[Cost-benefit of the pharmacologic treatment of cerebral palsy with spasticity in Mexico].
Cerebral palsy involving spasticity is a highly handicapping illness, especially among children, the treatment of which is limited to reducing the handicaps involved without any full cure. There is a drug treatment which affords the possibility of providing patients with a better quality of life, regarding which a cost effectiveness analysis is made, note being made of the individual achievements and social benefits. This analysis is based on nationwide information from Mexico which was obtained from secondary sources. The base data is set out within the framework of trends in the growth of this health problem, and the calculations affording the possibility of sizing up this problem are employed in order to ascertain the benefits thereof based on the following indicators: relative impact of this disease and years of healthy life lost and gained, based on which the social and economic benefit entailed in the drug treatment under analysis is estimated. The data reveals that the drug treatment in question is directly beneficial, because it lowers the relative impact of this disease from 0.92 to 0.40. At the individual level, the greatest benefit takes the form of the improved quality of life among the afflicted children within the 6-12 age range, they having gone from 0.08 years to 0.60 years of life in terms of quality. At the nationwide level, the 595,817 years of healthy life which would be lost without any treatment would be recouped. The monetary value involved in this treatment is that of 2,725.00 Mexican pesos (US $283.00) for administering the drug over a one-year period to each child suffering from this disability. This is a low-cost treatment, because it is currently impossible to reverse the neurological and physiological processes of cerebral palsy, this treatment therefore improving the quality of life of the children afflicted with this disease is the best possible benefit. The cost effectiveness analysis taking into account these indicators reveals a clear-cut relationship between the monetary values and the health benefits.


Whole-Genome-Sequencing characterization of bloodstream infection-causing hypervirulent Klebsiella pneumoniae of capsular serotype K2 and ST374.
Hypervirulent K. pneumoniae variants (hvKP) have been increasingly reported worldwide, causing metastasis of severe infections such as liver abscesses and bacteremia. The capsular serotype K2 hvKP strains show diverse multi-locus sequence types (MLSTs), but with limited genetics and virulence information. In this study, we report a hypermucoviscous K. pneumoniae strain, RJF293, isolated from a human bloodstream sample in a Chinese hospital. It caused a metastatic infection and fatal septic shock in a critical patient. The microbiological features and genetic background were investigated with multiple approaches. The Strain RJF293 was determined to be multilocis sequence type (ST) 374 and serotype K2, displayed a median lethal dose (LD50) of 1.5 × 102 CFU in BALB/c mice and was as virulent as the ST23 K1 serotype hvKP strain NTUH-K2044 in a mouse lethality assay. Whole genome sequencing revealed that the RJF293 genome codes for 32 putative virulence factors and exhibits a unique presence/absence pattern in comparison to the other 105 completely sequenced K. pneumoniae genomes. Whole genome SNP-based phylogenetic analysis revealed that strain RJF293 formed a single clade, distant from those containing either ST66 or ST86 hvKP. Compared to the other sequenced hvKP chromosomes, RJF293 contains several strain-variable regions, including one prophage, one ICEKp1 family integrative and conjugative element and six large genomic islands. The sequencing of the first complete genome of an ST374 K2 hvKP clinical strain should reinforce our understanding of the epidemiology and virulence mechanisms of this bloodstream infection-causing hvKP with clinical significance.


The minimal replicator element of the Kaposi's sarcoma-associated herpesvirus terminal repeat supports replication in a semiconservative and cell-cycle-dependent manner.
Kaposi's sarcoma-associated herpesvirus (KSHV) persists as episomes in infected cells by circularizing at the terminal repeats (TRs). The KSHV episome carries multiple reiterated copies of the terminal repeat, and each copy is capable of supporting replication. Expression of the latency-associated nuclear antigen (LANA) is critical for the replication of TR-containing plasmids. A 32-bp sequence upstream of LANA binding site 1 (LBS1), referred to as RE (replication element), along with LANA binding sites 1 and 2 (RE-LBS1/2), is sufficient to support replication (J. Hu and R. Renne, J. Virol. 79:2637-2642, 2005). In this report we demonstrate that the minimal replicator element (RE-LBS1/2) replicates in synchrony with the host cellular DNA, and only once, in a cell-cycle-dependent manner. Overexpression of the mammalian replication inhibitor geminin blocked replication of the plasmid containing the minimal replicator element, confirming the involvement of the host cellular replication control mechanism, and prevented rereplication of the plasmid in the same cell cycle. Overexpression of Cdt1 also rescued the replicative ability of the RE-LBS1/2-containing plasmids. A chromatin immunoprecipitation assay performed using anti-origin recognition complex 2 (alpha-ORC2) and alpha-LANA antibodies from cells transfected with RE-LBS1/2, RE-LBS1, LBS1, or RE showed the association of ORC2 with the RE region. Expression of LANA increased the number of copies of chromatin-bound DNA of replication elements, suggesting that LANA is important for the recruitment of ORCs and may contribute to the stabilization of the replication protein complexes at the RE site.


Recording the sleep EEG with periorbital skin electrodes.
The aim of the study was to examine whether the typical changes of the EEG in the course of a sleep episode can be recorded by skin electrodes placed at the outer canthi of the eyes. In sleep recording from young, healthy subjects, the signals from the electro-oculogram (EOG, E1-A2) derivation and a central scalp EEG derivation (C3-A2) were compared. Sleep stage scores obtained separately from each of the two signals yielded highly corresponding values with the exception of stages 2 and 4, for which there were discrepancies. Both signals were subjected to spectral analysis to compare the spectra and their evolution during sleep. An automated detection routine served to identify and eliminate epochs contaminated by eye movement potentials. The typical time course of EEG slow-wave activity (SWA; power density in the 0.75-4.5 Hz range) could be derived from both signals with only minor differences between the data sets. However, compared to the EEG spectra, power density of the EOG spectra was attenuated in frequencies higher than 2 Hz and the typical changes in the spindle frequency range were not evident. The results show that the major sleep parameters as well as the dynamics of SWA can be reliably determined from signals recorded from periorbital skin electrodes.


Selection for cuticular melanism reveals immune function and life-history trade-offs in Spodoptera littoralis.
Several insect species show an increase in cuticular melanism in response to high densities. In some species, there is evidence that this melanism is correlated with an up-regulation of certain immune system components, particularly phenoloxidase (PO) activity, and with the down-regulation of lysozyme activity, suggesting a trade-off between the two traits. As melanism has a genetic component, we selected both melanic and nonmelanic lines of the phase-polyphenic lepidopteran, Spodoptera littoralis, in order to test for a causative genetic link between melanism, PO activity and lysozyme activity, and to establish if there are any life-history costs associated with the melanic response. We found that, in fact, melanic lines had lower PO activity and higher lysozyme activity than nonmelanic lines, confirming a genetic trade-off between the two immune responses, but also indicating a genetic trade-off between melanism and PO activity. In addition, we found that lines with high PO activity had slower development rates suggesting that investment in PO, rather than in melanism, is costly.


Understanding the stigma of hyperemesis gravidarum: qualitative findings from an action research study.
Severe nausea and vomiting in pregnancy (hyperemesis gravidarum) can be a distressing and debilitating condition when it is uncontrolled. For all concerned, hyperemesis gravidarum can be difficult to treat satisfactorily, and women tend to be admitted to a hospital several times during early pregnancy. Our research objectives were to describe the experience of hyperemesis gravidarum from the perspective of affected women and to explore with health care professionals the barriers and facilitators to caring for women with the condition. A qualitative research design was used. A total of 18 women were interviewed, of whom 8 had two or more interviews. Seven focus groups were conducted with health care professionals. Thematic data analysis was undertaken. The main themes emerging from the women's data were the effect and burden of the symptoms of the condition and feeling unpopular with staff. From the practitioner data, the main themes were the validity (or invalidity) of hospitalization for women, skepticism of the severity of symptoms, the psychological and social dimensions of the condition, and inadequate primary care services. The main findings revealed that hyperemesis gravidarum is a debilitating condition and that the unhelpful attitudes of practitioners may affect whether women access timely and appropriate care. Many women appear to be unsupported by primary care services and are distressed when perceived either as "time wasters" or someone else's responsibility. We propose that a tailored assessment and care plan for each woman is needed to help them control their symptoms, which ideally should be delivered in the community.


[The clinical existence of isolated non-thrombotic insufficiency of the conductive veins of the leg].
Attention is paid to the set of problems connected with the nonthrombotic insufficiency of the conducting veins of the leg. Phlebographic and X-ray morphometric investigations of the last years were able to prove that the primary varicosis does not exclusively represent a disease of the superficial and perforating fasciae venous system, but that the subfascial venous system (system of conductive veins) is without doubt also included in the pathogenetic reactive process. Two casuistic descriptions of cases with phlebographically and Doppler-sonographically ascertained insufficiency of the conductive veins of the leg are demonstrated. It is referred to the diagnostic, clinical and therapeutic problems of the isolated nonthrombotic insufficiency of the conductive veins. Leading diagnostic criteria of the isolated ectatic (varicose) insufficiency of the conducting veins of the leg are: symptomatology of subjective complaints, such as sensation of tension, feeling of heaviness of the legs, inclination to swelling, pains, epifascial freedom from varices, phlebographic evidence of the ectasia of conductive veins and sonographic confirmation of reflux.


