Effects of a manual therapy technique in experimental lateral epicondylalgia.
In patients with lateral epicondylalgia, mobilization-with-movement (MWM) is used as an intervention aimed at achieving analgesia and enhancing grip force, although the mechanisms underlying these effects are unclear. The present study investigated the acute sensory and motor effects of an MWM intervention in healthy controls with experimentally induced lateral epicondylalgia. Twenty-four subjects were randomly allocated to either a MWM or a placebo group (n=12). In both groups, to generate the model of lateral epicondylalgia, delayed onset muscle soreness (DOMS) was provoked in one arm 24h prior (Day 0) to hypertonic saline-induced pain in the extensor carpi radialis brevis muscle (Day 1). Either a MWM or placebo intervention was applied during the saline-induced pain period. Saline-induced pain intensity (visual analogue scale: VAS), pain distribution and pain quality were assessed quantitatively. Pressure pain thresholds (PPTs) were recorded at the common extensor origin and the extensor carpi radialis brevis muscle. Maximal measures of grip and wrist extension force were recorded. In both groups (pooled data), DOMS was efficiently induced as demonstrated by a significant decrease in pre-exercise to pre-injection PPT at the common extensor origin (-45+/-19%) and at the extensor carpi radialis brevis (-61+/-23%; P<0.05), and a significant decrease in maximal grip force (-25+/-6%) and maximal wrist extension force (-40+/-12%; P<0.001). Moreover, both groups experienced a significant increase in muscle soreness (3.9+/-0.2; P<0.0001) at Day 1 compared to pre-exercise. During saline-induced pain and in response to intervention, there were no significant between-group differences in VAS profiles, pain distributions, induced deep tissue hyperalgesia or force attenuation. These data suggest that the lateral glide-MWM does not activate mechanisms associated with analgesia or force augmentation in subjects with experimentally induced features simulating lateral epicondylalgia.


Targeting receptor activator of nuclear factor-kappa B as a new therapy for bone metastasis in non-small cell lung cancer.
The review aims at comprehensively discussing our current knowledge on bone metastases incidence in non-small cell lung cancer (NSCLC), their related complications as well as clinical impact in patients suffering from advanced disease. After evoking the use of zoledronic acid as the established standard of care until recently, the new class of drugs available to prevent skeletal related events and targeting receptor activator of nuclear factor-kappa B (RANK) will be emphasized, reporting on denosumab clinical trials, a RANK-ligand (RANKL) targeting monoclonal antibody. Biological hypothesis regarding their mechanisms of action as well a potential direct impact on tumor cells are described according to the most recent laboratory as well as hypothesis-generating clinical data. Targeting the RANK pathway is an efficient way to prevent complications of bone metastases in NSCLC. Interesting additional direct effects on tumor biology and evolution are being analyzed and prospectively assessed in clinical trials.


Can extra care housing support the changing needs of older people living with dementia?
With over two-thirds of people with dementia living in the community and one-third of those living alone, it is important to consider the future housing needs of this population, particularly as symptoms of cognitive impairment increase. Policy in England has focused on enabling people living with dementia to remain in their own homes for as long as possible, often with the support of a family carer. However, many people struggle to maintain an acceptable quality of life in their own homes as their dementia advances, often due to the design limitations of mainstream housing and the challenge of finding specialist domiciliary care that is affordable and of sufficient quality. Extra care housing offers a model that aims to support older people living in their own apartments, whilst also offering specialist person-centred care as and when it is needed. This paper reports on a longitudinal project that explored how extra care housing can respond to the changing social care needs of residents, including those living with dementia. Participants included residents and staff from four extra care housing schemes, one of which was a specialist dementia scheme, in two regions of England. Interviews were carried with 51 residents across 4 rounds at 5 month intervals between October 2015 and June 2017. Interviews were also carried out with 7 managers, 20 care staff and 2 local authority commissioners of housing for older people. Key factors included person-centred care and support, flexible commissioning and staffing, appropriate design of the environment and suitable location of the scheme within the wider community. The challenge of delivering services that addresses these issues during a period of reduced public spending is acknowledged. Further research is suggested to compare different approaches to supporting people with dementia, including integrated and separated accommodation, and different stages of dementia.


The effect of circadian rhythm changes on fetal and placental development (experimental study).
To investigate the effect of circadian rhythm changes on fetal-placental development in pregnant rats. Pregnant rats were randomly allocated to 4 groups with 10 rats in each group. Group 1: 12 hours light 12 hours dark period (n:10, Control Group); Group 2: 6 hours light 6 hours dark period (n:10); Group 3: constant light group (n:10); Group 4: constant dark group (n:10). Rats were made to deliver by cesarean birth at the end of their pregnancy and their placenta, number and weight of the offspring, and placental histopathological changes were examined. Fetal number in the constant dark group was found significant in comparison to constant light group (p<0.01). Fetal weight in all groups with altered circadian rhythm was significantly lower than that in the control group (p<0.01). The decrease in fetal weight was more evident in the constant light group than in the constant dark group (p<0.01). Comparison of the histopathological findings of the placenta showed that placental edema, fibrin accumulation and leukocyte infiltration were significantly higher in constant light and constant dark groups than in other groups (p<0.01). Circadian rhythm change in pregnancy adversely affects the fetal-placental development. More detailed studies are needed to clarify this mechanism.


