Clinical characteristics of potential kidney donors with asymptomatic kidney stones.
Patients with symptomatic kidney stones are characterized by older age, male gender, white race, hypertension, obesity, metabolic syndrome and chronic kidney disease. Whether these characteristics differ in patients with asymptomatic kidney stones is unknown. All potential kidney donors who underwent protocol computed tomography angiograms/urograms (2000-08) at the Mayo Clinic were identified. Renal abnormalities, including kidney stones, were assessed radiographically. Comorbidities, including past symptomatic kidney stones, were abstracted from the medical record. Characteristics of persons with and without radiographic stones were compared. Stone burden among persons with and without past symptomatic stones was compared. Among 1957 potential kidney donors, 3% had past symptomatic stones and 11% had radiographic stones (10% had only asymptomatic radiographic stones). Asymptomatic stone formers were more likely to be of white race, have low urine volumes and have radiographic findings of renal parenchymal thinning, focal renal scarring, medullary sponge kidney and polycystic kidney disease. Asymptomatic stone formers were not characterized by older age, male gender, hypertension, obesity, metabolic syndrome, abnormal kidney function, hyperuricemia, hypercalcemia or hypophosphatemia. Among persons with radiographic stones, those with past symptomatic stones had a slightly higher number of stones (mean 2.7 versus 2.4; P = 0.04), but a much greater diameter for the largest stone (mean 4.8 versus 1.6 mm; P < 0.001). Asymptomatic kidney stone formers have different demographic characteristics and many lack the comorbidities that have been described in persons with symptomatic kidney stones. These findings suggest that different pathophysiologic mechanisms could be involved in asymptomatic stone formation versus symptomatic stone passage.


Targeting the WASF3-CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion.
Activation of the WASF3 protein by extracellular stimuli promotes actin cytoskeleton reorganization and facilitates cancer cell invasion, whereas WASF3 depletion suppresses invasion and metastasis. In quiescent cells, the interaction between WASF3 and a complex of proteins, including CYFIP1, acts as a conformational restraint to prevent WASF3 activation. Therefore, we took advantage of this endogenous regulatory mechanism to investigate potential sites that disrupt WASF3 function. Here, we show that genetic knockdown of CYFIP1 in cancer cells led to the destabilization of the WASF3 complex, loss of WASF3 function, and suppressed invasion. Based on existing crystallographic data, we developed stapled peptides, referred to as WASF Helix Mimics (WAHM), that target an α-helical interface between WASF3 and CYFIP1. Treatment of highly invasive breast and prostate cancer cells with WAHM inhibitor peptides significantly reduced motility and invasion in vitro. Mechanistic investigations revealed that these inhibitors suppressed the interaction between Rac and the WASF3 complex, which has been shown to promote cell migration. Furthermore, peptide-mediated inhibition of WASF3 also resulted in the dysregulation of known downstream targets such as MMP-9 and KISS1. Finally, we demonstrate that this invasive phenotype is specific to WASF3 as depletion of WASF1 and WASF2, which can also bind to CYFIP1, did not affect invasion. Collectively, our findings suggest that targeting WASF3 function with WAHM peptides could represent a promising therapeutic strategy for preventing tumor invasion and metastasis.


Serum proBDNF/BDNF and response to fluvoxamine in drug-naïve first-episode major depressive disorder patients.
We investigated the association between serum proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and response to fluvoxamine in patients with major depressive disorder (MDD) using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR): physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Fifty-one patients with MDD (M/F, 19:32; age, 38 ± 19 years) and 51 healthy controls (M/F, 22:29; age, 34 ± 17 years) were studied using DSM-IV-TR: physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Serum levels of proBDNF and MDNF were measured by sandwich enzyme-linked immunosorbent assay (ELISA). Serum mature BDNF levels in the MDD patients were significantly lower than those in the healthy controls (t = 3.046, p = 0.0018). On the other hand, no difference was found in serum proBDNF between the MDD patients and the healthy controls (t = -0.979, p = 0.833). A trend of negative correlation was found between baseline serum BDNF and baseline scores of the 17 items of the Hamilton Rating Scale for Depression (HAMD17) (r = -0.183, p = 0.071). No correlation was however found between HAMD17 scores and proBDNF at baseline (r = 0.092, p = 0.421). Furthermore, no correlation was observed between baseline HAMD17 scores and baseline proBDNF/BDNF (r = -0.130, p = 0.190). No changes were observed in serum levels of proBDNF and BDNF during the treatment periods. These results suggest that there is no association between serum proBDNF/BDNF and fluvoxamine response in MDD patients at least within 4 weeks of the treatment.


Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research.


Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.
Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.


Convincing similar and dissimilar others: the power of language abstraction in political communication.
Three studies examined the production of political messages and their persuasive impact on recipients as a function of speaker-audience similarity. The first two studies found support for the hypothesis that political leaders (Study 1) and party activists (Study 2) formulate more abstract messages when the audience is politically similar to them than when the audience is dissimilar or heterogeneous. The third study examined the persuasive impact of message abstractness versus concreteness. We predicted and found that abstract messages are more effective in convincing an audience whose political positions are similar to the speaker's and concrete messages are more effective in convincing an audience whose political positions differ from the speaker's or are heterogeneous. Implications of these findings for the relation between language and social cognition are discussed.


Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats.
Magnetic resonance imaging (MRI) techniques were used to determine the effect of preexisting hyperglycemia on the extent of cerebral ischemia/reperfusion injury and the level of cerebral perfusion. Middle cerebral artery occlusion (MCAO) was induced by a suture insertion technique. Forty one rats were divided into hyperglycemic and normoglycemic groups with either 4 hours of continuous MCAO or 2 hours of MCAO followed by 2 hours of reperfusion. Diffusion-weighted imaging (DWI) was performed at 4 hours after MCAO to quantify the degree of injury in 6 brain regions. Relative cerebral blood flow (CBF) and cerebral blood volume (CBV) were estimated using gradient echo (GE) bolus tracking and steady-state spin echo (SE) imaging techniques, respectively. Brain injury correlated with the perfusion level measured in both SE CBV and dynamic GE CBF images. In the temporary MCAO model, mean lesion size in DWI was 118% larger and hemispheric CBV was reduced by 37% in hyperglycemic compared with normoglycemic rats. Hyperglycemia did not significantly exacerbate brain injury or CBV deficit in permanent MCAO models. We conclude that preexisting hyperglycemia increases acute postischemic MRI-measurable brain cellular injury in proportion to an associated increased microvascular ischemia.


The 2006-2010 National Survey of Family Growth: sample design and analysis of a continuous survey.
The National Survey of Family Growth (NSFG) collects data on pregnancy, childbearing, men's and women's health, and parenting from a national sample of women and men 15-44 years of age in the United States. This report describes the sample design for the NSFG's new continuous design and the effects of that design on weighting and variance estimation procedures. A working knowledge of this information is important for researchers who wish to use the data. Two data files are being released--the first covering 2.5 years (30 months) of data collection and the second after all data have been collected. This report is being released with the first data file. A later report in this Series will include specific results of the weighting, imputation, and variance estimation. The NSFG's new design is based on an independent, national probability sample of women and men 15-44 years of age. Fieldwork was carried out by the University of Michigan's Institute for Social Research (ISR) under a contract with the National Center for Health Statistics (NCHS). In-person, face-to-face interviews were conducted by professional female interviewers using laptop computers. Analysis of NSFG data requires the use of sampling weights and estimation of sampling errors that account for the complex sample design and estimation features of the survey. Sampling weights are provided on the data files. The rate of missing data in the survey is generally low. However, missing data were imputed for about 600 key variables (called "recodes") that are used for most analyses of the survey. Imputation was accomplished using a multiple regression procedure with software called IVEware, available from the University of Michigan website.


Seizures as a predictor of long-term neurodevelopmental outcome in survivors of neonatal extracorporeal membrane oxygenation (ECMO).
A longitudinal, prospective study was conducted to determine the long-term neurodevelopmental outcome in neonatal extracorporeal membrane oxygenation (ECMO) survivors with and without seizures. One hundred sixty-two ECMO survivors from March 1985 until November 1995 were eligible for follow-up. Sixty-four returned at preschool age (4-6 years). Thirty-nine infants did not experience neonatal seizures (group 1); however, 25 exhibited seizures before or during ECMO (group 2). Twelve infants referred for ECMO, but managed medically, served as a clinical comparison group (group 3). At school age (7-9 years), 32 ECMO children (16 with seizures) returned for neuropsychologic evaluation. The results indicated that the preschool seizure group (group 2) demonstrated a significantly lower mean IQ than group 1 or 3 (P = .002). Furthermore, 56% of group 2 had IQ scores < or =84 (> or =1 SD below the mean). Group 2 also exhibited significantly higher rates of cerebral palsy (P < or = .001) and speech-language disorder than group 1 or 3 (P < .001). At school age, the seizure group continued to perform below average on intelligence testing, with 50% scoring < or =84 and 38% receiving special education. This study extends the previous findings that seizures associated with neonatal ECMO are a primary risk factor for neurodevelopmental sequelae and confirms the need for long-term follow-up to assist with academic programming.