Area-based methods to calculate hospitalization rates for the foreign-born population in Canada, 2005/2006.
Hospital records lack information about country of birth. This study describes a method for calculating hospitalization rates by the percentage of foreign-born in Census Dissemination Areas (DAs). Data from the 2006 Census were used to classify DAs by the percentage of the foreign-born population who lived in them. Quintile and tercile thresholds were created to classify DAs as having low to high percentages of foreign-born residents. This information was appended to the 2005/2006 Hospital Morbidity Database via postal codes. Age-sex standardized hospitalization rates were calculated for low to high foreign-born concentration DAs, nationally and subnationally. Nationally, quintile thresholds had better discriminatory power to detect variations in hospitalization rates by foreign-born concentration, but tercile thresholds produced reliable results at subnational levels. All-cause hospitalization rates were lowest among residents of the high foreign-born concentration terciles. Similar gradients emerged in hospitalization rates for heart disease, diseases of the circulatory system, and mental health conditions. The pattern varied more at the subnational level. With this approach, administrative data can be used to calculate hospitalization rates by foreign-born concentration.


KnotProt 2.0: a database of proteins with knots and other entangled structures.
The KnotProt 2.0 database (the updated version of the KnotProt database) collects information about proteins which form knots and other entangled structures. New features in KnotProt 2.0 include the characterization of both probabilistic and deterministic entanglements which can be formed by disulfide bonds and interactions via ions, a refined characterization of entanglement in terms of knotoids, the identification of the so-called cysteine knots, the possibility to analyze all or a non-redundant set of proteins, and various technical updates. The KnotProt 2.0 database classifies all entangled proteins, represents their complexity in the form of a knotting fingerprint, and presents many biological and geometrical statistics based on these results. Currently the database contains >2000 entangled structures, and it regularly self-updates based on proteins deposited in the Protein Data Bank (PDB).


Collision cross section measurements for biomolecules within a high-resolution FT-ICR cell: theory.
In this study, an energetic hard-sphere ion-neutral collision model was proposed to bridge-link ion collision cross section (CCS) with the image current collected from a high-resolution Fourier transform ion cyclotron resonance (FT-ICR) cell. By investigating the nonlinear effects induced by high-order electric fields and image charge forces, the energetic hard-sphere collision model was validated through experiments. Suitable application regions for the energetic hard-sphere collision model, as well as for the conventional Langevin and hard-sphere collision models, were also discussed. The energetic hard-sphere collision model was applied in the extraction of ion CCSs from high-resolution FT-ICR mass spectra. Discussions in the present study also apply to FT-Orbitraps and FT-quadrupole ion traps.


Addressing the distribution of proteins spotted on μPADs.
Adsorption is the most common approach to immobilize biorecognition elements on the surface of paper-based devices. Adsorption is also the route selected to coat the substrate with albumin, therefore minimizing the interaction of other proteins. While similar in nature, the structure of the selected proteins as well as the conditions selected from the immobilization have a significant effect on the amount and distribution of the resulting composites. To illustrate these differences and provide general guidelines to efficiently prepare these devices, this article explores the interaction (adsorption and desorption) of BSA with 3MM chromatography paper. The experimental conditions investigated were the protein concentration, the interaction time, the number of times the protein was spotted, the pH of buffer solution, and the ionic strength of the buffer solution. The proposed approach mimics the steps involved in the fabrication (adsorption) and use (rinsing induced by the sample) of paper-based microfluidic devices. To identify the protein location following the rinsing step, the protein was fixed by dehydration in a convection oven and then stained using Coomassie Blue. The color intensity, which was found to be proportional to the amount of protein immobilized, was determined using a desktop scanner. To highlight the importance of understanding the adsorption process to the rational development of μPADs, results were complemented by experiments performed with lysozyme and immunoglobulin G.


Retrospective Cohort Study to Assess the Risk of Rabies in Biting Dogs, 2013⁻2015, Republic of Haiti.
In canine rabies endemic countries the World Health Organization recommends post-exposure prophylaxis (PEP) be initiated immediately after exposure to an animal suspected to have rabies. Limited capacity in low and middle income countries to assess biting animals for rabies may result in the over prescription of rabies biologics. Few guidelines exist to determine the risk of whether a dog that has bitten someone is rabid. Given PEP cost and access limitations in many countries, accurate and timely assessment of dogs that have bitten people may reduce unwarranted PEP use and improve healthcare seeking behaviors. Haiti's animal rabies surveillance program utilizes veterinary professionals to conduct rabies assessments on reported biting dogs and records characteristics of the dog, health outcomes, and laboratory results in a national database. Characteristics of rabid dogs were assessed through a retrospective cohort study of biting dogs investigated during the period from January 2013⁻December 2015. 1409 biting dogs were analyzed; 1361 dogs that were determined to not have rabies were compared to 48 laboratory-confirmed rabid dogs. Rate ratios, sensitivity, specificity, positive predictive values, negative predictive values, likelihood ratios, quarantine survival of biting dogs, and a risk matrix were developed. The assessor's determination that the animal likely had rabies was the most significant predictive factor for a rabid dog (RR = 413.4, 95% CI 57.33⁻2985, Sn = 79.17, Sp = 91.92). Clinical factors significantly associated with rabid dogs included hypersalivation, paralysis, and lethargy (RR = 31.2, 19.7, 15.4, respectively). Rabid dogs were 23.2 times more likely to be found dead at the time of the investigation compared to case negative dogs (95% CI 14.0⁻38.6). Rabid dogs were also significantly more likely to lack a history of rabies vaccination or be unowned (RR = 10.3 95% CI 2.5⁻42.3 and RR = 4.5 95% CI 2.0⁻10.1, respectively). Rabid dogs were four times more likely to have bitten multiple people (RR = 4.0 95% CI 1.9⁻8.3). Most rabid dogs died or were killed before quarantine (75%) and all died by day 3 of quarantine, compared to <1% of quarantined case-negatives. The greatest risk of death was predicted to be for persons bitten on the head or neck from symptomatic dogs. Bites from dogs deemed healthy by veterinary assessors and which were available for quarantine presented less than a 0.05% risk of rabies death to the victim. Vaccination of all persons exposed to a suspected rabid dog is a highly effective approach to minimize human rabies deaths. However, this may place undue financial burden on bite victims that have had a low-risk exposure and over-prescription may contribute to regional supply shortages. The results here indicate that in a low-resource country such as Haiti, a well-trained veterinary assessor can provide an accurate risk assessment of biting dogs based on a standard case investigation protocol. In canine rabies endemic countries with limited access to PEP, or where PEP costs may cause undue burden on bite victims, structured risk assessments by trained professionals may be a reliable method of triaging PEP for bite victims. Evaluating rabies risk through a matrix of bite location and risk factor in the dog presents a clear delineation of high and low risk encounters and should be used to develop data-derived PEP recommendations.


Phenotypic changes of peripheral blood mononuclear cells upon corticosteroid treatment in idiopathic intermediate uveitis.
We analyzed phenotype and function of peripheral blood mononuclear cells in 9 patients with active idiopathic intermediate uveitis (IIU) before and after 6 and 12weeks of systemic corticosteroid (CS) treatment and compared to 28 healthy individuals. Monocytes from IIU patients showed increased MHCII expression compared with controls (p=0.09). Treatment reduced expression of MHCII, CD86, CD39 and CD124 (all p<0.05), whereas the percentage of CD121b-expressing monocytes was increased by week 6 (p=0.039). Patients showed alterations in T cell polarization (Th1/Th2 ratio: patients 5.2 versus controls 3.1, p=0.054; Th17/Treg ratio: 3.0 versus 1.7, p=0.027). S100A12 serum levels were higher in active IIU (p=0.057). Phagocytosis, oxidative burst and serum cytokine levels did not differ between patients and controls, and were not altered by treatment. In conclusion, monocytes from patients with active IIU show increased co-stimulatory capacities, which are modulated by systemic CS treatment, whereas innate immune cell functions are not altered.


Topographical thickness of the epithelium and total cornea after hydrogel and PMMA contact lens wear with eye closure.
To determine changes in topographical thickness of the epithelium and total cornea after hydrogel (2-hydroxyethyl methacrylate; HEMA or soft lens) and PMMA rigid contact lens wear with eyes closed, as measured by optical coherence tomography (OCT). Epithelial and total corneal thickness in 18 neophyte eyes was measured with OCT at intervals of 10 degrees across a 10-mm zone of the horizontal meridian of the cornea, before and after 3 hours of soft and rigid contact lens wear with the eye closed. These measurements were repeated 20 minutes after removal of the lenses. Lens type, time, and location were found to be significant main influences (P < 0.0001) on corneal swelling in patched eyes, by three-way ANOVA, and there was a significant three-way interaction among lens type, time, and location (F((16,272)) = 1.78, P = 0.033). However, there was no significant main effect and interaction of epithelial thickness (F((16, 272)) = 0.33, P = 0.99). Immediately after removal of the lenses, total corneal thickness in the horizontal meridian was significantly greater with both soft and PMMA lenses (P < 0.001) at each location with each lens, compared with the baseline measurements. With both lenses, the increase in actual thickness and percentage of corneal swelling at the center was greater than at each peripheral point (excluding the first 10 degrees points; P < 0.005). HEMA lenses caused greater corneal swelling than the PMMA lenses at each location immediately after removal of the lenses (P < 0.005). This study shows that corneal swelling is dependent on lens type and corneal location when eyes are closed, but epithelial thickness across the horizontal corneal meridian does not change during lens wear with eyes closed. OCT is an efficient method of measuring topographical corneal and epithelial thickness in response to contact lens wear.