Responses of Barley Cultivars and Lines to Isolates of Pyrenophora teres.
Net blotch, caused by Pyrenophora teres, is among the most damaging foliar diseases of barley worldwide. A knowledge of the reaction of local cultivars, putative resistant lines, and variability in the net blotch pathogen is necessary to develop a successful resistance breeding program. Disease responses of 38 barley lines to 15 P. teres isolates were studied at the seedling and adult plant stages in the glasshouse, and field responses to net blotch were evaluated at three Moroccan locations. No tested barley was resistant to all isolates, and resistance was apparently of the specific type. Pathogenic variability was great, as none of the 15 isolates were identical. For each isolate tested, a specific high level of resistance was found in one or more host lines. Seedling and adults plants often differed in response to the same isolate. Adult plant resistance was commonly observed in response to isolate I-1, and seedling resistance was more common to isolate I-14. Adult plant resistance of nine lines was undetected in seedling evaluations using isolate I-1. The seedling glasshouse and field responses of the barley lines varied considerably, limiting the value of seedling testing for resistance. Field reactions of resistant and moderately resistant were consistent across the three locations for the lines Heartland, Minn 7, CI 2333, and CI 2549. The variability observed in P. teres and failure to find lines with resistance to all isolates suggests that breeding for resistance should emphasize pyramiding of resistance genes.


A common β1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation.
In this study, we evaluated the impact of 2 common β1-adrenergic receptor (β1-AR) polymorphisms (G389R and S49G) in response to ventricular rate control therapy in patients with atrial fibrillation (AF). Randomized studies have shown that ventricular rate control is an acceptable treatment strategy in patients with AF. However, identification of patients who will adequately respond to rate-control therapy remains a challenge. We studied 543 subjects (63% men; age 61.8 ± 14 years) prospectively enrolled in the Vanderbilt AF registry and managed with rate-control strategy. A "responder" displayed adequate ventricular rate control based on the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) criteria: average heart rate (HR) at rest ≤80 beats/min; and maximum HR during a 6-min walk test ≤110 beats/min or average HR during 24-h Holter ≤100 beats/min. A total of 295 (54.3%) patients met the AFFIRM criteria. Baseline clinical characteristics were similar in responders and nonresponders except for mean resting HR (76 ± 20 beats/min vs. 70 ± 15 beats/min; p < 0.01) and smoking (6% vs. 1%; p < 0.01). Multiple clinical variables (age, gender, hypertension) failed to predict response to rate-control therapy. By contrast, carriers of Gly variant at 389 were more likely to respond favorably to rate-control therapy; 60% versus 51% in the Arg389Arg genotype, p = 0.04. This association persisted after correction for multiple clinical factors (odds ratio: 1.42, 95% confidence interval: 1.00 to 2.03, p < 0.05). Among responders, subjects carrying the Gly389 variant required the lowest doses of rate-control medications; atenolol: 92 mg versus 68 mg; carvedilol: 44 mg versus 20 mg; metoprolol: 80 mg versus 72 mg; diltiazem: 212 mg versus 180 mg, and verapamil: 276 mg versus 200 mg, respectively (p < 0.01 for all comparisons). We have identified a common β1-AR polymorphism, G389R, that is associated with adequate response to rate-control therapy in AF patients. Gly389 is a loss-of-function variant; consequently, for the same adrenergic stimulation, it produces reduced levels of adenyl cyclase, and hence, attenuates the β-adrenergic cascade. Mechanistically, the effect of rate-control drugs will be synergistic with that of the Gly389 variant, which could possibly explain our findings. These findings represent a step forward in the development of a long-term strategy of selecting treatment options in AF based on genotype.