Hereditary bone dysplasia with pathological fractures and nodal osteoarthropathy.
A father and daughter both had multiple pathological fractures and nodal osteoarthropathy. The father, aged 50 years, had at least 20 healed fractures of the axial and appendicular skeleton, sustained by minor trauma over his 50-year lifespan, many of which had been surgically fixed prior to his first presentation to us. Fractures of the clavicles, thoracic cage and long bones of the arms and legs, had healed with malalignment and deformity. Healed fractures were complicated by ankylosis of the cervical vertebrae and both elbows. He also had osteoarthritis of the hands, with exuberant osteophytosis, and profound perceptive deafness. His general health was good, his intellect and facies were normal, and his sclerae were white. The daughter, aged 27 years, had sustained at least seven fractures of the axial and appendicular skeleton following trivial injuries, in distribution similar to those of the father.She had also experienced painful swelling of the fingers,which preceded progressive development of nodal osteoarthropathy.Her hearing was normal. In both individuals,biochemical and immunological investigations yielded normal results. It was not possible for molecular studies to be undertaken. Pedigree data were consistent with autosomal dominant transmission, and this disorder appeared to be a previously undocumented heritable skeletal dysplasia.


Impacts of climate change on public health in India: future research directions.
Climate change and associated increases in climate variability will likely further exacerbate global health disparities. More research is needed, particularly in developing countries, to accurately predict the anticipated impacts and inform effective interventions. Building on the information presented at the 2009 Joint Indo-U.S. Workshop on Climate Change and Health in Goa, India, we reviewed relevant literature and data, addressed gaps in knowledge, and identified priorities and strategies for future research in India. The scope of the problem in India is enormous, based on the potential for climate change and variability to exacerbate endemic malaria, dengue, yellow fever, cholera, and chikungunya, as well as chronic diseases, particularly among the millions of people who already experience poor sanitation, pollution, malnutrition, and a shortage of drinking water. Ongoing efforts to study these risks were discussed but remain scant. A universal theme of the recommendations developed was the importance of improving the surveillance, monitoring, and integration of meteorological, environmental, geospatial, and health data while working in parallel to implement adaptation strategies. It will be critical for India to invest in improvements in information infrastructure that are innovative and that promote interdisciplinary collaborations while embarking on adaptation strategies. This will require unprecedented levels of collaboration across diverse institutions in India and abroad. The data can be used in research on the likely impacts of climate change on health that reflect India's diverse climates and populations. Local human and technical capacities for risk communication and promoting adaptive behavior must also be enhanced.


Computationally Efficient Algorithms for Sparse, Dynamic Solutions to the EEG Source Localization Problem.
Electroencephalography (EEG) and magnetoencephalography noninvasively record scalp electromagnetic fields generated by cerebral currents, revealing millisecond-level brain dynamics useful for neuroscience and clinical applications. Estimating the currents that generate these fields, i.e., source localization, is an ill-conditioned inverse problem. Solutions to this problem have focused on spatial continuity constraints, dynamic modeling, or sparsity constraints. The combination of these key ideas could offer significant performance improvements, but substantial computational costs pose a challenge for practical application of such approaches. Here, we propose a new method for EEG source localization that combines: 1) covariance estimation for both source and measurement noises; 2) linear state-space dynamics; and 3) sparsity constraints, using 4) novel computationally efficient estimation algorithms. For source covariance estimation, we use a locally smooth basis alongside sparsity enforcing priors. For EEG measurement noise covariance estimation, we use an inverse Wishart prior density. We estimate these model parameters using an expectation-maximization algorithm that employs steady-state filtering and smoothing to expedite computations. We characterized the performance of our method by analyzing simulated data and experimental recordings of eyes-closed alpha oscillations. Our sparsity enforcing priors significantly improved estimation of both the spatial distribution and time course of simulated data, while improving computational time by more than 12-fold over previous dynamic methods. We developed and demonstrated a novel method for improved EEG source localization employing spatial covariance estimation, dynamics, and sparsity. Our approach provides substantial performance improvements over existing methods using computationally efficient algorithms that will facilitate practical applications in both neuroscience and medicine.


Anticataleptic activity of Zamzam water in chlorpromazine induced animal model of Parkinson disease.
Parkinsonism is characterized by rest tremor, inflexibility, balance debilitation, slow motion and dementia. It is known to be caused by the deficiency of dopaminergic neurons in nigrostriatal pathway. Different studies propose that oxidative burden may be included in the apoptotic process in parkisnons disease. Zamzam water being alkaline in composition may diminish the oxidative stress and hence relieve the symptoms. Therefore, the purpose of this study was to explore the neuroprotective effect of zamzam water in chlorpromazine induced animal model of Parkinsonism. Results revealed that zamzam water did not show significant anticataleptic effect after 21 days as compared to chlorpromazine treated group. However, after 30 days of giving zamzam water showed highly significant decrease (p<0.001) in cataleptic score as compared to chlorpromazine treated group that is negative control. After 30 days of dosing, cataleptic scores by zamzam water were closer to standard drug but standard drug (levodopa/carbidopa) still showed better results than zamzam water. Results from histopathological study of rat's brain also revealed regenerative changes by zamzam treated water when compared with negative control. This regenerative change after zamzam water treatment might play a positive role in future if administered continuously. These results also suggest that zamzam water can be used in combination with standard drug to produce synergistic effect in the management of parkinsons disease.


Voice Recognition in Face-Blind Patients.
Right or bilateral anterior temporal damage can impair face recognition, but whether this is an associative variant of prosopagnosia or part of a multimodal disorder of person recognition is an unsettled question, with implications for cognitive and neuroanatomic models of person recognition. We assessed voice perception and short-term recognition of recently heard voices in 10 subjects with impaired face recognition acquired after cerebral lesions. All 4 subjects with apperceptive prosopagnosia due to lesions limited to fusiform cortex had intact voice discrimination and recognition. One subject with bilateral fusiform and anterior temporal lesions had a combined apperceptive prosopagnosia and apperceptive phonagnosia, the first such described case. Deficits indicating a multimodal syndrome of person recognition were found only in 2 subjects with bilateral anterior temporal lesions. All 3 subjects with right anterior temporal lesions had normal voice perception and recognition, 2 of whom performed normally on perceptual discrimination of faces. This confirms that such lesions can cause a modality-specific associative prosopagnosia.


A soft-bodied lophophorate from the Silurian of England.
Soft-bodied taxa comprise an important component of the extant lophophorate fauna, but convincing fossils of soft-bodied lophophorates are extremely rare. A small fossil lophophorate, attached to a brachiopod dorsal valve, is described from the Silurian (Wenlock Series) Herefordshire Lagerstätte of England. This unmineralized organism was bilaterally symmetrical and comprised a subconical body attached basally to the host and partially enclosed by a broad 'hood'; the body bore a small, coiled lophophore. Where the hood attached laterally, there is a series of transverse ridges and furrows. The affinities of this organism probably lie with Brachiopoda; the hood is interpreted as the homologue of a dorsal valve/mantle lobe, and the attachment as the homologue of the ventral valve and/or pedicle. The ridges are arranged in a manner that suggests constructional serial repetition, indicating that they are unlikely to represent mantle canals. Extant brachiopods are not serially structured, but morphological and molecular evidence suggests that their ancestors were. The new organism may belong to the brachiopod stem group, and might also represent a significant element of the Palaeozoic lophophorate fauna.


Responses of a model legume Lotus japonicus to lipochitin oligosaccharide nodulation factors purified from Mesorhizobium loti JRL501.
Lotus japonicus has been proposed as a model legume for molecular genetic studies of symbiotic plant-microbe interactions leading to the fixation of atmospheric nitrogen. Lipochitin oligosaccharides (LCOs), or Nod factors, were isolated from the culture of Mesorhizobium loti strain JRL501 (MAFF303099), an efficient microsymbiont of L. japonicus B-129 cv. Gifu. High-performance liquid chromatography and mass spectrometric analyses allowed us to identify at least five different structures of LCOs that were produced by JRL501. The major component was NodMl-V(C18:1, Me, Cb, AcFuc), an N-acetyl-glucosamine pentamer in which the nonreducing residue is N-acylated with a C18:1 acyl moiety, N-methylated, and carries a carbamoyl group and the reducing N-acetylglucosamine residue is substituted with 4-O-acetyl-fucose. Additional novel LCO structures bearing fucose instead of acetyl-fucose at the reducing end were identified. Mixtures of these LCOs could elicit abundant root hair deformation on L. japonicus roots at a concentration of 10(-7) to 10(-9) M. Spot inoculation of a few nanograms of LCOs on L. japonicus roots induced the formation of nodule primordia in which the early nodulin genes, ENOD40 and ENOD2, were expressed in a tissue-specific manner. We also observed the formation of a cytoplasmic bridge (preinfection thread) in the swollen outermost cortical cells. This is the first description of cytoplasmic bridge formation by purified LCOs alone in a legume-forming determinate nodules.