Velocity storage mechanism in zebrafish larvae.
The optokinetic reflex (OKR) and the angular vestibulo-ocular reflex (aVOR) complement each other to stabilize images on the retina despite self- or world motion, a joint mechanism that is critical for effective vision. It is currently hypothesized that signals from both systems integrate, in a mathematical sense, in a network of neurons operating as a velocity storage mechanism (VSM). When exposed to a rotating visual surround, subjects display the OKR, slow following eye movements frequently interrupted by fast resetting eye movements. Subsequent to light-off during optokinetic stimulation, eye movements do not stop abruptly, but decay slowly, a phenomenon referred to as the optokinetic after-response (OKAR). The OKAR is most likely generated by the VSM. In this study, we observed the OKAR in developing larval zebrafish before the horizontal aVOR emerged. Our results suggest that the VSM develops prior to and without the need for a functional aVOR. It may be critical to ocular motor control in early development as it increases the efficiency of the OKR.


Angiotensin-sodium interaction in blood pressure maintenance of renal hypertensive and normotensive rats.
A specific inhibitor of angiotensin II was used in rats to investigate whether angiotensin is involved in the maintenance of blood pressure in one-kidney Goldblatt hypertension, in which plasma renin levels are not usually increased. The inhibitor produced marked falls in blood pressure, often down to normal levels in the hypertensive animals only when they were depleted in sodium and not after sodium repletion. Much lesser but still significant falls in blood pressure were also produced in normotensive sodium-depleted rats but not in repleted rats. We conclude that the importance of angiotensin for maintaining blood pressure is largely determined by its relation to available sodium or fluid volume, since the renin component in maintenance of either the hypertensive or the normotensive state could be exposed only by sodium deprivation. Therefore, volume expansion per se or other pressor factors may be involved in maintaining blood pressure of these sodium-replete normotensive or hypertensive animals.


Do early neural correlates of visual consciousness show the oblique effect? A binocular rivalry and event-related potential study.
When dissimilar images are presented one to each eye, we do not see both images; rather, we see one at a time, alternating unpredictably. This is called binocular rivalry, and it has recently been used to study brain processes that correlate with visual consciousness, because perception changes without any change in the sensory input. Such studies have used various types of images, but the most popular have been gratings: sets of bright and dark lines of orthogonal orientations presented one to each eye. We studied whether using cardinal rival gratings (vertical, 0°, and horizontal, 90°) versus oblique rival gratings (left-oblique, -45°, and right-oblique, 45°) influences early neural correlates of visual consciousness, because of the oblique effect: the tendency for visual performance to be greater for cardinal gratings than for oblique gratings. Participants viewed rival gratings and pressed keys indicating which of the two gratings they perceived, was dominant. Next, we changed one of the gratings to match the grating shown to the other eye, yielding binocular fusion. Participants perceived the rivalry-to-fusion change to the dominant grating and not to the other, suppressed grating. Using event-related potentials (ERPs), we found neural correlates of visual consciousness at the P1 for both sets of gratings, as well as at the P1-N1 for oblique gratings, and we found a neural correlate of the oblique effect at the N1, but only for perceived changes. These results show that the P1 is the earliest neural activity associated with visual consciousness and that visual consciousness might be necessary to elicit the oblique effect.


Polyspecific pyrrolysyl-tRNA synthetases from directed evolution.
Pyrrolysyl-tRNA synthetase (PylRS) and its cognate tRNA(Pyl) have emerged as ideal translation components for genetic code innovation. Variants of the enzyme facilitate the incorporation >100 noncanonical amino acids (ncAAs) into proteins. PylRS variants were previously selected to acylate N(ε)-acetyl-Lys (AcK) onto tRNA(Pyl). Here, we examine an N(ε)-acetyl-lysyl-tRNA synthetase (AcKRS), which is polyspecific (i.e., active with a broad range of ncAAs) and 30-fold more efficient with Phe derivatives than it is with AcK. Structural and biochemical data reveal the molecular basis of polyspecificity in AcKRS and in a PylRS variant [iodo-phenylalanyl-tRNA synthetase (IFRS)] that displays both enhanced activity and substrate promiscuity over a chemical library of 313 ncAAs. IFRS, a product of directed evolution, has distinct binding modes for different ncAAs. These data indicate that in vivo selections do not produce optimally specific tRNA synthetases and suggest that translation fidelity will become an increasingly dominant factor in expanding the genetic code far beyond 20 amino acids.


Natural product driven diversity via skeletal remodeling of caryophyllene β-lactam.
(-)-β-Caryophyllene was decorated with a privileged β-lactam motif and subsequently converted into highly diverse scaffolds via remodeling of the ring system. The structures were defined by spectroscopic data, X-ray diffraction analysis, and experimental and calculated ECD data. Compound 19 displayed the most potent activity against the rice blast fungus, while 6 had a more potent α-glucosidase inhibition than the drug acarbose. These findings demonstrate a concise protocol to exploit natural product-driven diversity.


Effects of ambient temperature on the incidence of myocardial infarction.
While the effects of weather and, in particular, ambient temperature on overall mortality are well documented, the strength of the evidence base for the effects on acute myocardial infarction (MI) are less clear. To systematically review studies specifically focusing on the effects of temperature on MI. Medline, Embase, and GeoBase publication databases, as well as reference lists, and the websites of a number of relevant public organisations. Studies of original data in which ambient temperature was an exposure of interest and MI a specific outcome were selected. The reported effects of ambient temperature on the risk of MI, including effect sizes and confidence intervals, where possible, were recorded. Methodological details were also extracted, including study population, location and setting, ascertainment of MI events, adjustment for potential confounders and consideration of lagged effects. 19 studies were identified, of which 14 considered the short-term effects of temperature on a daily timescale, the remainder looking at longer-term effects. Overall, 8 of the 12 studies which included relevant data from the winter season reported a statistically significant short-term increased risk of MI at lower temperatures, while increases in risk at higher temperatures were reported in 7 of the 13 studies with relevant data. A number of differences were identified between studies in the population included demographics, location, local climate, study design and statistical methodology. A number of studies, including some that were large and relatively well controlled, suggested that both hot and cold weather had detrimental effects on the short-term risk of MI. However, further research with consistent methodology is needed to clarify the magnitude of these effects and to show which populations and individuals are vulnerable.


Moderate exercise with a dietary vitamin C and e combination protects against streptozotocin-induced oxidative damage to the kidney and lens in pregnant rats.
Moderate exercise and vitamin C and E (VCE) supplementation can be beneficial to diabetes due to reducing free radical production in lens and kidney of diabetic pregnant rats. We investigated the effect of VCE supplementation and moderate exercise on lipid peroxidation (MDA) and scavenging enzyme activity in the kidneys and lens of STZ-induced diabetic pregnant rats. Fifty female Wistar rats were used and were randomly divided into five groups. First and second were used as the control and pregnant control group. Third group was the pregnant diabetic group. The fourth group was the diabetic-pregnant-exercise group. VCE-supplemented feed was given to pregnant-diabetic-exercise rats constituting the fifth group. Animals in the exercised groups were moderately exercised daily on a treadmill (16.1 m/min, 45 min/d) for three weeks (five days a week). Diabetes was induced on day zero of the study. Plasma, lens, and kidney samples were taken from all animals on day 20. Exercise and administration of VCE to pregnant diabetic rats resulted in significant decrease in the albumin and total protein values and the elevated MDA, plasma creatinine, and urea levels as an indicator of oxidative stress and renal functional parameters. Exercise and VCE supplementation also increased glutathione peroxidase (GSH-Px), reduced glutathione (GSH), vitamin E, and beta-carotene levels in the kidney, GSH-Px and GSH in the lens, the albumin and total protein values in plasma. In the diabetic pregnant animals, the decreased vitamins A and E concentration and GSH levels in kidney, creatinine, and urea values in plasma did not improve through exercise only although their concentrations were increased by VCE supplementation. Kidney weight did not also affect either by exercise or VCE supplementation. In conclusion, these results suggest that exercise plus VCE affects antioxidant metabolism and reduces lipid peroxidation, thereby improving the damage caused by oxidative stress involved in the pathogenesis of lens and kidney in diabetic pregnant rats. Moderate exercise with dietary VCE may play a role in preventing nephropathy and cataract formation in diabetic pregnant rat.


Magnetic resonance evaluation of knee osteoarthritis among the Saudi Population.
Osteoarthritis (OA) is the most prevalent worldwide joint degenerative disorder with high morbidities and disabilities. The current study aimed to investigate the prevalence of knee osteoarthritis (KOA) in Arar by using magnetic resonance imaging (MRI). The prevalence of KOA was studied in Arar through MRI evaluation of randomly chosen sample from patients and their relatives attending the Prince Abdul Aziz Bin Mussad Hospital from October 2015 to November 2016. A total of 410 participants were enrolled in the study [328 (80%) male and 82 (20%) females]. After MRI, 163 participants [39.75% (95% CI) = 35.14 - 44.57%)] were diagnosed with KOA. The prevalence of OA was about 25.6% (95% CI = 20.8 - 31.1%) below the age of 40 years, which was found to increase by age in the enrolled volunteers. KOA prevalence was higher in females than males (75.6% and 27.7% respectively). There was a significant association between the age and genders of the participants and the prevalence of OA (p-value < 0.0001 for both variables). There was also a significant association between the age and gender of the participants and the MRI-estimated grading (p-value < 0.0001 and 0.0044 respectively). KOA is a common disease among Arar young population, especially females. Its prevalence increases by age with higher grades of severity affecting the elderly.