How house design affects malaria mosquito density, temperature, and relative humidity: an experimental study in rural Gambia.
Unprecedented improvements in housing are occurring across much of rural sub-Saharan Africa, but the consequences of these changes on malaria transmission remain poorly explored. We examined how different typologies of rural housing affect mosquito house entry and indoor climate. Five typologies of mud-block houses were constructed in rural Gambia: four were traditional designs with poorly fitted doors and one was a novel design with gable windows to improve ventilation. In each house, one male volunteer slept under a bednet and mosquitoes were collected indoors with a light trap. Typologies were rotated between houses weekly. Indoor conditions were monitored with data loggers and the perceived comfort of sleepers recorded with questionnaires. We used pyschrometric modelling to quantify the comfort of the indoor climate using the logger data. Primary measurements were mean number of Anopheles gambiae and mean temperature for each house typology. In thatched-roofed houses, closing the eaves reduced A gambiae house entry by 94% (95% CI 89-97) but increased the temperature compared with thatched-roofed houses with open eaves. In houses with closed eaves, those with metal roofs had more A gambiae, were hotter (1·5°C hotter [95% CI 1·3-1·7]) between 2100h and 2300 h, and had 25% higher concentrations of carbon dioxide (211·1 ppm higher [117·8-304·6]) than those with thatched roofs. In metal-roofed houses with closed eaves, mosquito house entry was reduced by 96% (91-98) by well fitted screened doors. Improved ventilation of metal-roofed houses made them as cool as thatched houses with open eaves. Metal-roofed houses with closed eaves were considered more uncomfortable than thatched ones with closed eaves. In metal-roofed houses, ventilated houses were more comfortable than unventilated houses before midnight, when people retired to bed. Closing the eaves reduced vector entry in thatched houses but increased entry in metal-roofed houses. Metal-roofed houses with closed eaves were, however, protected against malaria vectors by well fitted screened doors and were made comfortable by increasing ventilation. House designs that exclude mosquitoes and are comfortable to live in should be a priority in sub-Saharan Africa. Sir Halley Stewart Trust, Global Clinical Trials, and Global Challenges Research Fund.


Geometrical shape of micelles formed by cationic dimeric surfactants determined with small-angle neutron scattering.
The influence of spacer group on the geometrical shape of micelles formed by quaternary-bis dimeric (Gemini) surfactants C(12)H(25)N(CH(3))(2)(CH(2))(s)N(CH(3))(2)C(12)H(25) (12-s-12) has been investigated with small-angle neutron scattering (SANS). Dimeric surfactants with a short spacer unit (12-3-12 and 12-4-12) are observed to form elongated general ellipsoidal micelles with half axes a < b < c, whereas SANS data demonstrate that 12-s-12 surfactants with 6 ≤ s ≤ 12 form rather small spheroidal micelles rather than strictly spherical micelles. By means of comparing our present SANS results with previously determined growth rates using time-resolved fluorescence quenching, we are able to conclude that micelles formed by 12-6-12, 12-8-12, 12-10-12, and 12-12-12 are shaped as oblate rather than prolate spheroids. As a result, our present investigation suggests a never before reported structural behavior of Gemini surfactant micelles, according to which micelles transform from elongated ellipsoids to nonelongated oblate spheroids as the length of the spacer group is increased. The aggregation number of oblate micelles is observed to monotonously decrease with an increasing length of the surfactant spacer group, mainly as a result of a decreasing minor half axis (a), whereas the major half axis (b) is rather constant with respect to s. We argue that geometrically heterogeneous elongated micelles are formed by dimeric surfactants with a short spacer group mainly as a result of the surface charges becoming less uniformly distributed over the micelle interface. As the length of the spacer group increases, the distance between intramolecular charges become approximately equal to the average distance between charges on the micelle interface, and as a result, rather small oblate spheroidal micelles with a more uniform distribution of surface charges are formed by dimeric 12-s-12 surfactants with 6 ≤ s ≤ 12.


Sasanidus, a new generic name for Noemacheilus kermanshahensis Bănărescu & Nalbant, with discussion of Ilamnemacheilus and Schistura (Teleostei; Nemacheilidae).
Sasanidus, new genus, is described for Noemacheilus kermanshahensis Bănărescu & Nalbant, endemic to the Karkheh and Karun drainages in Iran. Sasanidus kermanshahensis was initially identified as a species in Oxynoemacheilus, from which it is distinguished by the absence of an external sexual dimorphism (i.e. longer pectoral fin, and nuptial tubercles on fins, head and back in males). Sasanidus is distinguished from all other genera of Nemacheilidae in the Middle East by a combination of the following character states: pelvic-fin origin behind of a vertical of the dorsal-fin origin, anus about one eye diameter in front of the anal-fin origin, dorsal adipose keel absent, a high crest on the bony capsule of the swim bladder present and colour pattern marbled or mottled or with an irregularly shaped midlateral stripe. Ilamnemacheilus longipinnis was examined and no difference could be found between Ilamnemacheilus and Oxynoemacheilus. Therefore, Ilamnemacheilus is treated as a synonym of Oxynoemacheilus. COI barcode sequences from all nemacheilid loach genera occurring in the Middle East and western India are analysed jointly for the first time. The view that Schistura is a paraphyletic assemblage is supported by the clustering of DNA sequences from 45 specimens placed in at least 20 species in the genus Schistura analysed here.