Health care utilisation and out-of-pocket expenditure associated with back pain: a nationally representative survey of Australian women.
Back pain impacts on a significant proportion of the Australian population over the life course and has high prevalence rates among women, particularly in older age. Back pain care is characterised by multiple practitioner and self-prescribed treatment options, and the out-of-pocket costs associated with consultations and self-prescribed treatments have not been examined to date. To analyse the extent of health care practitioner consultations and self-prescribed treatment for back pain care among Australian women, and to assess the self-reported costs associated with such usage. Survey of 1,310 women (response rate 80.9%) who reported seeking help for back pain from the '1946-51 cohort' of the Australian Longitudinal Study on Women's Health. Women were asked about their use of health care practitioners and self-prescribed treatments for back pain and the costs associated with such usage. In the past year 76.4% consulted a complementary and alternative practitioner, 56% an allied health practitioner and 59.2% a GP/medical specialist. Overall, women consulted with, on average, 3.0 (SD = 2.0) different health care practitioners, and had, on average, 12.2 (SD = 9.7) discrete health care practitioner consultations for back pain. Average self-reported out-of-pocket expenditure on practitioners and self-prescribed treatments for back pain care per annum was AU$873.10. Multiple provider usage for various but distinct purposes (i.e. pain/mobility versus anxiety/stress) points to the need for further research into patient motivations and experiences of back pain care in order to improve and enhance access to and continuity of care. Our results suggest that the cost of back pain care represents a significant burden, and may ultimately limit women's access to multiple providers. We extrapolate that for Australian working-age women, total out-of-pocket expenditure on back pain care per annum is in excess of AU$1.4 billion, thus indicating the prominence of back pain as a major economic, social and health burden.


Prevalence of cognitive impairment in patients with substance use disorder.
Cognitive impairments in substance use disorder predict treatment outcome and are assumed to differ between substances. They often go undetected, thus the current study focuses on the prevalence of and differences in cognitive functioning across substances by means of a cognitive screen at the early stage of addiction treatment. The Montreal Cognitive Assessment was administered to outpatients seeking treatment for substance use disorder. Patient characteristics (age, years of regular use, polysubstance use, severity of dependence/abuse, depression, anxiety and stress) were also taken into account. A total of 656 patients were included (n = 391 used alcohol, n = 123 used cannabis, n = 100 used stimulants and n = 26 used opioids). The prevalence of cognitive impairments was 31%. Patients using alcohol had a lower total- and memory domain score than those using cannabis. Patients using opioids scored lower on visuospatial abilities than those using cannabis or stimulants. Younger patients scored higher than older patients. No effect was found for the other investigated characteristics. Given the high prevalence of cognitive impairments, standard screening at an early stage of treatment is important to determine the course of treatment and maximise treatment outcome. Caution is needed in interpreting results about opioids due to an underrepresentation of this patient group, and more research is needed on the effect of age on Montreal Cognitive Assessment performance.


The impact of childhood obesity on musculoskeletal form.
Despite the greater prevalence of musculoskeletal disorders in obese adults, the consequences of childhood obesity on the development and function of the musculoskeletal system have received comparatively little attention within the literature. Of the limited number of studies performed to date, the majority have focused on the impact of childhood obesity on skeletal structure and alignment, and to a lesser extent its influence on clinical tests of motor performance including muscular strength, balance and locomotion. Although collectively these studies imply that the functional and structural limitations imposed by obesity may result in aberrant lower limb mechanics and the potential for musculoskeletal injury, empirical verification is currently lacking. The delineation of the effects of childhood obesity on musculoskeletal structure in terms of mass, adiposity, anthropometry, metabolic effects and physical inactivity, or their combination, has not been established. More specifically, there is a lack of research regarding the effect of childhood obesity on the properties of connective tissue structures, such as tendons and ligaments. Given the global increase in childhood obesity, there is a need to ascertain the consequences of persistent obesity on musculoskeletal structure and function. A better understanding of the implications of childhood obesity on the development and function of the musculoskeletal system would assist in the provision of more meaningful support in the prevention, treatment and management of the musculoskeletal consequences of the condition.


Novel mechanism for reverse transcription in hepatitis B viruses.
Reverse transcription of all retroviruses and most retroid elements requires tRNA as a primer for DNA synthesis. However, in hepatitis B viruses the viral polymerase itself acts as a primer for reverse transcription (G.-H. Wang and C. Seeger, Cell 71:663-670, 1992). We have now demonstrated that in order to prime DNA synthesis, the polymerase binds to an RNA hairpin, which then serves as a template for the formation of a short DNA primer that is covalently linked to protein. Following its synthesis, the nascent DNA strand apparently dissociates from its template and reanneals with complementary sequences at the 3' end of the RNA genome, where DNA synthesis continues. Since this RNA hairpin also functions as a packaging signal for viral RNA, hepadnaviruses have adopted a replication strategy that relies on the same signal for two biochemically distinct events, RNA packaging and reverse transcription. This mechanism is without precedent among all known retroid elements and among other viruses and bacteriophages that use protein as a primer for RNA or DNA synthesis. It could provide an effective target for antiviral therapy, which is required for the treatment of more than 300 million carriers of hepatitis B virus.


Nonconscious emotional activation colors first impressions: a regulatory role for conscious awareness.
Emotions can color people's attitudes toward unrelated objects in the environment. Existing evidence suggests that such emotional coloring is particularly strong when emotion-triggering information escapes conscious awareness. But is emotional reactivity stronger after nonconscious emotional provocation than after conscious emotional provocation, or does conscious processing specifically change the association between emotional reactivity and evaluations of unrelated objects? In this study, we independently indexed emotional reactivity and coloring as a function of emotional-stimulus awareness to disentangle these accounts. Specifically, we recorded skin-conductance responses to spiders and fearful faces, along with subsequent preferences for novel neutral faces during visually aware and unaware states. Fearful faces increased skin-conductance responses comparably in both stimulus-aware and stimulus-unaware conditions. Yet only when visual awareness was precluded did skin-conductance responses to fearful faces predict decreased likability of neutral faces. These findings suggest a regulatory role for conscious awareness in breaking otherwise automatic associations between physiological reactivity and evaluative emotional responses.


Primary prevention of gestational diabetes mellitus and large-for-gestational-age newborns by lifestyle counseling: a cluster-randomized controlled trial.
Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM. We conducted a cluster-randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8-12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] ≥ 25 kg/m(2), glucose intolerance or newborn's macrosomia (≥ 4,500 g) in any earlier pregnancy, family history of diabetes, age ≥ 40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71-2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size -133 g, 95% CI -231 to -35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30-3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16-0.57, p < 0.001), decreased their intake of saturated fatty acids (adjusted coefficient -0.63, 95% CI -1.12 to -0.15, p = 0.01) and intake of saccharose (adjusted coefficient -0.83, 95% CI -1.55 to -0.11, p = 0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI -37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group. The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM. Current Controlled Trials ISRCTN33885819. Please see later in the article for the Editors' Summary.


Compression as a universal principle of animal behavior.
A key aim in biology and psychology is to identify fundamental principles underpinning the behavior of animals, including humans. Analyses of human language and the behavior of a range of non-human animal species have provided evidence for a common pattern underlying diverse behavioral phenomena: Words follow Zipf's law of brevity (the tendency of more frequently used words to be shorter), and conformity to this general pattern has been seen in the behavior of a number of other animals. It has been argued that the presence of this law is a sign of efficient coding in the information theoretic sense. However, no strong direct connection has been demonstrated between the law and compression, the information theoretic principle of minimizing the expected length of a code. Here, we show that minimizing the expected code length implies that the length of a word cannot increase as its frequency increases. Furthermore, we show that the mean code length or duration is significantly small in human language, and also in the behavior of other species in all cases where agreement with the law of brevity has been found. We argue that compression is a general principle of animal behavior that reflects selection for efficiency of coding.


Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice.
Thevarepsilon4 allele of apolipoprotein E (apoE) is associated with an increased risk of developing Alzheimer's disease (AD). To accurately determine the isoform-specific effects of human apoE on brain functions under physiological and pathological situations, we created mice expressing human apoE4 isoform in place of mouse apoE by utilizing the gene-targeting technique on the embryonic stem cells (knock-in). The homozygousvarepsilon4 (4/4) mice correctly expressed human apoE4 in the serum and the brain. The human apoE in the brain was found primarily in the astrocytes as was the mouse apoE in the wild-type (+/+) mice. In the 4/4 mice, the serum cholesterol level was 2.5-fold that of the +/+ littermate controls on a regular diet. This marked elevation was accounted for by an accumulation of very low and low density lipo-proteins. In the brains of the 4/4 mice, however, the amounts of total cholesterol and phospholipids were significantly decreased compared with the +/+ littermates. These findings indicate that cholesterol and lipid metabolism is markedly altered in the 4/4 mice. Our human apoE4 knock-in mice will be useful in clarifying the role of apoE in the etiologies of AD and cardiovascular diseases in relation to cholesterol and lipid metabolism.


Brief fixation enables same-day breast cancer diagnosis with reliable assessment of hormone receptors, E-cadherin and HER2/Neu.
Preoperative core needle biopsy (CNB) is commonly used to confirm the diagnosis of breast cancer. For treatment purposes and for determining histological type, especially in case of neoadjuvant therapy, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and E-cadherin assessments are crucial. Considering the increasing demand for same-day diagnosis of breast lesions, an accelerated method of CNB processing was developed, in which the tissue fixation time is radically reduced. To determine whether short fixation time frustrates assessment of ER, PR and E-cadherin immunohistochemistry (IHC) and HER2 fluorescence in situ hybridisation (FISH), 69 consecutive patients with 70 invasive breast carcinomas were included through the same-day diagnostics programme of breast lesions of the Radboud university medical center and the hospital Pantein. IHC for ER, PR and E-cadherin and HER2 FISH were compared between CNBs fixed for approximately 60-90 min and traditionally fixed resection specimens. Overall agreement between CNBs and resection specimens was 98.6% for ER (p<0.001; κ=0.93), 90.0% for PR (p<0.001; κ=0.75), 100% for E-cadherin (p<0001; κ=1.00) and 98.6% (p<0.001; κ=0.94) for HER2 FISH. Positive and negative predictive values were respectively 98.4% and 100% for ER, 95.9% and 76.2% for PR, 100% and 100% for E-cadherin and 90% and 100% for HER2 FISH. Hormone receptors and E-cadherin IHC and HER2 FISH are highly comparable between briefly fixed CNBs and the corresponding traditionally fixed resection specimens, and can therefore reliably be used in the daily clinical practice of same-day diagnostics of breast cancer.


Rare missense variants in the human cytosolic antibody receptor preserve antiviral function.
The genetic basis of most human disease cannot be explained by common variants. One solution to this 'missing heritability problem' may be rare missense variants, which are individually scarce but collectively abundant. However, the phenotypic impact of rare variants is under-appreciated as gene function is normally studied in the context of a single 'wild-type' sequence. Here, we explore the impact of naturally occurring missense variants in the human population on the cytosolic antibody receptor TRIM21, using volunteer cells with variant haplotypes, CRISPR gene editing and functional reconstitution. In combination with data from a panel of computational predictors, the results suggest that protein robustness and purifying selection ensure that function is remarkably well-maintained despite coding variation.


Cascade CuH-Catalysed Conversion of Alkynes to Enantioenriched 1,1-Disubstituted Products.
Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalyzed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centers. In contrast, applying CuH cascade catalysis to achieve reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboronates via CuH-catalyzed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product in favor of alternative homodifunctionalized, 1,2-heterodifunctionalized, or reductively monofunctionalized byproducts, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.


Association of HIV infection with metabolic syndrome among normal or underweight young adults: evidence from the CHART cohort.
Metabolic syndrome (MS) is common among obese people. Little is known about the magnitude and characteristics of MS in people living with HIV (PLWH) in Asian countries in general and China in particular. Using baseline data collected between February 2017 through January 2020 from the Comparative HIV and Aging Research in Taizhou (CHART) cohort in China, we examined MS among 2,227 PLWH and 5,264 matched people without HIV, respectively. MS was defined using the criteria set forth by the International Diabetes Federation (IDF). Approximately 76.7% of PLWH had body mass index (BMI) < 24.0 kg/m2, significantly higher than people without HIV (50.3%). Among participants with BMI < 24.0 kg/m2, PLWH had a significantly higher prevalence of MS than people without HIV (20.6% vs. 14.5%; aOR: 1.41, 95% CI: 1.19-1.68) overall, and at an age of 18-29 (10.4% vs. 3.4%, aOR: 3.49, 95% CI: 1.99-6.11) and 30-44 years (17.3% vs. 8.5%, aOR: 2.03, 95% CI: 1.47-2.81), respectively. Among participants with BMI ≥ 24.0 kg/m2, MS prevalence was not significantly different between PLWH and people without HIV overall, but significantly lower in PLWH than people without HIV for those aged over 60 years (65.9% vs. 77.8%, aOR: 0.53, 95% CI: 0.32-0.88). Among PLWH, MS was significantly associated with older age and higher CD4 cell count, and with stavudine (d4T) use only in the group of BMI < 24.0 kg/m2. Our finding is indicative of a relatively higher risk for early onset of MS among HIV-infected young adults with lower BMI. Research is needed to elucidate the pathogenic mechanism for MS among PLWH.


Ternary structure reveals mechanism of a membrane diacylglycerol kinase.
Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The γ-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. The active site architecture shows clear evidence of having arisen by convergent evolution.


Immunohistochemical detection of p53 and bcl-2 proteins in non-Hodgkin's lymphoma.
We have investigated the immunohistochemical expression of p53 protein in 96 cases of non-Hodgkin's lymphoma using a panel of five antibodies. Positive neoplastic cells were found in 30 (31.2%) cases, which could be divided into two groups according to their patterns of reactivity with the different antibodies; i.e. those positive with both polyclonal and monoclonal antibodies, and those which were stained only by monoclonal antibodies PAb1801 and/or PAb240. Positivity was nuclear in all but six cases in which cytoplasmic staining was found. In view of the hypothesis recently raised that p53 protein induces apoptosis we have compared our results with parallel staining for bcl-2 protein since bcl-2 is believed to be important, at least in lymphomas, in suppression of apoptosis. Staining for bcl-2 protein was performed on 83 cases and it was shown that p53-positive cases accounted for 10 out of 17 (59%) of the bcl-2-negative lymphomas but only for 15 out of the 66 (23%) bcl-2-positive cases, suggesting a possible relationship between the expression of these two proteins. Thus, our data show that p53 protein is abnormally expressed in a substantial proportion of non-Hodgkin's lymphomas and bears a significant inverse relationship to bcl-2 protein expression. However the molecular basis of this expression remains to be elucidated.


Highly sensitive and adaptable fluorescence-quenched pair discloses the substrate specificity profiles in diverse protease families.
Internally quenched fluorescent (IQF) peptide substrates originating from FRET (Förster Resonance Energy Transfer) are powerful tool for examining the activity and specificity of proteases, and a variety of donor/acceptor pairs are extensively used to design individual substrates and combinatorial libraries. We developed a highly sensitive and adaptable donor/acceptor pair that can be used to investigate the substrate specificity of cysteine proteases, serine proteases and metalloproteinases. This novel pair comprises 7-amino-4-carbamoylmethylcoumarin (ACC) as the fluorophore and 2,4-dinitrophenyl-lysine (Lys(DNP)) as the quencher. Using caspase-3, caspase-7, caspase-8, neutrophil elastase, legumain, and two matrix metalloproteinases (MMP2 and MMP9), we demonstrated that substrates containing ACC/Lys(DNP) exhibit 7 to 10 times higher sensitivity than conventional 7-methoxy-coumarin-4-yl acetic acid (MCA)/Lys(DNP) substrates; thus, substantially lower amounts of substrate and enzyme can be used for each assay. We therefore propose that the ACC/Lys(DNP) pair can be considered a novel and sensitive scaffold for designing substrates for any group of endopeptidases. We further demonstrate that IQF substrates containing unnatural amino acids can be used to investigate protease activities/specificities for peptides containing post-translationally modified amino acids. Finally, we used IQF substrates to re-investigate the P1-Asp characteristic of caspases, thus demonstrating that some human caspases can also hydrolyze substrates after glutamic acid.


Addition reactions and diazomethane capture by the intramolecular P-O-B FLP: tBu2POBcat.
FLPs, R2POBcat (R = tBu 1, Mes 2), are readily derived from the reactions of the corresponding phosphine oxides, nBuLi and ClBcat. Despite the poor Lewis acidity of boron, these species react with PhOH, CO2, CS2, PhNCO, MesCNO, O2, 9,10-phenanthrenedione, and diazomethanes to effect FLP addition reactions affording a series of heterocycles. The reaction of 1 with EtO2CCHN2 gives the bicyclic product, EtO2CCHN2(tBu2POBcat)2. High-level DFT calculations reveal that these cyclization processes proceed via 1,1-addition to the terminal N of diazomethane followed by 1,2-boron-migration affording the five membered rings. The reaction of the EtO2CCHN2 derivative with the second equivalent of FLP 1 is attributed to less steric demands.


Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.
The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. US National Heart, Lung, and Blood Institute and National Cancer Institute.


High-Resolution Imaging by Fourier Transform X-ray Holography.
Fourier transform x-ray holography has been used to image gold test objects with submicrometer structure, resolving features as small as 60 nanometers. The hologram-recording instrument uses coherent 3.4-nanometer radiation from the soft x-ray undulator beamline X1A at the National Synchrotron Light Source. The specimen to be imaged is placed near the first-order focal spot produced by a Fresnel zone plate; the other orders, chiefly the zeroth, illuminate the specimen. The wave scattered by the specimen interferes with the spherical reference wave from the focal spot, forming a hologram with fringes of low spatial frequency. The hologram is recorded in digital form by a charge-coupled device camera, and the specimen image is obtained by numerical reconstruction.


Interactions Between Alcohol Metabolism Genes and Religious Involvement in Association With Maximum Drinks and Alcohol Dependence Symptoms.
Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes. Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1Brs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance. Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement. This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.


Identification of the salmon somatolactin receptor, a new member of the cytokine receptor family.
Somatolactin (SL) is a pituitary hormone of the GH/prolactin (PRL) family that so far has been found only in fish. Compared with GH and PRL, the primary structure of SL is highly conserved among divergent fish species, suggesting it has an important function and a discriminating receptor that constrains structural change. However, SL functions are poorly understood, and receptors for SL have not yet been identified. During cloning of GH receptor cDNA from salmon, we found a variant with relatively high (38-58%) sequence identity to vertebrate GH receptors and low (28-33%) identity to PRL receptors; however, the recombinant protein encoding the extracellular domain showed only weak binding of GH. Ligand binding of the recombinant extracellular domain for this receptor confirmed that the cDNA encoded a specific receptor for SL. The SL receptor (SLR) has common features of a GH receptor including FGEFS motif, six cysteine residues in the extracellular domain, a single transmembrane region, and Box 1 and 2 regions in the intracellular domain. These structural characteristics place the SLR in the cytokine receptor type I homodimeric group, which includes receptors for GH, PRL, erythropoietin, thrombopoietin, granulocyte-colony stimulating factor, and leptin. Transcripts for SLR were found in 11 tissues with highest levels in liver and fat, supporting the notion that a major function of SL is regulation of lipid metabolism. Cloning SLR cDNA opens the way for discovery of new SL functions and target tissues in fish, and perhaps novel members of this receptor family in other vertebrates.


Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients.
The transcription factors in the myocyte enhancer factor 2 (MEF2) family play important roles in cell survival by regulating nuclear gene expression. Here, we report that MEF2D is present in rodent neuronal mitochondria, where it can regulate the expression of a gene encoded within mitochondrial DNA (mtDNA). Immunocytochemical, immunoelectron microscopic, and biochemical analyses of rodent neuronal cells showed that a portion of MEF2D was targeted to mitochondria via an N-terminal motif and the chaperone protein mitochondrial heat shock protein 70 (mtHsp70). MEF2D bound to a MEF2 consensus site in the region of the mtDNA that contained the gene NADH dehydrogenase 6 (ND6), which encodes an essential component of the complex I enzyme of the oxidative phosphorylation system; MEF2D binding induced ND6 transcription. Blocking MEF2D function specifically in mitochondria decreased complex I activity, increased cellular H(2)O(2) level, reduced ATP production, and sensitized neurons to stress-induced death. Toxins known to affect complex I preferentially disrupted MEF2D function in a mouse model of Parkinson disease (PD). In addition, mitochondrial MEF2D and ND6 levels were decreased in postmortem brain samples of patients with PD compared with age-matched controls. Thus, direct regulation of complex I by mitochondrial MEF2D underlies its neuroprotective effects, and dysregulation of this pathway may contribute to PD.


High-intensity focused ultrasound for the treatment of liver tumours.
High-intensity focused ultrasound (HIFU) has been investigated as a tool for the treatment of cancer for many decades, but is only now beginning to emerge as a potential alternative to conventional therapies. In recent years, clinical trials have evaluated the clinical efficacy of a number of devices worldwide. In Oxford, UK, we have been using the JC HIFU system (HAIFU Technology Company, Chongqing, PR China) in clinical trials since November 2002. This is the first report of its clinical use outside mainland China. The device is non-invasive, and employs an extracorporeal transducer operating at 0.8-1.6 MHz (aperture 12-15 cm, focal length 9-15 cm), operating clinically at Isp (free field) of 5-15 KWcm(-2). The aims of the trials are to evaluate the safety and performance of the device. Performance is being evaluated through two parallel protocols. One employs radiological assessment of response with the use of follow-up magnetic resonance imaging and microbubble-contrast ultrasound. In the other, histological assessment will be made following elective surgical resection of the HIFU treated tumours. Eleven patients with liver tumours have been treated with HIFU to date. Adverse events include transient pain and minor skin burns. Observed response from the various assessment modalities is discussed.


MAIT cells in liver inflammation and fibrosis.
Mucosal-associated invariant T cells or MAIT cells are an abundant cell type in humans and especially so in the liver. MAIT cells are a subset of T lymphocytes that sit at a bridge between innate and adaptive immunity, so-called innate-like or "unconventional" T cells. The specificity of their antigen receptor (T cell receptor or TCR) is for the conserved major histocompatibility complex (MHC)-related molecule MR1, which presents a modified bacterial metabolite from the vitamin B2 biosynthesis pathway - this allows them to respond in the presence of many bacteria or yeast. MAIT cells also possess an array of cytokine receptors, which allows triggering independently of the TCR. The combination of such signals drives their functionality - this means they can respond to a range of stimuli and likely play a role not only in infection or inflammation, but also under homeostatic conditions.In this review, we will look at the question of what MAIT cells are doing in the normal liver and how they behave in the setting of disease. These questions are of relevance because MAIT cells are such a distinctive cell type enriched in the liver under normal conditions, and their modulation could be of therapeutic benefit. The recent discovery that they appear to be involved in liver fibrosis is particularly of interest in this context.


Intact regulation of muscle expression and circulating levels of myokines in response to exercise in patients with type 2 diabetes.
Regular exercise plays an important role in the prevention and treatment of type 2 diabetes (T2D). The synthesis and secretion of myokines in response to contraction may contribute to the beneficial metabolic effects of exercise. However, some exercise-induced responses may be attenuated in T2D. Here, we investigated whether the effect of acute exercise on selected myokines are impaired in T2D. Skeletal muscle biopsies and blood samples were obtained from 13 men with T2D and 14 weight-matched, glucose-tolerant men before, immediately after and 3-h after acute exercise (60 min cycling) to examine muscle expression and plasma/serum levels of selected myokines. One-hour of exercise increased muscle expression of IL6, FGF21, ANGPTL4, CHI3L1, CTGF and CYR61, of which FGF21, ANGPTL4 and CHI3L1 increased further 3-h into recovery, whereas expression of IL6, CYR61, and CTGF returned to baseline levels. There was no immediate effect of exercise on IL15 expression, but it decreased 3-h into recovery. Plasma IL-6 increased robustly, whereas circulating levels of FGF21, ANGPTL4, IL-15, and CHI3L1 increased only modestly in response to exercise. All returned toward baseline levels 3-h into recovery except for plasma ANGPTL4, which increased further. No significant differences in these responses to exercise were observed between the groups. Our results demonstrate that muscle expression and circulating levels of selected known and putative myokines were equally regulated by acute exercise in patients with T2D and weight-matched controls. This suggests that the potential beneficial metabolic effects of these myokines are not impaired in patients with T2D.


Strengths use as a secret of happiness: Another dimension of visually impaired individuals' psychological state.
It is well recognized that visual impairments (VI) worsen individuals' mental condition. However, little is known about the positive aspects including subjective happiness, positive emotions, and strengths. Therefore, the purpose of this study was to investigate the positive aspects of persons with VI including their subjective happiness, positive emotions, and strengths use. Positive aspects of persons with VI were measured using the Subjective Happiness Scale (SHS), the Scale of Positive and Negative Experience-Balance (SPANE-B), and the Strengths Use Scale (SUS). A cross-sectional analysis was utilized to examine personal information in a Tokyo sample (N = 44). We used a simple regression analysis and found significant relationships between the SHS or SPANE-B and SUS; on the contrary, VI-related variables were not correlated with them. A multiple regression analysis confirmed that SUS was a significant factor associated with both the SHS and SPANE-B. Strengths use might be a possible protective factor from the negative effects of VI.


