castrated eNOS(-/-) mice. In addition, VEGF145 significantly increased phosphorylation of eNOS at Serine 1177 by approximately 2-fold in penes of both intact and castrated WT mice. The data provide a molecular explanation for VEGF stimulatory effect on penile erection, which involves phosphorylated eNOS (Serine 1177) mediation.


Hemispheric lateralization in reasoning.
A growing body of evidence suggests that reasoning in humans relies on a number of related processes whose neural loci are largely lateralized to one hemisphere or the other. A recent review of this evidence concluded that the patterns of lateralization observed are organized according to two complementary tendencies. The left hemisphere attempts to reduce uncertainty by drawing inferences or creating explanations, even at the cost of ignoring conflicting evidence or generating implausible explanations. Conversely, the right hemisphere aims to reduce conflict by rejecting or refining explanations that are no longer tenable in the face of new evidence. In healthy adults, the hemispheres work together to achieve a balance between certainty and consistency, and a wealth of neuropsychological research supports the notion that upsetting this balance results in various failures in reasoning, including delusions. However, support for this model from the neuroimaging literature is mixed. Here, we examine the evidence for this framework from multiple research domains, including an activation likelihood estimation analysis of functional magnetic resonance imaging studies of reasoning. Our results suggest a need to either revise this model as it applies to healthy adults or to develop better tools for assessing lateralization in these individuals.


TNFalpha-induced macrophage chemokine secretion is more dependent on NF-kappaB expression than lipopolysaccharides-induced macrophage chemokine secretion.
The transcription factor NF-kappaB is a pivotal intracellular regulator of many inflammatory responses and it has been proposed that it represents a potential therapeutic target. As chemokines are important for the progress of an inflammatory response by the recruitment of immuno-competent cells, the role NF-kappaB plays in TNFalpha- or lipopolysaccharides (LPS)-induced chemokine secretion by human monocyte-derived macrophages was examined. Secretion of the CXC chemokines IL-8, GROalpha and ENA-78, induced by TNFalpha, was significantly suppressed by inhibiting NF-kappaB, using overexpression of IkappaBalpha. However, when induced by LPS the expression of these chemokines was unaffected. In contrast, expression of the CC chemokines MIP-1alpha, MCP-1 and RANTES inducedby TNFalpha or LPS was significantly inhibited by the overexpression of IkappaBalpha. Therefore, there appear to be different mechanisms regulating CC and CXC chemokine secretion by macrophages, depending on the stimulus and that TNFalpha and LPS can use different signaling mechanisms in macrophages to regulate chemokine synthesis.


Descriptive Study of Employee Engagement With Workplace Wellness Interventions in the UK.
To explore sequential steps of employee engagement in wellness interventions and the impact of wellness interventions on employee health. Using previously collected survey data from 23,667 UK employees, we tabulated intervention availability, awareness, participation, and associated health improvement and compared engagement by participation and risk status. Employees' awareness of wellness interventions at their workplaces was often low (mean 43.3%, range 11.6%-82.3%). Participation was highest in diet/nutrition initiatives (94.2%) and lowest in alcohol counseling and smoking cessation interventions (2.1%). Employees with health risks were less likely than lower-risk employees to report awareness, participation, and health improvements from wellness interventions addressing the relevant health concern. Employers and policymakers should consider variation in intervention engagement as they plan and implement wellness interventions. Engaging employee populations with higher health risks requires a more targeted approach.


Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis.
Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results. The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug. In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.


Towards Semantic e-Science for Traditional Chinese Medicine.
Recent advances in Web and information technologies with the increasing decentralization of organizational structures have resulted in massive amounts of information resources and domain-specific services in Traditional Chinese Medicine. The massive volume and diversity of information and services available have made it difficult to achieve seamless and interoperable e-Science for knowledge-intensive disciplines like TCM. Therefore, information integration and service coordination are two major challenges in e-Science for TCM. We still lack sophisticated approaches to integrate scientific data and services for TCM e-Science. We present a comprehensive approach to build dynamic and extendable e-Science applications for knowledge-intensive disciplines like TCM based on semantic and knowledge-based techniques. The semantic e-Science infrastructure for TCM supports large-scale database integration and service coordination in a virtual organization. We use domain ontologies to integrate TCM database resources and services in a semantic cyberspace and deliver a semantically superior experience including browsing, searching, querying and knowledge discovering to users. We have developed a collection of semantic-based toolkits to facilitate TCM scientists and researchers in information sharing and collaborative research. Semantic and knowledge-based techniques are suitable to knowledge-intensive disciplines like TCM. It's possible to build on-demand e-Science system for TCM based on existing semantic and knowledge-based techniques. The presented approach in the paper integrates heterogeneous distributed TCM databases and services, and provides scientists with semantically superior experience to support collaborative research in TCM discipline.