Rheolytic pharmacomechanical thrombectomy in experimental chronic deep vein thrombosis: effect of L-arginine on thrombogenicity and endothelial vasomotor function.
Endovascular removal of intravascular thrombus using the AngioJet rheolytic thrombectomy (RT) system has been shown to be clinically effective. This system also permits the concomitant infusion of thrombolytic agent followed by thrombectomy, thus creating a novel strategy known as pharmacomechanical thrombectomy (PMT). Although these interventions have gained wide clinical application, little is known regarding the vessel wall response following thrombectomy therapy. The aims of this study were to assess the effect of thrombectomy interventions on endothelial function in a porcine model of deep venous thrombosis (DVT) and to evaluate the effect of nitric oxide (NO) precursor L-arginine on endothelial function following thrombectomy therapy. Deep vein thrombosis was created in bilateral iliac veins by deploying a self-expanding stent-graft incorporating an intraluminal stenosis from a groin approach. Five pigs underwent sham operation. Following 14 days of DVT, animals were randomized to three groups: the first group received RT treatment (RT group, n = 5); the second group received pharmacomechanical thrombectomy (PMT) with tissue plasminogen activator (alteplase 10 mg; PMT group, n = 5); and the third group received PMT with tPA plus intravenous L-arginine (20 mmol/l) (arginine group, n = 5). Iliac vein patency was evaluated by venography and intravascular ultrasound at 1 week. Nitric oxide level was determined by a chemiluminescent assay of the nitrite/nitrate metabolites (NO(x)). Thrombogenicity was evaluated by radiolabeled platelet and fibrin deposition. Veins were harvested and evaluated with light microscopy and scanning electron microscopy (SEM). Endothelial function was evaluated using organ chamber analysis. The luminal areas in the sham, RT, PMT, and arginine groups were 34 +/- 10 mm(2), 21 +/- 13 mm(2), 35 +/- 18 mm(2), and 37 +/- 16 mm(2), respectively. All iliac veins remained patent at 2 weeks. No difference in endothelial cell structure was observed between the three treatment groups by means of light microscopic or SEM examination. A decrease in platelet deposition occurred in the arginine group compared to the RT and PMT groups (P < 0.05). The arginine group also showed a greater endothelium-dependent relaxation compared to the RT or PMT groups in response to A23187, bradykinin, and ADP (P < 0.05). Local NO(x) level was higher in the arginine group than in the RT or PMT group (2.6 +/- 0.6 micromol/l versus 0.3 +/- 0.1 micromol/l and 0.3 +/- 0.2 micromol/l; P < 0.01). AngioJet RT and PMT interventions resulted in similar attenuated endothelium-dependent vasoreactivity and morphologic effect. L-Arginine supplementation preserves endothelial vasoreactivity and reduces platelet deposition following PMT in iliac DVT. Additionally, L-arginine enhances NO production at sites of venous thrombosis. The NO precursor L-arginine may have a therapeutic potential in preserving endothelial function following mechanical thrombectomy.


Hepatitis G virus infection before and after liver transplantation. Liver Transplantation Database.
The hepatitis G virus is a newly discovered flavivirus that has been linked to acute and chronic hepatitis of unknown cause. We determined the prevalence of hepatitis G virus infection in 179 selected patients undergoing liver transplantation at three centers participating in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database. Pretransplantation and posttransplantation specimens were tested for hepatitis G virus RNA by polymerase chain reaction. Before transplantation, 9 of 38 (24%) patients with fulminant hepatic failure, 9 of 62 (15%) with cryptogenic cirrhosis, 3 of 35 (9%) with cholestatic liver disease, and 5 of 44 (11%) with chronic hepatitis C were positive for hepatitis G virus RNA (P = .27). Patients with and without viral RNA were similar in clinical features, liver test abnormalities, and survival after transplantation. Posttransplantation serum specimens were tested from 73 patients; 9 of 11 (82%) who were positive for viral RNA before transplantation remained positive, but 35 of 62 (56%) patients who were initially negative became positive after transplantation, a rate consistent with that predicted from the number of blood products administered. Only 5% of de novo HGV infections could be attributed to preexisting hepatitis G virus RNA in the donor. Comparison of patients with and without hepatitis G virus infection showed no difference in incidence of hepatitis after transplantation. Thus, hepatitis G virus infection was present in 15% of patients before and appeared de novo in half of patients after liver transplantation. Although hepatitis G virus infection was not associated with poor outcome, the frequency of this infection after transplantation calls for further long-term evaluation.


"Burnishing" demineralization of root surfaces: ultrastructural surface characteristics.
The purpose of this study was to compare the surface topography of roots treated with a resin bonding demineralizing agent using either a "placed" or "burnished" application technique. Fifteen roots of human teeth were sectioned in half and a treatment area prepared on the coronal portion of each proximal section. This area was root planed to expose dentin. Treatment areas were demineralized with (1) a commercially available demineralizing agent (10% citric acid with 3% ferric chloride) (Amalgambond; Parkell) or (2) 30% citric acid solution. Cotton pellets saturated in either solution were placed or burnished (vigorously rubbed) on the treatment area for 3 min. Sections were prepared for SEM analysis using liquid CO2 dehydration. Areas of cementum and dentin were evident on most treatment areas. Specimens of both placed groups lacked a smear layer and exhibited a cracked-eroded, flat surface of matted or ridged fibrous material. Specimens in both burnished groups also lacked a smear layer, yet in stark contrast, exhibited an abundant array of deeply tufted fibril material similar to that of a "shag carpet". Two types of tufted fibril patterns were present: a lace-like array of shorter fibrils seen on dentin, and a voluminous mass of longer fibrils seen on cementum. Root cementum and dentin, treated with either demineralizing agent using the burnishing application technique, were ultrastructurally similar in that both displayed an abundant array of deeply tufted fibril material. This differed from the flat/matted fibril material seen using the placed application technique.