Major dietary patterns and risk of renal cell carcinoma in a prospective cohort of Swedish women.
Links between specific foods and the risk of renal cell carcinoma (RCC) are not well established. Dietary patterns may be a better predictor of RCC risk. Our aim was to identify and examine major dietary patterns and their relation to the risk of RCC in a large prospective cohort study of Swedish women. Complete dietary information was available from a FFQ from 46,572 women aged 40-76 y at baseline. We conducted factor analysis to identify dietary patterns. Cox proportional hazard models were used to estimate rate ratios (RRs) and 95% CIs. During a mean of 14.3 y of follow-up, we identified 93 cases of RCC. We observed 3 major dietary patterns in the cohort: Healthy (vegetables, tomato, fish, fruits, poultry, whole grains), Western (sweets, processed meat, refined grains, margarine/butter, high-fat dairy products, fried potato, soft drinks, meat) and Drinker (wine, hard liquor, beer, snacks) pattern. Higher Healthy pattern scores were not significantly associated with decreased risk of RCC (highest vs. lowest tertile RR = 0.81; 95% CI 0.45-1.48 and RR = 0.54; 95% CI 0.27-1.10 among women < or = 65 y). There was a suggestion of an inverse association between the Drinker pattern and RCC risk (RR comparing the 2nd and 3rd with the first tertile, 0.56; 95% CI, 0.34-0.95; and 0.72; 95% CI, 0.42-1.22, respectively, P = 0.08 by Wald test); the association was clearer among women < or = 65 y (P = 0.02 by Wald test). Our data suggest an inverse association between Drinker pattern and the risk of RCC.


Early expansion of donor-specific Tregs in tolerant kidney transplant recipients.
Allograft tolerance, in which a graft is accepted without long-term immunosuppression, could overcome numerous obstacles in transplantation. Human allograft tolerance has been intentionally induced across HLA barriers via combined kidney and bone marrow transplantation (CKBMT) with a regimen that induces only transient chimerism. Tregs are enriched early after CKBMT. While deletional tolerance contributes to long-term tolerance, the role of Tregs remains unclear. We have optimized a method for identifying the donor-specific Treg repertoire and used it to interrogate the fate of donor-specific Tregs after CKBMT. We expanded Tregs with several different protocols. Using functional analyses and T cell receptor sequencing, we found that expanding sorted Tregs with activated donor B cells identified the broadest Treg repertoire with the greatest potency and donor specificity of suppression. This method outperformed both alloantigen stimulation with CTLA4Ig and sequencing of CFSElo cells from the primary mixed lymphocyte reaction. In 3 tolerant and 1 nontolerant CKBMT recipients, we sequenced donor-specific Tregs before transplant and tracked them after transplant. Preexisting donor-specific Tregs were expanded at 6 months after CKBMT in tolerant patients and were reduced in the nontolerant patient. These results suggest that early expansion of donor-specific Tregs is involved in tolerance induction following CKBMT.


On what motivates us: a detailed review of intrinsic v. extrinsic motivation.
Motivational processes underlie behaviors that enrich the human experience, and impairments in motivation are commonly observed in psychiatric illness. While motivated behavior is often examined with respect to extrinsic reinforcers, not all actions are driven by reactions to external stimuli; some are driven by 'intrinsic' motivation. Intrinsically motivated behaviors are computationally similar to extrinsically motivated behaviors, in that they strive to maximize reward value and minimize punishment. However, our understanding of the neurocognitive mechanisms that underlie intrinsically motivated behavior remains limited. Dysfunction in intrinsic motivation represents an important trans-diagnostic facet of psychiatric symptomology, but due to a lack of clear consensus, the contribution of intrinsic motivation to psychopathology remains poorly understood. This review aims to provide an overview of the conceptualization, measurement, and neurobiology of intrinsic motivation, providing a framework for understanding its potential contributions to psychopathology and its treatment. Distinctions between intrinsic and extrinsic motivation are discussed, including divergence in the types of associated rewards or outcomes that drive behavioral action and choice. A useful framework for understanding intrinsic motivation, and thus separating it from extrinsic motivation, is developed and suggestions for optimization of paradigms to measure intrinsic motivation are proposed.


Application of fullerenes in nanomedicine: an update.
Fullerenes are carbon spheres presently being pursued globally for a wide range of applications in nanomedicine. These molecules have unique electronic properties that make them attractive candidates for diagnostic, therapeutic and theranostic applications. Herein, the latest research is discussed on developing fullerene-based therapeutics as antioxidants for inflammatory diseases, their potential as antiviral/bacterial agents, utility as a drug delivery device and the promise of endohedral fullerenes as new MRI contrast agents. The recent discovery that certain fullerene derivatives can stabilize immune effector cells to prevent or inhibit the release of proinflammatory mediators makes them potential candidates for several diseases such as asthma, arthritis and multiple sclerosis. Gadolinium-containing endohedral fullerenes are being pursued as diagnostic MRI contrast agents for several diseases. Finally, a new class of fullerene-based theranostics has been developed, which combine therapeutic and diagnostic capabilities to specifically detect and kill cancer cells.


Intraprostatic ozone therapy: A minimally invasive approach in benign prostatic hyperplasia.
Transurethral resection of prostate (TURP) remains the golden standard therapy since decades. There are various minimally invasive therapies (MITs) for the treatment of benign prostatic hyperplasia (BPH). Still, there is a need for therapy with lesser side effects and better outcome. We had studied the effect of intraprostatic ozone injection (IPOI) as an MIT for patients with BPH who have failed trial without catheter (TWOC). Thirty elderly patients with BPH with a prostate size of 30 g or more were enrolled for the study. Forty milliliters of ozone at a concentration of 30 μg/dl was injected in prostate (20 ml in each lateral lobe) per rectally. Prostate volume (PV) by ultrasonography was assessed after catheter removal on the 7th day and after 1 month. Totally thirty patients (mean age - 67.8 years) with mean prostatic volume (MPV) of 46.10cc received IPOI. MPV came as 44.96cc on the 7th day of postozone therapy (P = 0.008). Successful voiders showed a significant reduction in PV (mean = 13.12cc) as compared to unsuccessful voiders (mean = 2.61cc) after 1 month. Intraprostatic ozone injection helps to reduce the PV to some extent and can be helpful in patients who have failed TWOC even on alpha blockers and are unfit for TURP. Larger studies are required to assess the efficacy and long-term results of this technique.


Interleukin 6 is associated with cachexia in patients with prostate cancer.
To evaluate the relationship between serum interleukin (IL)-6 and cachexia in patients with prostate cancer. Serum levels of IL-6, total protein, albumin, total cholesterol, and hemoglobin concentration were determined in 164 blood samples from patients with prostate cancer. The body mass index and performance status were also determined. The serum total protein, albumin, and cholesterol levels, hemoglobin levels, and body mass index of the patients whose serum IL-6 level was 7 pg/mL or greater were significantly lower (P <0.05) than the corresponding values in patients with a serum IL-6 level of less than 7 pg/mL. The serum IL-6 level of patients with a serum albumin level of less than 3.5 g/dL, serum total protein level of less than 7.0 g/dL, serum total cholesterol level of less than 180 mg/dL, hemoglobin level of less than 11.0 g/dL, and body mass index of less than 21 kg/m2 were significantly greater (P <0.05) than the values in their respective counterparts. A significant correlation was found between the elevation of serum IL-6 and performance status (P <0.05). The mortality rate of patients with greater serum IL-6 levels was significantly greater than that of those with lower serum IL-6 levels in patients with untreated disease, patients in remission, and patients with relapse (all P <0.05). These findings suggest that IL-6 may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer (all P <0.05).


Relationships between muscle strength and bone mineral density of three body regions in sedentary postmenopausal women.
This cross-sectional study was designed to investigate correlations between muscle strength and regional bone mineral density (BMD) in sedentary postmenopausal women. Sixty-two women who ranged in age from 41 to 76 years were investigated. Hip and trunk muscle strength was measured by isokinetic dynamometry. Grip strength of the nondominant hand was measured using a hand-held dynamometer. Bone mineral density of the lumbar spine, femur, and distal radius was measured by dual-energy X-ray absorptiometry. Only the correlation between hip abductor strength and femoral BMD was significant (P = 0.009, r = 0.327). There was no correlation between trunk muscle strength and lumbar vertebral BMD or between grip strength and distal radius BMD. Subjects with osteoporosis (T score < -2.5) or osteopenia T (-2.5 to -1) and normal subjects (T > -1) exhibited similar isokinetic hip and trunk muscle strength. Women with osteoporotic distal radii had significantly lower grip strength than subjects who were osteopenic or normal at this site, but the osteoporotic group was also significantly older. In conclusion, our results indicate that the isokinetic strength of hip abductors weakly correlates with femoral BMD in postmenopausal women with and without osteoporosis. Trunk muscle strength did not correlate with lumbar vertebral BMD in either of these groups. The weaker handgrip we observed in the women with osteoporotic radii may be attributed to older age.