Refixation frequency and memory mechanisms in visual search.
Visual search-looking for a target object in the presence of a number of distractor items-is an everyday activity for humans (for example, finding the car in a busy car park) and animals (for example, foraging for food). Our understanding of visual search has been enriched by an interdisciplinary effort using a wide range of research techniques including behavioural studies in humans [1], single-cell electrophysiology [2], transcranial magnetic stimulation [3], event-related potentials [4] and studies of patients with focal brain injury [5]. A central question is what kind of information controls the search process. Visual search is typically accompanied by a series of eye movements, and investigating the nature and location of fixations helps to identify the kind of information that might control the search process. It has already been demonstrated that objects are fixated if they are visually similar to the target [6]. Also, if an item has been fixated, it is less likely to be returned to on the subsequent saccade. This automatic process is referred to as inhibition of return (IOR [7,8]). Here, we investigated the role of memory for which items had been fixated previously. We found that, during search, subjects often refixated items that had been previously fixated. Although there were fewer return saccades than would be expected by chance, the number of refixations indicated limited functional memory, indeed the memory effects that were present may primarily be a result of IOR.


Inter-species horizontal transfer resulting in core-genome and niche-adaptive variation within Helicobacter pylori.
Horizontal gene transfer is central to evolution in most bacterial species. The detection of exchanged regions is often based upon analysis of compositional characteristics and their comparison to the organism as a whole. In this study we describe a new methodology combining aspects of established signature analysis with textual analysis approaches. This approach has been used to analyze the two available genome sequences of H. pylori. This gene-by-gene analysis reveals a wide range of genes related to both virulence behaviour and the strain differences that have been relatively recently acquired from other sequence backgrounds. These frequently involve single genes or small numbers of genes that are not associated with transposases or bacteriophage genes, nor with inverted repeats typically used as markers for horizontal transfer. In addition, clear examples of horizontal exchange in genes associated with 'core' metabolic functions were identified, supported by differences between the sequenced strains, including: ftsK, xerD and polA. In some cases it was possible to determine which strain represented the 'parent' and 'altered' states for insertion-deletion events. Different signature component lengths showed different sensitivities for the detection of some horizontally transferred genes, which may reflect different amelioration rates of sequence components. New implementations of signature analysis that can be applied on a gene-by-gene basis for the identification of horizontally acquired sequences are described. These findings highlight the central role of the availability of homologous substrates in evolution mediated by horizontal exchange, and suggest that some components of the supposedly stable 'core genome' may actually be favoured targets for integration of foreign sequences because of their degree of conservation.


AP-1 and KIF13A coordinate endosomal sorting and positioning during melanosome biogenesis.
Specialized cell types exploit endosomal trafficking to deliver protein cargoes to cell type-specific lysosome-related organelles (LROs), but how endosomes are specified for this function is not known. In this study, we show that the clathrin adaptor AP-1 and the kinesin motor KIF13A together create peripheral recycling endosomal subdomains in melanocytes required for cargo delivery to maturing melanosomes. In cells depleted of AP-1 or KIF13A, a subpopulation of recycling endosomes redistributes to pericentriolar clusters, resulting in sequestration of melanosomal enzymes like Tyrp1 in vacuolar endosomes and consequent inhibition of melanin synthesis and melanosome maturation. Immunocytochemistry, live cell imaging, and electron tomography reveal AP-1- and KIF13A-dependent dynamic close appositions and continuities between peripheral endosomal tubules and melanosomes. Our results reveal that LRO protein sorting is coupled to cell type-specific positioning of endosomes that facilitate endosome-LRO contacts and are required for organelle maturation.


Transcriptome analysis reveals the mechanism of the effect of flower tea Coreopsis tinctoria on hepatic insulin resistance.
Non-Camellia tea and herbal medicine help prevent the development of diabetes and other metabolic diseases. Previous studies revealed that Coreopsis tinctoria (CT) flower tea increases insulin sensitivity and, in some high-fat diet (HFD)-fed rats, even prevents hepatic metabolic disorders. However, the molecular mechanisms by which CT improves insulin resistance are not known. In this study, six-week-old rats were fed a normal diet (ND), an HFD or an HFD supplemented with CT for 8 weeks. Serum samples were collected, and the livers were extracted for RNA-seq gene expression analysis. Real-time PCR and western blotting further verified the RNA-seq results. In our results, dietary CT ameliorated HFD-induced hepatosteatosis, glucose intolerance, and insulin resistance. In the HFD group, 1667 differentially expressed genes (DEGs) were identified compared with the ND group. In the CT group, 327 DEGs were identified compared with the HFD group. Some of these DEGs were related to insulin signalling, hepatic lipogenesis and glucose homeostasis. This study suggested that insulin resistance with hyperinsulinaemia, and not insulin insufficiency, is an early problem in HFD-fed rats, and CT downregulates insulin secretion genes (e.g., Rasd1, Stxbp1 and Sfxn1). Hepatic gene and protein expression analyses indicated that the regulatory effects of CT on glucose and lipid homeostasis are likely mediated via the Akt/FoxO1 signalling pathway and are regulated by the transcription factors hairy and enhancer of split 1 (HES1) and small heterodimer partner (SHP). Our study provides transcriptomic evidence of the complex pathogenic mechanism involved in hepatic insulin resistance and proves that supplementation with CT improves insulin resistance at a global scale.


Investigation of immunosuppressive mechanisms in a mouse glioma model.
The development of an immune competent mouse model for the study of immunosuppressive mechanisms is important for improving the efficacy of brain tumor immunotherapy. In the present study we investigated regulatory T cells (Tregs), TGF-beta1 and other putative immunosuppressive cytokines using GL261 mouse glioma in C57BL mice. We explored whether tumor growth factor-beta1 (TGF-beta1) is expressed and secreted by glioma cells constitutively or in response to a T-cell mediated immunity (simulated by conditioned media from T cells (TCM) activated by anti-CD3 antibody). We also investigated TGF-beta1's role in Treg mediated immunosuppression by quantifying TGF-beta1secretion from T regulatory cells (Tregs) co-incubated with GL261 cells as compared to Tregs alone. Finally, we studied other newly identified cytokines that were secreted preferentially by glioma cells in response to CD3 activated TCM versus cytokines secreted by glioma cells in absence of T-cell activation (naïve TCM). TGF-beta1expression was studied using RT-PCR and secretion was quantified using ELISA. A 308 protein cytokine array was used to identify and quantify cytokine expression. TGF-beta1expression and secretion from glioma cells was found to be up-regulated by conditioned media from CD3-activated T cells, suggesting that this immunosuppressive cytokine is not secreted constitutively but in response to immunity. TGF-beta1 was not found to be differentially secreted by Tregs co-incubated with glioma cells as compared to Tregs alone. This data suggest that TGF-beta1immunosupppression may not be a Treg dependent mechanism in this glioma model. Finally, the cytokine array elucidated several other cytokines which were up-regulated or down-regulated by CD3-activated TCM. These results have several implications for enhancing immunotherapy treatment, including the potential benefit of TGF-beta1inhibition in conjunction with immunotherapy, as well as the illumination of several other potential cytokine targets to be explored as shown by the cytokine array.


Transition and change: prospective effects of posttraumatic stress on smoking trajectories in the first year of college.
College matriculation begins a period of transition that is marked by new freedoms and responsibilities and by increases in a variety of risky behaviors, including smoking. Trauma and posttraumatic stress disorder (PTSD) are well-established risk factors for smoking outcomes, and thus may be a point of intervention for college smoking. Yet, no studies have examined associations among trauma, PTSD, and smoking in college students. The present study provides such an examination. Matriculating student smokers (N = 346) completed surveys in September (T1) and at 5 subsequent time points (T2-T6) over their first year of college. With latent growth analysis, we modeled smoking trajectories conditioned on PTSD symptom status (i.e., No PTSD Symptoms vs. Partial PTSD vs. Full PTSD). Results showed that although smoking tended to decline during the first semester for all groups, significant risk for escalation in smoking during the second semester was conferred specifically by the presence of PTSD at matriculation. Interventions that offer support and resources to students entering college with PTSD may help to prevent smoking behaviors from escalating and may ultimately prevent the adoption of daily smoking in later adulthood.


Cigarette smoking and chewing gum: response to a laboratory-induced stressor.
The current study examined the anxiolytic effects of cigarette smoking and chewing gum on urge to smoke, withdrawal, and anxiety in response to a public speaking task in 45 undergraduate smokers. Participants were asked to smoke, chew gum, or do nothing in response to the stressor. Participants completed measures of anxiety, withdrawal symptoms, and urge to smoke pre- and poststressor. The smoke group reported fewer urges to smoke pre- and poststressor than the other groups. The smoke and gum groups reported fewer withdrawal symptoms than did the control group poststressor. Chewing gum was helpful in managing levels of withdrawal symptoms compared with the control group. Groups did not differ on measures of anxiety. Results suggest that smoking in response to a stressor may not reduce levels of affective stress. Furthermore, chewing gum may be helpful in managing withdrawal symptoms in response to a stressor.