Additive effect of walnut and chokeberry on regulation of antioxidant enzyme gene expression and attenuation of lipid peroxidation in d-galactose-induced aging-mouse model.
Studies have highlighted the association between the cellular damage caused by reactive oxygen species and aging. The reducing sugar d-galactose causes aging-related changes and oxidative stress. Lipids are the first target of free radicals, and lipid peroxidation is related to aging. Walnut (Juglans regia Chandler) kernel contains antioxidant phenolic compounds, and chokeberry (Aronia melanocarpa) is one of the richest sources of polyphenols, including anthocyanins, among other fruits. Polyphenols from chokeberry exhibit antioxidant and anti-inflammatory activities. In this study, the additive antioxidative effect of walnut and chokeberry mixture was evaluated by oxidative stress index in d-galactose-induced aging model. Thirty-five Balb/c mice (8 weeks old) were divided into following five groups (n = 7 in each group): normal control (C), d-galactose control (D), d-galactose with chokeberry diet (CH), d-galactose with walnut diet (W), and d-galactose with walnut and chokeberry mixture diet (WCH). In all treatment diets groups, the levels of serum, hepatic, and kidney malonaldehyde were significantly lower than D group and the levels were approaching to control level. Moreover, the kidney malondialdehyde levels were significantly lower in WCH group compared with the control group. This study also confirmed the activities of antioxidant enzymes in liver, as the levels of superoxide dismutase, and glutathione peroxidase were significantly increased in CH group compared to in W or CH groups. The results of this study supported the additive effect of walnut and chokeberry on increment of antioxidant enzyme gene expression in liver and consequently the attenuation of lipid peroxidation in serum, liver, and kidney in d-galactose-induced aging-mouse model. Further studies are needed to investigate the detailed mechanism underlying the additive antioxidative effects in various tissues.


Measurement of transverse single-spin asymmetries for Dijet production in proton-proton collisions at sqrt[s]=200 GeV.
We report the first measurement of the opening angle distribution between pairs of jets produced in high-energy collisions of transversely polarized protons. The measurement probes (Sivers) correlations between the transverse spin orientation of a proton and the transverse momentum directions of its partons. With both beams polarized, the wide pseudorapidity (-1< or = eta < or = +2) coverage for jets permits separation of Sivers functions for the valence and sea regions. The resulting asymmetries are all consistent with zero and considerably smaller than Sivers effects observed in semi-inclusive deep inelastic scattering. We discuss theoretical attempts to reconcile the new results with the sizable transverse spin effects seen in semi-inclusive deep inelastic scattering and forward hadron production in pp collisions.


Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.
The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.


Secondary cell-mediated lympholysis: importance of H-2 LD and SD factors.
Lymphocytes stimulated in mixed leukocyte cultures and left for 13-17 days, i.e. beyond their peak proliferative and cytotoxic reactivities, can be restimulated to give a secondary-type rapid and strong proliferative and cytotoxic response when confronted with cells of the original sensitizing cell donor. We have concerned ourselves primarily with the requirements of restimulation for the presence of LD and/or SD stimuli on the restimulating cells. (a) The low level cell-mediated lympholysis (CML) associated with LD differences in a primary CML can be restimulated to give a secondary-type response by those same LD antigens. (b) If the original sensitizing cells differ from the responding cells by both LD and SD antigens, restimulation with only the LD antigens, or third-party cells presumably carrying cross-reactive LD antigens, can restimulate the secondary CML responses directed against the SD antigens on the original sensitizing cells. (c) The presence of SD antigens on the restimulating cells that are cross-reactive with the primary sensitizing SD antigens (as determined in a primary CML) leads to the preferential activation of cytotoxic T lymphocytes reactive to those antigens although maximum cytotoxicity is still directed at cells carrying the original sensitizing SD antigens. A model to explain these results is presented.


Anorectal malformations.
Anorectal malformations (ARMs) are among the more frequent congenital anomalies encountered in paediatric surgery, with an estimated incidence ranging between 1 in 2000 and 1 in 5000 live births. Antenatal diagnosis of an isolated ARM is rare. Most cases are diagnosed in the early neonatal period. There is a wide spectrum of presentation ranging from low anomalies with perineal fistula having simple management to high anomalies with complex management. Advances in the imaging techniques with improvement in knowledge of the embryology, anatomy and physiology of ARM cases have refined diagnosis and initial management. There has been marked improvement in survival of such patient over the last century. The management of ARM has moved forward from classical procedures to PSARP to minimal invasive procedures. But still the fecal and urinary incontinence can occur even with an excellent anatomic repair, mainly due to associated problems. There has been a paradigm shift in approach to these patients which involves holistic approach to the syndrome of Anorectal malformations with a long term goal of achievement of complete fecal and urinary continence with excellent quality of life.