Parent-of-origin effect in multiple sclerosis: observations in half-siblings.
Multiple sclerosis is a complex trait in which occurrence rates in offspring are 20-50-fold greater than in the general population. Parent-of-origin effects have been difficult to screen for, since most cases are sporadic. We have compared recurrence risks in half-siblings with respect to their parent in common. Of the 1567 index cases with half-siblings in multiple sclerosis clinics across Canada, we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% (chi2 test, p=0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of 1577), (p=0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility.


A multidimensional approach to measuring well-being in students: Application of the PERMA framework.
Seligman recently introduced the PERMA model with five core elements of psychological well-being: positive emotions, engagement, relationships, meaning, and accomplishment. We empirically tested this multidimensional theory with 516 Australian male students (age 13-18). From an extensive well-being assessment, we selected a subset of items theoretically relevant to PERMA. Factor analyses recovered four of the five PERMA elements, and two ill-being factors (depression and anxiety). We then explored the nomological net surrounding each factor by examining cross-sectional associations with life satisfaction, hope, gratitude, school engagement, growth mindset, spirituality, physical vitality, physical activity, somatic symptoms, and stressful life events. Factors differentially related to these correlates, offering support for the multidimensional approach to measuring well-being. Directly assessing subjective well-being across multiple domains offers the potential for schools to more systematically understand and promote well-being.


A profile of cases of gestational trophoblastic neoplasia at a large tertiary centre in dubai.
Objectives. To study (1) the prevalence of different types of gestational trophoblastic neoplasia (GTN) in the local and nonlocal population of women at Al Wasl Hospital, a tertiary level referral centre for northern Emirates, (2) the safety of cervical preparation before uterine evacuation, (3) the role of repeat uterine evacuation in curing these cases, and (4) the percentage of cases ultimately requiring chemotherapy. Material and Methods. Retrospective analysis of case records of 35 women with diagnosis of gestational trophoblastic neoplasia were managed in the Department of Obstetrics and Gynecology at Al Wasl Hospital, over a 2-year period between January 2007 to December 2008. Results. 35 cases of gestational trophoblastic neoplasia were seen in a 2-year period (January 2007 to December 2008) at Al Wasl Hospital, with 7000 deliveries per year, prevalence being 1 in 400 live births. 60% cases were local Arabs. Histopathology revealed complete mole in 13 cases, partial mole in 17 cases, hydropic degeneration of villi in 4 cases, and no identifiable tissue in 1 case. No cases of choriocarcinoma or placental site trophoblastic tumour were seen during the study period. 34% cases received cervical preparation with prostaglandins prior to surgical curettage. Complications were minor. 62% were cured by primary suction curettage, 12% after second (repeat) uterine evacuation, and 25% needed single drug chemotherapy. 8% cases defaulted after primary evacuation and were lost to followup. Conclusions. Prevalence of GTN in the local Arab population is similar to other Asian populations. The majority of cases are cured by simple suction uterine curettage. Cervical preparation with prostaglandins should be done in selected cases to avoid perforation during evacuation. Second (repeat) uterine evacuation can be curative in some cases with strict selection criteria and avoid the need for chemotherapy. Regional registry of cases is needed to estimate the true incidence of this disease.


The evolution of meaning: spatio-temporal dynamics of visual object recognition.
Research on the spatio-temporal dynamics of visual object recognition suggests a recurrent, interactive model whereby an initial feedforward sweep through the ventral stream to prefrontal cortex is followed by recurrent interactions. However, critical questions remain regarding the factors that mediate the degree of recurrent interactions necessary for meaningful object recognition. The novel prediction we test here is that recurrent interactivity is driven by increasing semantic integration demands as defined by the complexity of semantic information required by the task and driven by the stimuli. To test this prediction, we recorded magnetoencephalography data while participants named living and nonliving objects during two naming tasks. We found that the spatio-temporal dynamics of neural activity were modulated by the level of semantic integration required. Specifically, source reconstructed time courses and phase synchronization measures showed increased recurrent interactions as a function of semantic integration demands. These findings demonstrate that the cortical dynamics of object processing are modulated by the complexity of semantic information required from the visual input.


[Evidence about the power of intention].
Intention is defined as a directed thought to perform a determined action. Thoughts targeted to an end can affect inanimate objects and practically all living things from unicelular organisms to human beings. The emission of light particles (biophotons) seems to be the mechanism through which an intention produces its effects. All living organisms emit a constant current of photons as a mean to direct instantaneous nonlocal signals from one part of the body to another and to the outside world. Biophotons are stored in the intracelular DNA. When the organism is sick changes in biophotons emissions are produced.Direct intention manifests itself as an electric and magnetic energy producing an ordered flux of photons. Our intentions seem to operate as highly coherent frequencies capable of changing the molecular structure of matter. For the intention to be effective it is necessary to choose the appropriate time. In fact, living beings are mutually synchronized and to the earth and its constant changes of magnetic energy. It has been shown that the energy of thought can also alter the environment. Hypnosis, stigmata phenomena and the placebo effect can also be considered as types of intention, as instructions to the brain during a particular state of consciousness. Cases of spontaneous cures or of remote healing of extremely ill patients represent instances of an exceedingly great intention to control diseases menacing our lives. The intention to heal as well as the beliefs of the sick person on the efficacy of the healing influences promote his healing. In conclusion, studies on thought and consciousness are emerging as fundamental aspects and not as mere epiphenomena that are rapidly leading to a profound change in the paradigms of Biology and Medicine.


Mitochondrial aldehyde dehydrogenase in diabetes associated with mitochondrial tRNA(Leu(UUR)) mutation at position 3243.
To ascertain why alcohol is prone to manifest unpleasant effects in diabetes associated with mitochondrial tRNA(Leu(UUR) mutation at position 3243 (DM-Mt3243), we investigated the genotype of aldehyde dehydrogenase (ALDH) 2 and alcohol dehydrogenase 2 (ADH2) in DM-Mt3243. Nineteen unrelated patients with DM-Mt3243 were included in the study (12 men and 7 women). They were recruited from approximately 700 diabetic patients at three different institutes, without prior information of alcohol habit. ALDH2, ADH2, and 3243 mutation were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. There were 461 unrelated Japanese individuals and 170 non-3243 mutant NIDDM patients enrolled as control subjects. In the DM-Mt3243 group, 15 (79%) patients had inactive ALDH2 and 18 (95%) had atypical ADH2. The frequency of the inactive ALDH2 genotype was higher than that in the normal control subjects (P < 0.002) and that in the NIDDM control subjects (P < 0.003). However, the frequencies of ADH2 genotype in the DM-Mt3243 group, the normal control subjects, and the NIDDM control subjects were not different. Inactive ALDH2 genotype was frequently observed in DM-Mt3243. It suggests that DM-Mt3243 is associated with ALDH2 inactivity. We speculate the trait of acetaldehyde accumulation on ALDH2 inactivity may favor mitochondrial DNA abnormalities, thereby worsening ATP production and impairing insulin secretion. In addition, the interaction of ALDH1 and ALDH2 may alter the retinoid metabolism in the pancreas, thereby influencing insulin secretion and precipitating diabetes. Thus, this association of ALDH2 genotype with DM-Mt3243 provides insight into the etiology of diabetes in the mitochondrial diseases.


Comparison of Commonly Used Questionnaires to Identify Obstructive Sleep Apnea in a High-Risk Population.
Sleep apnea is associated with adverse health outcomes. Despite being an important comorbidity in obesity, type 2 diabetes, heart failure, and resistant hypertension, it is underdiagnosed in these patient groups. An inexpensive and readily accessible sleep apnea screening tool would help address this problem. We sought to compare three commonly used screening tools. We recruited 812 patients who had not previously been investigated for sleep apnea from our institution's diabetes (n = 512), obesity (n = 129), resistant hypertension (n = 74) and heart failure (n = 43) clinics. Patients completed three frequently used sleep apnea screening questionnaires (STOP-BANG, Berlin, and OSA50). A total of 758 patients had a valid (> 4 hours' duration) level 3 home sleep study. Studies were reported by a sleep physician and were deemed positive if they recorded a respiratory event index (REI) ≥ 15 events/h. The 758 patients with valid sleep studies were age 59 ± 11 years and 63% were male. A total of 38% of patients had a positive test. The respective sensitivities and specificities of the screening questionnaires at the recommended screening thresholds (REI ≥ 15 events/h) were STOP-BANG ≥ 3 (95% and 19%), STOP-BANG ≥ 5 (60% and 69%), Berlin (75% and 38%), and OSA50 (88% and 21%). We identified six independent predictors (age, sex, body mass index, neck circumference, snoring ≥ 3 days per week, observed apnea ≥ 3 days per week). However, combining these factors was no better than the STOP-BANG in predicting sleep apnea. All patients with a STOP-BANG < 3 had an REI < 30 events/h. There is a high prevalence of undiagnosed symptomatic sleep apnea in high-risk patient groups. The STOP-BANG questionnaire appeared superior, though all questionnaires had significant limitations. Incorporation of STOP-BANG ≥ 3 in this high-risk population might reduce the need for sleep testing in a resource-constrained setting.