CRISPR-Cas9 Causes Chromosomal Instability and Rearrangements in Cancer Cell Lines, Detectable by Cytogenetic Methods.
CRISPR-Cas9 has quickly become the method of choice for genome editing, with multiple publications describing technical advances and novel applications. It has been widely adopted as a tool for basic research and has significant translational and clinical potential. However, its usage has outpaced the establishment of essential and rigorous controls for unwanted off-target effects, manifested as small mutations, large deletions of target loci, or large-scale chromosomal rearrangements. A common application of CRISPR-Cas9 is as a tool for creating isogenic cell-line models to study the effects of precise mutations, or variants, on disease traits. Here, we describe the effect of standard CRISPR-Cas9 mutagenesis protocols on well characterized cancer cell lines. We demonstrate that commonly used methods for detecting correctly mutated clones fail to uncover large-scale rearrangements. We show that simple cytogenetic methods can be used to identify clones carrying chromosomal abnormalities and large mutations at target loci. These methods are quick and cost-efficient, and we suggest that such controls should be performed prior to publication of studies based on novel CRISPR-Cas9 mutated cancer cell lines.


Exploratory study into the effect of abdominal mass loading on airways resistance and ventilatory failure.
We hypothesised that the airway resistance during tidal breathing would correlate with a particular pattern of increasing obesity, particularly when supine, and would differ between participants with and without ventilatory failure. In our cross-sectional cohort study, 72 morbidly obese patients (40 males, 32 females, mean body mass index (BMI) 47.2) had measurements of both airways resistance (by impulse oscillometry (IOS)) and adiposity (by dual-energy X-ray absorptiometry (DXA)). All measures of airways resistance increased in the supine position: total airways resistance (R5) +37% (p<0.0005); large airways resistance (R20) +29% (p<0.0005); and small airways resistance (R5-R20) +52% (p<0.0005). BMI was correlated with seated R5, seated R5-R20, supine R5 and supine R5-R20 (r=0.33 p<0.006, r=0.32 p<0.004, r=0.30 p<0.02 and r=0.36 p<0.04, respectively). Visceral adipose tissue mass was correlated with supine R5-20 (r=0.46 p<0.05). Supine measures of total airways resistance (R5) and large airways resistance (R20) differed between those with and without ventilatory failure, as did mean weight and BMI. Our study identifies a potentially detrimental effect of the supine posture on tidal breathing airways resistance in obese patients. This change is correlated most with visceral adipose tissue mass and the small airways. We were able to demonstrate that supine increases in airways resistance during tidal breathing, within obese patients, are different between those with and without ventilatory failure. NCT01380418; pre-results.


Nonosmotic diabetic cataracts.
It has been suggested that sugar cataracts associated with diabetes mellitus result from the accumulation of excess sorbitol within lens fibrils. Swelling of lens fibrils occurs when water moves in to maintain osmotic balance; the excess water causes disruption of fibrils and cataract formation. Other studies have indicated that more than sorbitol-induced osmotic stress is involved. Our study used lenses collected from rats after 21 or 44 d of streptozotocin diabetes. Cataracts formed in untreated 44-d streptozotocin diabetic rats, but were not apparent in the 21-d untreated diabetic animals. Lens sorbitol increased in the diabetic animals both before and after cataract formation. Lens taurine varied inversely with the sorbitol content in a fashion that resulted in no net change in total lens osmoles. Lens water did not increase in the diabetic animals with or without cataracts. The aldose reductase inhibitor Sorbinil prevented the increase in lens sorbitol in both the 21- and 44-d streptozotocin diabetic rats; cataract formation was prevented in the 44-d diabetic animals. The lens water in untreated diabetic animals with cataracts did not differ from lens water in the Sorbinil-treated diabetic animals that did not develop cataracts. Sorbinil treatment of diabetic animals was associated with normalization of both lens sorbitol and taurine levels. Taurine has been shown to serve both as an osmoregulator and as an antioxidant. The apparent increase in lens osmolality attributed to sorbitol was counterbalanced by an equimolar reduction in taurine concentration. The reciprocal relationship between taurine and sorbitol reduces the likelihood of an osmotic mechanism for sugar cataractogenesis; the reduced lens taurine, however, may increase the risk of lens protein oxidation and subsequent cataract formation. Thus in vivo sugar cataract formation may be an oxidative process rather than an osmotic phenomenon.


Does the transparency of the counting system affect children's numerical abilities?
The Welsh language uses a regular counting system, whereas English uses an irregular counting system, and schools within Wales teach either through the medium of Welsh or English. This provides the opportunity to compare linguistic effects on arithmetical skills in the absence of many other confounding factors that arise in international comparisons. This study investigated the hypothesis that language properties influence children's performance in certain numerical tasks by comparing the performance of 20 Welsh- and 20 English-medium Year Two pupils in non-verbal line estimations and transcoding. Groups did not differ on global arithmetic abilities, but the pupils taught through the medium of Welsh on average performed better in the non-verbal line estimation tasks than the English-medium group. This superiority was most apparent in comparisons involving numbers over 20: a result which was complicated by the fact that Welsh-medium pupils showed a lower range of error scores than the English-medium pupils. These results were thought to be related to the increased transparency of the Welsh counting system.


Technical and operative factors affecting magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: experience from 250 treatments.
Magnetic resonance imaging-guided focused ultrasound (MRgFUS) provides real-time monitoring of patients to assess tremor control and document any adverse effects. MRgFUS of the ventral intermediate nucleus (VIM) of the thalamus has become an effective treatment option for medically intractable essential tremor (ET). The aim of this study was to analyze the correlations of clinical and technical parameters with 12-month outcomes after unilateral MRgFUS thalamotomy for ET to help guide future clinical treatments. From October 2013 to January 2019, data on unilateral MRgFUS thalamotomy from the original pivotal study and continued-access studies from three different geographic regions were collected. Authors of the present study retrospectively reviewed those data and evaluated the efficacy of the procedure on the basis of improvement in the Clinical Rating Scale for Tremor (CRST) subscore at 1 year posttreatment. Safety was based on the rates of moderate and severe thalamotomy-related adverse events. Treatment outcomes in relation to various patient- and sonication-related parameters were analyzed in a large cohort of patients with ET. In total, 250 patients were included in the present analysis. Improvement was sustained throughout the 12-month follow-up period, and 184 (73.6%) of 250 patients had minimal or no disability due to tremor (CRST subscore < 10) at the 12-month follow-up. Younger age and higher focal temperature (Tmax) correlated with tremor improvement in the multivariate analysis (OR 0.948, p = 0.013; OR 1.188, p = 0.025; respectively). However, no single statistically significant factor correlated with Tmax in the multivariate analysis. The cutoff value of Tmax in predicting a CRST subscore < 10 was 55.8°C. Skull density ratio (SDR) was positively correlated with heating efficiency (β = 0.005, p < 0.001), but no significant relationship with tremor improvement was observed. In the low-temperature group, 1-3 repetitions to the right target with 52°C ≤ Tmax ≤ 54°C was sufficient to generate sustained tremor suppression within the investigated follow-up period. The high-temperature group had a higher rate of balance disturbances than the low-temperature group (p = 0.04). The authors analyzed the data of 250 patients with the aim of improving practices for patient screening and determining treatment endpoints. These results may improve the safety, efficacy, and efficiency of MRgFUS thalamotomy for ET.


Oral Health Care Reform in Finland - aiming to reduce inequity in care provision.
In Finland, dental services are provided by a public (PDS) and a private sector. In the past, children, young adults and special needs groups were entitled to care and treatment from the public dental services (PDS). A major reform in 2001 - 2002 opened the PDS and extended subsidies for private dental services to all adults. It aimed to increase equity by improving adults' access to oral health care and reducing cost barriers. The aim of this study was to assess the impacts of the reform on the utilization of publicly funded and private dental services, numbers and distribution of personnel and costs in 2000 and in 2004, before and after the oral health care reform. An evaluation was made of how the health political goals of the reform: integrating oral health care into general health care, improving adults' access to care and lowering cost barriers had been fulfilled during the study period. National registers were used as data sources for the study. Use of dental services, personnel resources and costs in 2000 (before the reform) and in 2004 (after the reform) were compared. In 2000, when access to publicly subsidised dental services was restricted to those born in 1956 or later, every third adult used the PDS or subsidised private services. By 2004, when subsidies had been extended to the whole adult population, this increased to almost every second adult. The PDS reported having seen 118,076 more adult patients in 2004 than in 2000. The private sector had the same number of patients but 542,656 of them had not previously been entitled to partial reimbursement of fees.The use of both public and subsidised private services increased most in big cities and urban municipalities where access to the PDS had been poor and the number of private practitioners was high. The PDS employed more dentists (6.5%) and the number of private practitioners fell by 6.9%. The total dental care expenditure (PDS plus private) increased by 21% during the study period. Private patients who had previously not been entitled to reimbursements seemed to gain most from the reform. The results of this study indicate that implementation of a substantial reform, that changes the traditionally defined tasks of the public and private sectors in an established oral health care provision system, proceeds slowly, is expensive and probably requires more stringent steering than was the case in Finland 2001 - 2004. However, the equity and fairness of the oral health care provision system improved and access to services and cost-sharing improved slightly.


Eight challenges in phylodynamic inference.
The field of phylodynamics, which attempts to enhance our understanding of infectious disease dynamics using pathogen phylogenies, has made great strides in the past decade. Basic epidemiological and evolutionary models are now well characterized with inferential frameworks in place. However, significant challenges remain in extending phylodynamic inference to more complex systems. These challenges include accounting for evolutionary complexities such as changing mutation rates, selection, reassortment, and recombination, as well as epidemiological complexities such as stochastic population dynamics, host population structure, and different patterns at the within-host and between-host scales. An additional challenge exists in making efficient inferences from an ever increasing corpus of sequence data.