Mechano- and pH-sensing convergence on Ca2+-mobilising proteins - A recipe for cancer?
Alterations in the (bio)chemical and physical microenvironment of cells accompany and often promote disease formation and progression. This is particularly well established for solid cancers, which are typically stiffer than the healthy tissue in which they arise, and often display profound acidification of their interstitial fluid. Cell surface receptors can sense changes in the mechanical and (bio)chemical properties of the surrounding extracellular matrix and fluid, and signalling through these receptors is thought to play a key role in disease development and advancement. This review will look at ion channels and G protein coupled receptors that are activated by mechanical cues and extracellular acidosis, and stimulation of which results in increases in intracellular Ca2+ concentrations. Cellular Ca2+ levels are dysregulated in cancer as well as cancer-associated cells, and mechano- and proton-sensing proteins likely contribute to these aberrant intracellular Ca2+ signals, making them attractive targets for therapeutic intervention.


Effect of maturation on the composition and biological activity of the essential oil of a commercially important Satureja species from Turkey: Satureja cuneifolia Ten. (Lamiaceae).
The essential oil obtained by hydrodistillation from aerial parts of Satureja cuneifolia Ten., collected in three different maturation stages such as preflowering, flowering, and postflowering, were analyzed simultaneously by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Thymol (42.5-45.2%), p-cymene (19.4-24.3%), and carvacrol (8.5-13.2%) were identified as the main constituent in all stages. At the same time, the essential oils and main components were evaluated for their antimicrobial activity using a microdilution assay resulting in the inhibition of a number of common human pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and the yeasts Candida albicans and Candida tropicalis. The minimum inhibitory concentrations (MIC) varied between 62.5 and 250 microg/mL within a moderate antimicrobial activity range. Furthermore, the antioxidant capacity of the essential oils and major components thymol and carvacrol were examined in vitro. The essential oils obtained from S. cuneifolia in three different stages and its main components were interacted with 1,1-diphenyl-2-picrylhydrazyl (DPPH (*)) as a nitrogen-centered stable radical, resulting in IC 50 = 1.6-2.1 mg/mL. In addition, the effects on inhibition of lipid peroxidation of the essential oils were assayed using the beta-carotene bleaching method. All of the tested oils inhibited the linoleic acid peroxidation at almost the same level as butylated hydroxytoluene (BHT) (93.54-94.65%). BHT and ascorbic acid were used as positive controls in the antioxidant assays.


Dynamic UltraFast 2D EXchange SpectroscopY (UF-EXSY) of hyperpolarized substrates.
In this work, we present a new ultrafast method for acquiring dynamic 2D EXchange SpectroscopY (EXSY) within a single acquisition. This technique reconstructs two-dimensional EXSY spectra from one-dimensional spectra based on the phase accrual during echo times. The Ultrafast-EXSY acquisition overcomes long acquisition times typically needed to acquire 2D NMR data by utilizing sparsity and phase dependence to dramatically undersample in the indirect time dimension. This allows for the acquisition of the 2D spectrum within a single shot. We have validated this method in simulations and hyperpolarized enzyme assay experiments separating the dehydration of pyruvate and lactate-to-pyruvate conversion. In a renal cell carcinoma cell (RCC) line, bidirectional exchange was observed. This new technique revealed decreased conversion of lactate-to-pyruvate with high expression of monocarboxylate transporter 4 (MCT4), known to correlate with aggressive cancer phenotypes. We also showed feasibility of this technique in vivo in a RCC model where bidirectional exchange was observed for pyruvate-lactate, pyruvate-alanine, and pyruvate-hydrate and were resolved in time. Broadly, the technique is well suited to investigate the dynamics of multiple exchange pathways and applicable to hyperpolarized substrates where chemical exchange has shown great promise across a range of disciplines.


Host and Viral Proteins Modulating Ebola and Marburg Virus Egress.
The filoviruses Ebolavirus and Marburgvirus are among the deadliest viral pathogens known to infect humans, causing emerging diseases with fatality rates of up to 90% during some outbreaks. The replication cycles of these viruses are comprised of numerous complex molecular processes and interactions with their human host, with one key feature being the means by which nascent virions exit host cells to spread to new cells and ultimately to a new host. This review focuses on our current knowledge of filovirus egress and the viral and host factors and processes that are involved. Within the virus, these factors consist of the major matrix protein, viral protein 40 (VP40), which is necessary and sufficient for viral particle release, and nucleocapsid and glycoprotein that interact with VP40 to promote egress. In the host cell, some proteins are hijacked by filoviruses in order to enhance virion budding capacity that include members of the family of E3 ubiquitin ligase and the endosomal sorting complexes required for transport (ESCRT) pathway, while others such as tetherin inhibit viral egress. An understanding of these molecular interactions that modulate viral particle egress provides an important opportunity to identify new targets for the development of antivirals to prevent and treat filovirus infections.