The Search for Candidate Relevant Subsets of Variables in Complex Systems.
We describe a method to identify relevant subsets of variables, useful to understand the organization of a dynamical system. The variables belonging to a relevant subset should have a strong integration with the other variables of the same relevant subset, and a much weaker interaction with the other system variables. On this basis, extending previous work on neural networks, an information-theoretic measure, the dynamical cluster index, is introduced in order to identify good candidate relevant subsets. The method does not require any previous knowledge of the relationships among the system variables, but relies on observations of their values over time. We show its usefulness in several application domains, including: (i) random Boolean networks, where the whole network is made of different subnetworks with different topological relationships (independent or interacting subnetworks); (ii) leader-follower dynamics, subject to noise and fluctuations; (iii) catalytic reaction networks in a flow reactor; (iv) the MAPK signaling pathway in eukaryotes. The validity of the method has been tested in cases where the data are generated by a known dynamical model and the dynamical cluster index is applied in order to uncover significant aspects of its organization; however, it is important that it can also be applied to time series coming from field data without any reference to a model. Given that it is based on relative frequencies of sets of values, the method could be applied also to cases where the data are not ordered in time. Several indications to improve the scope and effectiveness of the dynamical cluster index to analyze the organization of complex systems are finally given.


Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation.
Recruitment manoeuvres involve transient elevations in airway pressure applied during mechanical ventilation to open ('recruit') collapsed lung units and increase the number of alveoli participating in tidal ventilation. Recruitment manoeuvres are often used to treat patients in intensive care who have acute respiratory distress syndrome (ARDS), but the effect of this treatment on clinical outcomes has not been well established. This systematic review is an update of a Cochrane review originally published in 2009. Our primary objective was to determine the effects of recruitment manoeuvres on mortality in adults with acute respiratory distress syndrome.Our secondary objective was to determine, in the same population, the effects of recruitment manoeuvres on oxygenation and adverse events (e.g. rate of barotrauma). For this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), the Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCO), Latin American and Caribbean Health Sciences (LILACS) and the International Standard Randomized Controlled Trial Number (ISRCTN) registry from inception to August 2016. We included randomized controlled trials (RCTs) of adults who were mechanically ventilated that compared recruitment manoeuvres versus standard care for patients given a diagnosis of ARDS. Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Ten trials met the inclusion criteria for this review (n = 1658 participants). We found five trials to be at low risk of bias and five to be at moderate risk of bias. Six of the trials included recruitment manoeuvres as part of an open lung ventilation strategy that was different from control ventilation in aspects other than the recruitment manoeuvre (such as mode of ventilation, higher positive end-expiratory pressure (PEEP) titration and lower tidal volume or plateau pressure). Six studies reported mortality outcomes. Pooled data from five trials (1370 participants) showed a reduction in intensive care unit (ICU) mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.72 to 0.97, P = 0.02, low-quality evidence), pooled data from five trials (1450 participants) showed no difference in 28-day mortality (RR 0.86, 95% CI 0.74 to 1.01, P = 0.06, low-quality evidence) and pooled data from four trials (1313 participants) showed no difference in in-hospital mortality (RR 0.88, 95% CI 0.77 to 1.01, P = 0.07, low-quality evidence). Data revealed no differences in risk of barotrauma (RR 1.09, 95% CI 0.78 to 1.53, P = 0.60, seven studies, 1508 participants, moderate-quality evidence). We identified significant clinical heterogeneity in the 10 included trials. Results are based upon the findings of several (five) trials that included an "open lung ventilation strategy", whereby the intervention group differed from the control group in aspects other than the recruitment manoeuvre (including co-interventions such as higher PEEP, different modes of ventilation and higher plateau pressure), making interpretation of the results difficult. A ventilation strategy that included recruitment manoeuvres in participants with ARDS reduced intensive care unit mortality without increasing the risk of barotrauma but had no effect on 28-day and hospital mortality. We downgraded the quality of the evidence to low, as most of the included trials provided co-interventions as part of an open lung ventilation strategy, and this might have influenced results of the outcome.


Eclipse prediction on the ancient Greek astronomical calculating machine known as the Antikythera Mechanism.
The ancient Greek astronomical calculating machine, known as the Antikythera Mechanism, predicted eclipses, based on the 223-lunar month Saros cycle. Eclipses are indicated on a four-turn spiral Saros Dial by glyphs, which describe type and time of eclipse and include alphabetical index letters, referring to solar eclipse inscriptions. These include Index Letter Groups, describing shared eclipse characteristics. The grouping and ordering of the index letters, the organization of the inscriptions and the eclipse times have previously been unsolved. A new reading and interpretation of data from the back plate of the Antikythera Mechanism, including the glyphs, the index letters and the eclipse inscriptions, has resulted in substantial changes to previously published work. Based on these new readings, two arithmetical models are presented here that explain the complete eclipse prediction scheme. The first model solves the glyph distribution, the grouping and anomalous ordering of the index letters and the structure of the inscriptions. It also implies the existence of lost lunar eclipse inscriptions. The second model closely matches the glyph times and explains the four-turn spiral of the Saros Dial. Together, these models imply a surprisingly early epoch for the Antikythera Mechanism. The ancient Greeks built a machine that can predict, for many years ahead, not only eclipses but also a remarkable array of their characteristics, such as directions of obscuration, magnitude, colour, angular diameter of the Moon, relationship with the Moon's node and eclipse time. It was not entirely accurate, but it was an astonishing achievement for its era.


PFAPA syndrome: new clinical aspects disclosed.
The recently described PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis) syndrome is characterised by periodic fever, aphthous stomatitis, pharyngitis and adenitis. However, there are currently relatively few data on the natural history of this syndrome. To describe the presentation, clinical course, doctors' awareness, therapeutic response and long-term follow-up of children with PFAPA syndrome. Children with PFAPA syndrome referred over a 5-year period (from January 1999 to January 2004) were enrolled in the study. Data were gathered from medical records, parents' interviews, physical examination and telephone calls. 54 patients with PFAPA syndrome were evaluated. Our patients had a higher rate of abdominal pain (65%) and a lower rate of aphthous stomatitis (39%) than those in previous reports. Four different patterns of disease evolution were identified, including the relatively common (n = 14, 26%) and newly described course of alternating remissions and relapses. The remissions lasted 8.5 months on average (range 4-36 months). Diagnosis was established by primary paediatricians in 30 of 54 (56%) patients. However, a substantial delay in diagnosis was apparent (mean 15 months). Episodes were curtailed by a much lower dose of prednisone or equivalent corticosteroid (mean 0.6 mg/kg/day, range 0.15-1.5 mg/kg/day) than reported previously. Tonsillectomy was successful in the prevention of recurrence of further episodes in all six patients who underwent the procedure. We describe several new characteristics of PFAPA syndrome in children, contributing to our knowledge of this relatively unrecognised but troublesome syndrome. Early diagnosis and appropriate treatment can markedly improve the quality of life of both patients and families.


Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development.
The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium-chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec-butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo-controlled randomized controlled trials, with promising efficacy and safety results.


Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma.
Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to inhibit growth and to induce apoptosis in human hepatocellular carcinoma (HCC) cells. However, the potential benefit of pravastatin in HCC patients has still not been characterized, which prompted us to test the efficacy of pravastatin in patients with advanced HCC. We investigated prospectively a cohort of 183 HCC patients who had been selected for palliative treatment by transarterial chemoembolization (TACE). Fifty-two patients received TACE combined with pravastatin (20-40 mg/day) and 131 patients received chemoembolization alone. Six independent predictors of survival according to the Vienna survival model for HCC were equally distributed in both groups. During the observation period of up to 5 years, 31 (23.7%) out of 131 patients treated by TACE alone and 19 (36.5%) out of 52 patients treated by TACE and pravastatin survived. Median survival was significantly longer in HCC patients treated by TACE and pravastatin (20.9 months, 95% CI 15.5-26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0 months, 95% CI 10.3-13.7). Combined treatment of chemoembolization and pravastatin improves survival of patients with advanced HCC in comparison to patients receiving chemoembolization alone.