Early intestinal Th1 inflammation and mucosal T cell recruitment during acute graft-versus-host reaction.
Little is understood about the earliest cytokine responses and the role(s) of donor CD4 T cells in the intestine during the induced graft-vs-host reaction (GVHR). We investigated the activation and mucosal homing phenotype of the donor CD4 cells and the kinetics of cytokine responses within the intestine and associated lymphoid tissues during early GVHR. Significant frequencies of donor CD4 cells accumulated within recipient Peyer's patches (PP), mesenteric lymph nodes (MLN), lamina propria (LP), and spleen (SP), during the first 9 days of GVHR. Many donor CD4 cells in SP, MLN, and LP expressed CD44 and also expressed de novo the mucosal homing integrin alpha(4)beta(7) (LPAM-1). A large IFN-gamma response occurred by day 3 in cells from PP and MLN, but much later (day 9) in SP and LP cells. IL-10 production by SP and MLN cells was elevated initially but declined substantially by day 9. IL-4 production by SP, MLN, and PP cells was low on day 3 and showed gradual decline in LP by day 9. IL-5 production by LP cells gradually increased in direct contrast to IL-5 production by MLN cells. The MLN CD4 cells showed the most dynamic changes, with high numbers of activated/effector donor CD4 cells and altered cytokine production consistent with a developing Th1 response. The IFN-gamma responses in PP and MLN preceded that of the SP, suggesting an intestinal origin for some Th1 effector cells in GVHR. Donor CD4 T cells apparently acquire the ability to home to the LP during early GVHR.


Pre-Clovis occupation 14,550 years ago at the Page-Ladson site, Florida, and the peopling of the Americas.
Stone tools and mastodon bones occur in an undisturbed geological context at the Page-Ladson site, Florida. Seventy-one radiocarbon ages show that ~14,550 calendar years ago (cal yr B.P.), people butchered or scavenged a mastodon next to a pond in a bedrock sinkhole within the Aucilla River. This occupation surface was buried by ~4 m of sediment during the late Pleistocene marine transgression, which also left the site submerged. Sporormiella and other proxy evidence from the sediments indicate that hunter-gatherers along the Gulf Coastal Plain coexisted with and utilized megafauna for ~2000 years before these animals became extinct at ~12,600 cal yr B.P. Page-Ladson expands our understanding of the earliest colonizers of the Americas and human-megafauna interaction before extinction.


Prognostic Role of in Vitro Survival Efficiency in Human Transitional-Cell Carcinoma.
The purpose of this study was to assess the correlation of in vitro growth features of transitional-cell carcinoma (TCC) specimens with the clinical behavior of the respective tumors. We also analyzed the impact of depth of tumor invasion, histologic differentiation, morphologic characteristics, and nuclear p53 accumulation of tumors on the in vitro survival efficiency of microtumor cultures and the significance of these factors in predicting recurrence and progression of bladder cancer. The tumor cell lines derived from surgical specimens were cultured at 37 degrees C in 5% CO(2) and constant humidity. Microtumor cultures were classified into three groups according to their in vitro lifespan. Our results indicate that higher survival efficiency implies a propensity for aggressive clinical behavior of the tumor in vivo. Factors that imply a poorer prognosis account for longer lifespans for microtumour cultures. These prognostic indicators are also associated with higher rates of recurrence and progression for tumors that exhibit higher survival efficiency in vitro.


In the eye of the beholder: to make global health estimates useful, make them more socially robust.
A plethora of new development goals and funding institutions have greatly increased the demand for internationally comparable health estimates in recent years, and have brought important new players into the field of health estimate production. These changes have rekindled debates about the validity and legitimacy of global health estimates. This paper draws on country case studies and personal experience to support our opinion that the production and use of estimates are deeply embedded in specific social, economic, political and ideational contexts, which differ at different levels of the global health architecture. Broadly, most global health estimates tend to be made far from the local contexts in which the data upon which they are based are collected, and where the results of estimation processes must ultimately be used if they are to make a difference to the health of individuals. Internationally standardised indicators are necessary, but they are no substitute for data that meet local needs, and that fit with local ideas of what is credible and useful. In other words, data that are both technically and socially robust for those who make key decisions about health. We suggest that greater engagement of local actors (and local data) in the formulation, communication and interpretation of health estimates would increase the likelihood that these data will be used by those most able to translate them into health gains for the longer term. Besides strengthening national information systems, this requires ongoing interaction, building trust and establishing a communicative infrastructure. Local capacities to use knowledge to improve health must be supported.


RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression.
Abasic substitutions within DNA or RNA are tools for evaluating the impact of absent nucleobases. Because of the importance of abasic sites in genetic damage, most research has involved DNA. Little information is available on the impact of abasic substitutions within RNA or on RNA interference (RNAi). Here, we examine the effect of abasic substitutions on RNAi and allele-selective gene silencing. Huntington's disease (HD) and Machado Joseph Disease (MJD) are severe neurological disorders that currently have no cure. HD and MJD are caused by an expansion of CAG repeats within one mRNA allele encoding huntingtin (HTT) and ataxin-3 (ATX-3) proteins. Agents that silence mutant HTT or ATX-3 expression would remove the cause of HD or MJD and provide an option for therapeutic development. We describe flexible syntheses for abasic substitutions and show that abasic RNA duplexes allele-selectively inhibit both mutant HTT and mutant ATX-3. Inhibition involves the RNAi protein argonaute 2, even though the abasic substitution disrupts the catalytic cleavage of RNA target by argonaute 2. Several different abasic duplexes achieve potent and selective inhibition, providing a broad platform for subsequent development. These findings introduce abasic substitutions as a tool for tailoring RNA duplexes for gene silencing.


Manipulating graded exercise test variables affects the validity of the lactate threshold and [Formula: see text].
To determine the validity of the lactate threshold (LT) and maximal oxygen uptake ([Formula: see text]) determined during graded exercise test (GXT) of different durations and using different LT calculations. Trained male cyclists (n = 17) completed five GXTs of varying stage length (1, 3, 4, 7 and 10 min) to establish the LT, and a series of 30-min constant power bouts to establish the maximal lactate steady state (MLSS). [Formula: see text] was assessed during each GXT and a subsequent verification exhaustive bout (VEB), and 14 different LTs were calculated from four of the GXTs (3, 4, 7 and 10 min)-yielding a total 56 LTs. Agreement was assessed between the highest [Formula: see text] measured during each GXT ([Formula: see text]) as well as between each LT and MLSS. [Formula: see text] and LT data were analysed using mean difference (MD) and intraclass correlation (ICC). The [Formula: see text] value from GXT1 was 61.0 ± 5.3 mL.kg-1.min-1 and the peak power 420 ± 55 W (mean ± SD). The power at the MLSS was 264 ± 39 W. [Formula: see text] from GXT3, 4, 7, 10 underestimated [Formula: see text] by ~1-5 mL.kg-1.min-1. Many of the traditional LT methods were not valid and a newly developed Modified Dmax method derived from GXT4 provided the most valid estimate of the MLSS (MD = 1.1 W; ICC = 0.96). The data highlight how GXT protocol design and data analysis influence the determination of both [Formula: see text] and LT. It is also apparent that [Formula: see text] and LT cannot be determined in a single GXT, even with the inclusion of a VEB.


"Picolog," a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo.
Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway. Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.


Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.
Inherited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's ataxia (FA), for which there is no successful treatment. We identified a redox deficiency in FA cells and used this to model the disease. We screened a 1600-compound library to identify existing drugs, which could be of therapeutic benefit. We identified the topical anesthetic dyclonine as protective. Dyclonine increased FXN transcript and FXN protein dose-dependently in FA cells and brains of animal models. Dyclonine also rescued FXN-dependent enzyme deficiencies in the iron-sulfur enzymes, aconitase and succinate dehydrogenase. Dyclonine induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which we show binds an upstream response element in the FXN locus. Additionally, dyclonine also inhibited the activity of histone methyltransferase G9a, known to methylate histone H3K9 to silence FA chromatin. Chronic dosing in a FA mouse model prevented a performance decline in balance beam studies. A human clinical proof-of-concept study was completed in eight FA patients dosed twice daily using a 1% dyclonine rinse for 1 week. Six of the eight patients showed an increase in buccal cell FXN levels, and fold induction was significantly correlated with disease severity. Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA.


Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere.
ALPK3 encodes α-kinase 3, a muscle-specific protein of unknown function. ALPK3 loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood. We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues. Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function. ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.


The HOMO Nodal Arrangement in Polychromophoric Molecules and Assemblies Controls the Interchromophoric Electronic Coupling.
Triptycenes spontaneously assemble into two-dimensional networks in which long-range charge transport is facilitated by the extensive electronic coupling through the triptycene framework (intramolecularly) and by cofacial π-stacking (intermolecularly). While designing and synthesizing next-generation triptycenes containing polyaromatic chromophores, the electronic coupling amongst the chromophores was observed to be highly dependent on the nature and position of the substituents. Herein, we demonstrate using hexaalkoxytriptycenes that the electronic coupling amongst the chromophores is switched on and off by a simple repositioning of the substituents, which alters the nodal arrangement of the HOMOs of the individual chromophores. A visual inspection of the HOMOs can thus provide a ready evaluation of the electronic coupling in polychromophoric molecules/assemblies, and will serve as an important tool for the rational design of modern charge-transport materials.