Evaluating hypotheses of basal animal phylogeny using complete sequences of large and small subunit rRNA.
We studied the evolutionary relationships among basal metazoan lineages by using complete large subunit (LSU) and small subunit (SSU) ribosomal RNA sequences for 23 taxa. After identifying competing hypotheses, we performed maximum likelihood searches for trees conforming to each hypothesis. Kishino-Hasegawa tests were used to determine whether the data (LSU, SSU, and combined) reject any of the competing hypotheses. We also conducted unconstrained tree searches, compared the resulting topologies, and calculated bootstrap indices. Shimodaira-Hasegawa tests were applied to determine whether the data reject any of the topologies resulting from the constrained and unconstrained tree searches. LSU, SSU, and the combined data strongly contradict two assertions pertaining to sponge phylogeny. Hexactinellid sponges are not likely to be the basal lineage of a monophyletic Porifera or the sister group to all other animals. Instead, Hexactinellida and Demospongia form a well-supported clade of siliceous sponges, Silicea. It remains unclear, on the basis of these data alone, whether the calcarean sponges are more closely related to Silicea or to nonsponge animals. The SSU and combined data reject the hypothesis that Bilateria is more closely related to Ctenophora than it is to Cnidaria, whereas LSU data alone do not refute either hypothesis. LSU and SSU data agree in supporting the monophyly of Bilateria, Cnidaria, Ctenophora, and Metazoa. LSU sequence data reveal phylogenetic structure in a data set with limited taxon sampling. Continued accumulation of LSU sequences should increase our understanding of animal phylogeny.


Evaluation of a quantitative magnetic resonance imaging system for whole body composition analysis in rodents.
We evaluated the EchoMRI-900 combination rat and mouse quantitative magnetic resonance (QMR) body composition method in comparison to traditional whole-body chemical carcass composition analysis (CCA) for measurements of fat and fat-free mass in rodents. Live and postmortem (PM) QMR fat and lean mass measurements were obtained for lean, obese and outbred strains of rats and mice, and compared with measurements obtained using CCA. A second group of rats was measured before and after 18 h food or water deprivation. Significant positive correlations between QMR and CCA fat and lean mass measurements were shown for rats and mice. Although all live QMR fat and lean measurements were more precise than CCA for rats, values obtained for mice significantly differed from CCA for lean mass only. QMR performed PM slightly overestimated fat and lean values relative to live QMR but did not show lower precision than live QMR. Food deprivation reduced values for both fat and lean mass; water deprivation reduced estimates of lean mass only. In summary, all measurements using this QMR system were comparable to those obtained by CCA, but with higher overall precision, similar to previous reports for the murine QMR system. However, PM QMR measurements slightly overestimated live QMR values, and lean and fat mass measurements in this QMR system are influenced by hydration status and animal size, respectively. Despite these caveats, we conclude that the EchoMRI QMR system offers a fast in vivo method of body composition analysis, well correlated to but with greater overall precision than CCA.


Paraneoplastic neurological disorders in children with benign ovarian tumors.
Paraneoplastic neurological diseases (PND) are rare, but potentially treatable disorders. Paraneoplastic encephalitis is rapidly emerging as an important but likely under-recognized condition in children. The aim of this study was to assess the prevalence and spectrum of PND in children with benign ovary tumor and the long-term outcome. We retrospectively reviewed the charts of all female patients below 18years of age diagnosed with a benign ovarian tumor proven by pathology between January 1993 and December 2010. All the clinical symptoms developed within 5years of tumor diagnosis and the related investigations were recorded. There were total 133 children and adolescents with benign ovarian tumors, mostly mature teratoma. Six patients (4.5%) had neuropsychiatric manifestations and all but one were beyond age 10years. The most common neuropsychiatric presentations were depression or low mood (84%), headache (50%), mutism (50%), hypoventilation (50%), seizures (30%), hallucination (30%), vomiting and hypersalivation (30%). Three patients (2.2%) had serious PND including acute disseminated encephalomyelitis in 1 and anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in 2. Although all of three improved after tumor removal, one without immunotherapy had neurological sequelae and prolonged ICU stay. The prevalence of PND in benign ovary tumor is not so uncommon in children. It is important to survey ovary tumors in female adolescents with subacute presentation of multiple-level involvement of neuraxis where no clear alternate diagnosis is possible. Treatment of serious PND associated with ovary tumors should include immunotherapy in addition to tumor removal.


Metal mesh interference filters for the far infrared.
Far ir Fabry-Perot type interference filters consisting of two parallel, closely spaced metal meshes have been reported by others. Using improved techniques, filters of this type have been fabricated with larger finesse and peak transmittance. Measured transmittance curves, obtained with the Aerospace lamellar grating interferometer have led to transmittance peaks whose sharpness appears to be limited principally by the beam convergence angle within the instrument (8 degrees ). From the measured peaks, finesses as large as 100 are obtained. Available mesh materials permit the construction of filters for any frequency from 10 cm(-1) (or lower) to at least 200 cm(-1). These will require absorbing components to eliminate unwanted harmonics.