Bcl-xL antisense oligonucleotide and cisplatin combination therapy extends survival in SCID mice with established mesothelioma xenografts.
Bcl-xL functions as a dominant regulator of apoptotic cell death and is implicated in chemotherapeutic resistance of malignant pleural mesothelioma (MPM). Mesothelioma cell lines demonstrate increasing levels of Bcl-xL as resistant clones are selected in vitro. Moreover, upon introduction of antisense oligonucleotides specific to Bcl-xL mRNA, MPM cells are sensitized to chemotherapeutic agents. Here we describe the therapeutic effects of a novel combination therapy, Bcl-xL antisense oligonucleotide (ASO 15999) and cisplatin, on mesothelioma cell lines in vitro and in vivo; in addition, efficacy of ASO 15999 in decreasing tumor load as well as its effect on survival in an animal model. Finally, we initiated preliminary toxicity studies involved with intraperitoneal (IP) injections of ASO 15999 into mice. This novel combination, with doses of cisplatin four times below established IC(50) levels, significantly decreased viability of MPM cell lines after 48 hr. The growth of established mouse flank human tumor xenografts was reduced with intra-tumor administration of ASO 15999. Local spread and development of IP xenografts was reduced with treatments of ASO alone, and survival of mice afflicted with these xenografts was prolonged after administration of ASO alone and ASO 15999 + cisplatin combination therapy. These findings suggest that ASO 15999 sensitizes MPM cell lines to the toxic effects of cisplatin. ASO 15999 induced reduction of Bcl-xL is effective in slowing the progression of human mesothelioma cell lines both in vitro and in vivo. More notably, the combination of Bcl-xL ASO and cisplatin extends survival in an orthotopic tumor xenograft model.


Influence of ionization on ultrafast gas-based nonlinear fiber optics.
We numerically investigate the effect of ionization on ultrashort high-energy pulses propagating in gas-filled kagomé-lattice hollow-core photonic crystal fibers by solving an established uni-directional field equation. We consider the dynamics of two distinct regimes: ionization induced blue-shift and resonant dispersive wave emission in the deep-UV. We illustrate how the system evolves between these regimes and the changing influence of ionization. Finally, we consider the effect of higher ionization stages.


Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer's disease model mice.
Molecular signaling mechanisms underlying Alzheimer's disease (AD) remain unclear. Maintenance of memory and synaptic plasticity depend on de novo protein synthesis, dysregulation of which is implicated in AD. Recent studies showed AD-associated hyperphosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2), which results in inhibition of protein synthesis. We tested to determine whether suppression of eEF2 phosphorylation could improve protein synthesis capacity and AD-associated cognitive and synaptic impairments. Genetic reduction of the eEF2 kinase (eEF2K) in 2 AD mouse models suppressed AD-associated eEF2 hyperphosphorylation and improved memory deficits and hippocampal long-term potentiation (LTP) impairments without altering brain amyloid β (Aβ) pathology. Furthermore, eEF2K reduction alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, de novo protein synthesis, and dendritic polyribosome assembly. Our results link eEF2K/eEF2 signaling dysregulation to AD pathophysiology and therefore offer a feasible therapeutic target.


The Health-e Babies App for antenatal education: Feasibility for socially disadvantaged women.
The use of mobile technology such as phone applications (apps) has been proposed as an efficient means of providing health and clinical information in a variety of healthcare settings. We developed the Health-e Babies app as an Android smart phone application for pregnant women attending a tertiary hospital in a low socio-economic community, with the objective of providing health information about early pregnancy that would increase maternal confidence and reduce anxiety. Based on our earlier research, this form of health communication was viewed as a preferred source of information for women of reproductive age. However, the pilot study had a poor participation rate with 76% (n = 94) not completing the study requirements. These initial findings raised some very important issues in relation to the difficulties of engaging women with a pregnancy app. This paper analyses the characteristics of the participants who did not complete the study requirements in an attempt to identify potential barriers associated with the implementation of a pregnancy app. This retrospective review of quantitative and qualitative data collected at the commencement of the Health-e Babies App trial, related to the participant's communication technology use, confidence in knowing where to seek help and mental health status, maternal-fetal attachment and parenting confidence. Engagement and use of the Health-e Babies App was measured by the completion of a questionnaire about the app and downloaded data from participant's phones. Mental health status, confidence and self-efficacy were measured by questionnaires. All women were similar in terms of age, race, marital status and level of education. Of the 94 women (76%) who did not complete the trial, they were significantly more anxious as indicated by State Trait Anxiety Inventory (p = 0.001 Student T-test) and more likely to be unemployed (50% vs 31%, p = 0.012 Student T-Test). This study provides important information about the challenges associated with the implementation of a pregnancy app in a socially disadvantaged community. The data suggests that factors including social and mental health issues, financial constraints and technological ability can affect women's engagement with a mobile phone app.