Extended-spectrum-β-lactamase-producing Enterobacteriaceae isolated from vegetables imported from the Dominican Republic, India, Thailand, and Vietnam.
To examine to what extent fresh vegetables imported into Switzerland represent carriers of extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae, 169 samples of different types of fresh vegetables imported into Switzerland from the Dominican Republic, India, Thailand, and Vietnam were analyzed. Overall, 25.4% of the vegetable samples yielded one or more ESBL-producing Enterobacteriaceae, 78.3% of which were multidrug resistant. Sixty isolates were obtained: Escherichia coli, 26; Klebsiella pneumoniae, 26; Enterobacter cloacae, 6; Enterobacter aerogenes, 1; and Cronobacter sakazakii, 1. We found 29 isolates producing CTX-M-15, 8 producing CTX-M-14, 7 producing CTX-M-55, 3 producing CTX-M-65, 1 each producing CTX-M-1, CTX-M-3, CTX-M-27, and CTX-M-63, 5 producing SHV-2, 3 producing SHV-12, and 1 producing SHV-2a. Four of the E. coli isolates belonged to epidemiologically important clones: CTX-M-15-producing B2:ST131 (1 isolate), D:ST405 (1 isolate), and D:ST38 (2 isolates). One of the D:ST38 isolates belonged to the extraintestinal enteroaggregative E. coli (EAEC) D:ST38 lineage. Two of the K. pneumoniae isolates belonged to the epidemic clones sequence type 15 (ST15) and ST147. The occurrence of antibiotic-resistant pathogenic and commensal Enterobacteriaceae in imported agricultural foodstuffs constitutes a source of ESBL genes and a concern for food safety.


What's the Catch? The Significance of Catch Bonds in T Cell Activation.
One of the main goals in T cell biology has been to investigate how TCR recognition of peptide:MHC (pMHC) determines T cell phenotype and fate. Ag recognition is required to facilitate survival, expansion, and effector function of T cells. Historically, TCR affinity for pMHC has been used as a predictor for T cell fate and responsiveness, but there have now been several examples of nonfunctional high-affinity clones and low-affinity highly functional clones. Recently, more attention has been paid to the TCR being a mechanoreceptor where the key biophysical determinant is TCR bond lifetime under force. As outlined in this review, the fundamental parameters between the TCR and pMHC that control Ag recognition and T cell triggering are affinity, bond lifetime, and the amount of force at which the peak lifetime occurs.


Childhood socioeconomic position and physical capability in late-middle age in two birth cohorts from the Copenhagen aging and midlife biobank.
This study examines the association between childhood socioeconomic position and objective physical capability including new functional measures of potential relevance to a population in late-middle age. The study population covers two Danish birth cohorts followed-up in the Copenhagen Aging and Midlife Biobank (age 48-58 years, 2009-2011, N = 4,204). Results from linear regression models revealed that being born in higher socioeconomic position was associated with higher jump height: Paternal occupational class four = 0.19 cm (95% confidence interval (CI): -0.44, 0.82), three = 0.59 cm (95% CI: -0.02, 1.19), two = 1.29 cm (95% CI: 0.64, 1.94), and one = 1.29 cm (95% CI: 0.45, 2.13) (reference = five); medium parental social class = 0.88 cm (95% CI: 0.03, 1.72) and high = 1.79 cm (95% CI: 0.94, 2.63) (reference = low). Higher childhood socioeconomic position was also associated with better chair rise performance and hand grip strength, while among women it was related to reduced flexibility: Medium parental social class = -1.31 cm (95% CI: -3.05, 0.42) and high = -2.20 cm (95% CI: -3.94, -0.47) (reference = low); unwed mother = 1.75 cm (95% CI: 0.36, 3.14) (reference = married). Overall, the findings suggest that higher childhood socioeconomic position is primarily related to moderately better scores in the most strenuous physical capability measures and hand grip strength among healthy adults in late-middle age.


Setting research priorities in tobacco control: a stakeholder engagement project.
The Cochrane Tobacco Addiction Group (TAG) conducts systematic reviews of the evidence for tobacco cessation and prevention interventions. In 2016 TAG conducted a priority-setting, stakeholder engagement project to identify where further research is needed in the areas of tobacco control and smoking cessation. The project comprised two surveys and a workshop. A range of stakeholders participated, including members of the public (smokers and ex-smokers), clinicians, researchers, research funders, health-care commissioners and public health organizations. The first survey phase identified unanswered research questions in the field of tobacco control. The second phase asked participants to rank these, with overall rankings calculated by combining scores across participants. The workshop allowed attendees to discuss prioritization of topics and questions in more depth. Workshop discussions were transcribed and analysed thematically, and a final voting activity at the close of the workshop allowed participants to choose topics to prioritize and to de-prioritize. A total of 304 stakeholders (researchers, health professionals, smokers and ex-smokers, guideline developers, research funders and policymakers, representing 28 countries) identified 183 unanswered research questions. These were categorized into 15 research categories. A total of 175 participants prioritized categories and questions in the second survey phase, with 'electronic cigarettes'; 'addressing inequalities'; and 'mental health and other substance abuse' prioritized as the top three categories. Forty-three stakeholders attended the workshop and discussed reasons for and against category prioritization. Prioritized research categories largely mirrored those in the survey stage, although 'treatment delivery' also emerged as a key category. Five cross-cutting themes emerged: efficacy; relative efficacy; cost effectiveness; addressing inequalities; and different types of evidence. There are many unanswered questions in the field of tobacco control. Stakeholders highlighted electronic cigarettes, addressing inequalities and mental health and other substance abuse as key areas for further research, and efficacy, relative efficacy, cost-effectiveness and use of non-randomized studies as important themes cutting across research areas. Future prioritization work would benefit from targeting non-US and non-UK stakeholders explicitly and from examining where priorities may differ based on stakeholder group.


Self-hydration and thermoregulatory processes of average-level paddlers during international surfski events in a tropical climate.
The aim was to investigate thermal response, hydration behaviour and performance in flatwater kayaking races in tropical conditions (35.9 ± 2.8°C and 64 ± 4% RH). Eight regionally ranked paddlers (ARP) participated in the 2012 Surfski Ocean Racing World Cup in Guadeloupe (an inline 15-km downwind race). Core temperature (Tc) and heart rate (HR) were measured using portable telemetry units, while water intake was deduced from backpack absorption. The kayakers were asked to rate both their comfort sensation and thermal sensation on a scale before and after the race. The performance was not related to any measured parameters, and high values of post-race Tc were related to high pre-race Tc. The present study demonstrated that average-range paddlers are able to perform in a tropical climate, drinking little and paddling at high intensity without any interference from thermal sensations. Core temperature at the end of the race was positively related to pre-race Tc, which reinforces the importance of beginning surfski races with a low Tc and raises the question of pre-cooling strategies for paddlers, and more specifically for those with a low convection body surface.


Polymorphisms in the mitochondrial DNA control region and frailty in older adults.
Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults. To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95% CI = -3.33- -0.74, p = 0.002). This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.


Limited evidence that competitive food and beverage practices affect adolescent consumption behaviors.
Childhood obesity is emerging as a considerable public health problem with no clear antidote. The school food environment is a potential intervention point for policy makers, with competitive food and beverage regulation as a possible policy lever. This research examines the link between competitive food and beverage availability in school and adolescent consumption patterns using data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999. Results from value-added multivariate regression models reveal limited evidence that competitive food policy affects fruit and vegetable consumption. Findings suggest a stronger link between competitive beverage policy and consumption of sweetened beverages for population subgroups.


Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease.
Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver characterized by hypergammaglobulinemia, characteristic autoantibodies, association with HLA DR3 or DR4 and a favorable response to immunosuppressive treatment. The etiology is unknown. The detection of non-organ and liver-related autoantibodies remains the hallmark for the diagnosis of the disease in the absence of viral, metabolic, genetic, and toxic etiology of chronic hepatitis or hepatic injury. The current classification of AIH and the several autoantibodies/target-autoantigens found in this disease are reported. Current aspects on the significance of these markers in the differential diagnosis and the study of pathogenesis of AIH are also stated. AIH is subdivided into two major types; AIH type 1 (AIH-1) and type 2 (AIH-2). AIH-1 is characterized by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Determination of antineutrophil cytoplasmic autoantibodies (ANCA), antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies against to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of patients who are seronegative for ANA/SMA. AIH-2 is characterized by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). Cytochrome P450 2D6 (CYP2D6) has been documented as the major target-autoantigen of anti-LKM-1 autoantibodies in both AIH-2 and HCV infection. Recent convincing data demonstrated the expression of CYP2D6 on the surface of hepatocytes suggesting a pathogenetic role of anti-LKM-1 autoantibodies for the liver damage. Family 1 of UDP-glycuronosyltransferases has been identified as the target-autoantigen of anti-LKM-3. For these reasons the distinction between AIH and chronic viral hepatitis (especially of HCV) is of particular importance. Recently, the molecular target of anti-SLA/LP and anti-LC1 autoantibodies were identified as a 50 kDa UGA-suppressor tRNA-associated protein and a liver specific enzyme, the formiminotransferase cyclodeaminase, respectively. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate closely with disease severity and response to treatment suggesting a pathogenetic role of these autoantibodies for the hepatocellular injury. In general however, autoantibodies should not be used to monitor treatment, predict AIH activity or outcome. Finally, the current aspects on a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) are also given. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies detected in AIH as a disease component of APECED but also in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target-autoantigen of anti-LM autoantibodies in both APECED-related AIH and dihydralazine-induced hepatitis. The latter may indicate that similar autoimmune pathogenetic mechanisms can lead to liver injury in susceptible individuals irrespective of the primary defect. Characterization of the autoantigen-autoantibody repertoire continues to be an attractive and important tool to get access to the correct diagnosis and to gain insight into the as yet unresolved mystery of how hepatic tolerance is given up and AIH ensues.


Reporting knee meniscal tears: technical aspects, typical pitfalls and how to avoid them.
Magnetic resonance imaging (MRI) is the most accurate imaging technique in the diagnosis of meniscal lesions and represents a standard tool in knee evaluation. MRI plays a critical role in influencing the treatment decision and enables information that would obviate unnecessary surgery including diagnostic arthroscopy. An accurate interpretation of the knee depends on several factors, starting with technical aspects including radiofrequency coils, imaging protocol and magnetic field strength. The use of dedicated high-resolution orthopaedic coils with a different number of integrated elements is mandatory in order to ensure high homogeneity of the signal and high-resolution images. The clinical imaging protocol of the knee includes different MRI sequences with high-spatial resolution in all orientations: sagittal, coronal, and axial. Usually, the slice thickness is 3 mm or less, even with standard two-dimensional fast spin echo sequences. A common potential reason for pitfalls and errors of interpretation is the unawareness of the normal tibial attachments and capsular attachment of the menisci. Complete description of meniscal tears implies that the radiologist should be aware of the patterns and the complex classification of the lesions. • Technical factors may influence MRI interpretation. • Unawareness of the normal meniscal anatomy may lead to errors of interpretation. • Description of meniscal tears implies the knowledge of meniscal tear classification.


A graphic guide for clinical management of latent syphilis.
A graphic luetic record form is used as a guide to physicians in diagnosis and management of latent syphilis. The form provides a uniform method of recording laboratory and clinical findings as well as treatment. It facilitates checking progress and forwarding of information necessary to assure continuity in treatment of patients with latent syphilis who are transferred to other medical facilities. It is designed primarily as a guide to the clinician who does not specialize in the treatment of syphilis.


Sample Enrichment for Bioanalytical Assessment of Disinfected Drinking Water: Concentrating the Polar, the Volatiles, and the Unknowns.
Enrichment methods used in sample preparation for the bioanalytical assessment of disinfected drinking water result in the loss of volatile and hydrophilic disinfection byproducts (DBPs) and hence likely tend to underestimate biological effects. We developed and evaluated methods that are compatible with bioassays, for extracting nonvolatile and volatile DBPs from chlorinated and chloraminated drinking water to minimize the loss of analytes. For nonvolatile DBPs, solid-phase extraction (SPE) with TELOS ENV as solid phase performed superior compared to ten other sorbents. SPE yielded >70% recovery of nonpurgeable adsorbable organic halogens (AOX). For volatile DBPs, cryogenic vacuum distillation performed unsatisfactorily. Purge and cold-trap with crushed ice serving as condensation nuclei achieved recoveries of 50-100% for trihalomethanes and haloacetonitriles and approximately 60-90% for purged AOX from tap water. We compared the purgeable versus the nonpurgeable fraction by combining purge-and-trap extraction with SPE. The purgeable DBP fraction enriched with the purge-and-trap method exerted a lower oxidative stress response in mammalian cells than the nonpurgeable DBPs enriched with SPE after purging, while contributions of both fractions to bacterial cytotoxicity was more variable. 37 quantified DBPs explained almost the entire AOX in the purge-and-trap extracts, but <16% in the SPE extracts demonstrating that the nonpurgeable fraction is dominated by unknown DBPs.


Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.
A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. ES-SCZ was associated with the GAF dimensions in patients (symptom: B = -1.53, p-value = 0.001; disability: B = -1.44, p-value = 0.001), siblings (symptom: B = -3.07, p-value < 0.001; disability: B = -2.52, p-value < 0.001), and healthy controls (symptom: B = -1.50, p-value < 0.001; disability: B = -1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group. Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.


Workers' compensation, Social Security Disability Insurance, and the offset: a fact sheet.
This article offers a brief summary of the workers' compensation and Social Security Disability Insurance programs. Information highlighted includes the differences between the two programs' types and terms of coverage. It compares the differing patterns in workers' compensation and Social Security disability benefits as a percentage of wages over the past few decades and considers the potential causes for such trends. The article also explains the offset provision included in the 1965 Social Security Amendments, the intention behind the offset, and how and when offsets are applied.


SRF mediates activity-induced gene expression and synaptic plasticity but not neuronal viability.
Synaptic activity-dependent gene expression is critical for certain forms of neuronal plasticity and survival in the mammalian nervous system, yet the mechanisms by which coordinated regulation of activity-induced genes supports neuronal function is unclear. Here, we show that deletion of serum response factor (SRF) in specific neuronal populations in adult mice results in profound deficits in activity-dependent immediate early gene expression, but components of upstream signaling pathways and cyclic AMP-response element binding protein (CREB)-dependent transactivation remain intact. Moreover, SRF-deficient CA1 pyramidal neurons show attenuation of long-term synaptic potentiation, a model for neuronal information storage. Furthermore, in contrast to the massive neurodegeneration seen in adult mice lacking CREB family members, SRF-deficient adult neurons show normal morphologies and basal excitatory synaptic transmission. These findings indicate that the transcriptional events underlying neuronal survival and plasticity are dissociable and that SRF plays a prominent role in use-dependent modification of synaptic strength in the adult brain.


Modelling radicalization: how small violent fringe sects develop into large indoctrinated societies.
We model radicalization in a society consisting of two competing religious, ethnic or political groups. Each of the 'sects' is divided into moderate and radical factions, with intra-group transitions occurring either spontaneously or through indoctrination. We also include the possibility of one group violently attacking the other. The intra-group transition rates of one group are modelled to explicitly depend on the actions and characteristics of the other, including violent episodes, effectively coupling the dynamics of the two sects. We use a game theoretic framework and assume that radical factions may tune 'strategic' parameters to optimize given utility functions aimed at maximizing their ranks while minimizing the damage inflicted by their rivals. Constraints include limited overall resources that must be optimally allocated between indoctrination and external attacks on the other group. Various scenarios are considered, from symmetric sects whose behaviours mirror each other, to totally asymmetric ones where one sect may have a larger population or a superior resource availability. We discuss under what conditions sects preferentially employ indoctrination or violence, and how allowing sects to readjust their strategies allows for small, violent sects to grow into large, indoctrinated communities.


Consanguineous marriage and differentials in age at marriage, contraceptive use and fertility in Pakistan.
Fertility rates in Pakistan have remained consistently high over the past three decades. While numerous studies have examined sociodemographic determinants, the role of biological factors, and particularly consanguinity, has received little attention, even though marriage between close biological relatives continues to be the norm in Pakistan. Reproductive behaviour among women in consanguineous (first cousin) and non-consanguineous unions was compared, using data from a 1995 study of multi-ethnic communities in Karachi and the 1990-91 Pakistan Demographic & Health Survey (PDHS). The results show that, although female age at first marriage has been gradually rising in both study samples, women in consanguineous unions married at younger ages and were less likely to use modern contraceptive methods. In the Karachi sample, women in first cousin unions experienced a higher mean number of pregnancies and also reported a higher mean number of children ever born (CEB). However, their mean number of surviving children did not differ from those born to women in non-consanguineous unions, implying higher prenatal and/or postnatal losses in couples related as first cousins. On the other hand, the PDHS showed both lower CEB values for women in consanguineous marriages and a lower number of surviving children. Given the continuing popularity of consanguineous marriage, these findings have important implications for future fertility reduction in Pakistan.


Food caching by red foxes and some other carnivores.
Food caching by the red fox, Vulpes vulpes, may safeguard surplus food for future consumption. Because of practical difficulties involved in observation the extent to which the fox making a cache, or any other fox, can utilise the hoard was not known. This problem is tackled through extended observation, using unfra-red binoculars, on wild foxes (some of which were radio-tagged), together with experiments involving hand-reared tame foxes, either walked on a long leash or free and radio-tagged. The results demonstrate the fox's ability to rediscover its caches and shed light on the adaptive significance of the behaviour, which is then dsicussed in the context of food safeguarding by other carnivores.


Quantitative Structural Interpretation of Protein Crosslinks.
Chemical crosslinking, combined with mass spectrometry analysis, is a key source of information for characterizing the structure of large protein assemblies, in the context of molecular modeling. In most approaches, the interpretation is limited to simple spatial restraints, neglecting physico-chemical interactions between the crosslinker and the protein and their flexibility. Here we present a method, named NRGXL (new realistic grid for crosslinks), which models the flexibility of the crosslinker and the linked side-chains, by explicitly sampling many conformations. Also, the method can efficiently deal with overall protein dynamics. This method creates a physical model of the crosslinker and associated energy. A classifier based on it outperforms others, based on Euclidean distance or solvent-accessible distance and its efficiency makes it usable for validating 3D models from crosslinking data. NRGXL is freely available as a web server at: https://nrgxl.pasteur.fr.