Adrenomedullin in experimental congestive heart failure: cardiorenal activation.
Adrenomedullin (ADM) is a new member of a family of vasodilating and natriuretic peptides that plays an important role in cardiorenal regulation. This study was designed to establish the plasma, urinary, cardiac, and renal tissue concentrations and immunohistochemical localizations of ADM in normal dogs and dogs with experimental congestive heart failure (CHF) produced by rapid ventricular pacing. Plasma ADM concentration was 5.6 +/- 0.4 pg/ml in normal dogs and significantly increased to 14.5 +/- 2.5 pg/ml in CHF dogs (P < 0.05). Ventricular and renal tissue ADM were significantly increased in CHF dogs compared with normals. Immunohistochemical examination revealed positive ADM immunostaining within the myocytes, and ventricular ADM immunoreactivity was significantly more intense in CHF dogs than in normals. ADM immunoreactivity was also observed in the glomerulus, distal tubules, and medullary collecting duct cells in the kidney, and the intensities of ADM immunoreactivity in these sites were increased in CHF dogs compared with normals. In addition, ventricular ADM was a powerful marker for left ventricular mass, and circulating ADM correlated positively with left ventricular end-diastolic pressure and inversely with cardiac output and ejection fraction. Despite an increase in renal tissue ADM, urinary ADM did not increase in CHF dogs. The current study demonstrates that plasma concentration of ADM is increased in experimental CHF and that ventricular and renal ADM is activated in the progression of CHF. Tissue and circulating ADM also are markers for the alterations in myocardial structure and function. This study supports a potential role for ADM in the neurohumoral activation in experimental CHF.


A retrospective serologic survey of hantavirus infections in the county of Cássia dos Coqueiros, State of São Paulo, Brazil.
In recent years, hantavirus infections producing severe diseases have obtained an increased attention from public health authorities from the countries of Eurasia to the Americas. Brazil has reported 1,300 cases of hantavirus cardiopulmonary syndrome (HCPS) from 1993 to 2010, with about 80 of them occurring in the northeast of the State of São Paulo, with 48% fatality rate. Araraquara virus was the causative agent of HCPS in the region. Considering that hantaviruses causing human disease in the Americas were unknown until 1993, we have looked for hantavirus infections in the population of Cássia dos Coqueiros county, northeast of the State of São Paulo, Brazil, before this time. This county has about 2,800 inhabitants and an economy based on agriculture, including cultivation of Brachiaria decumbens grass. The grass seeds are an important rodent attraction, facilitating transmission of hantavirus to man. Four HCPS cases were reported so far in the county. In this study, 1,876 sera collected from 1987 to 1990 were tested for IgG to hantavirus by IgG-ELISA, using the N recombinant protein of Araraquara virus as antigen. Positive results were observed in 89 (4.7%) samples, which were all collected in 1987. The positivity among urban inhabitants was 5.3%, compared with 4.3% among those living in rural areas. Our results showed that hantavirus infections occurred in Cássia dos Coqueiros, completely unrecognized, even before hantaviruses were described in the Americas.


New treatment options for the management of restless leg syndrome.
Restless leg syndrome (RLS), also known as Willis-Ekbom disease, is a condition that includes sensations such as crawling, tingling, or aching in the limbs and creates an urge to move. The prevalence is estimated at 3% to 15% of the population and may present as primary RLS or secondary RLS. Secondary RLS may be a result of some medications, iron deficiency, or conditions such as neuropathies, or it may be related to pregnancy. The guidelines for diagnosis, which is usually made on clinical presentation, are discussed in the article. Medication use is not always necessary in the management of RLS. Multiple options are available and are reviewed within the article. Since 2011, two medications have been approved for the treatment of RLS, and these are discussed in detail. Neupro (rotigotine) is a dopamine agonist available as a patch that has been approved for the treatment of RLS as well as Parkinson disease. One of the major issues in treating RLS with dopamine agonists is augmentation, meaning symptoms occur earlier in the day due to medication use. This rate of augmentation with use of rotigotine is significantly lower than other dopamine agonists. Horizant (gabapentin enacarbil) is the only nondopaminergic medication approved for the treatment of RLS. Bioavailability is greater in gabapentin enacarbil as compared to gabapentin. Augmentation has not been associated with gabapentin or gabapentin enacarbil. Neupro (rotigotine) and Horizant (gabapentin enacarbil) provide additional treatment options for patients with RLS who are in need of medications. Consideration of each individual patient is necessary when determining if medication is needed and in choosing the appropriate agent.


Genetic architecture of resilience of executive functioning.
The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H² = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 × 10⁻⁷). rs3748348 is in strong linkage disequilibrium (D' of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 × 10⁻⁷). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.


Vasoconstrictor-mediated release of lactate from the perfused rat hindlimb.
The effects of different vasomodulators on lactate release by the constant-flow-perfused rat hindlimb were examined and compared with that by perfused mesenteric artery, incubated preparations of aortas, soleus and epitrochlearis muscles, and perifused soleus muscles. Infusion of vasopressin (0.5 nM), angiotensin II (5 nM), norepinephrine (50 nM), and methoxamine (10 microM) into the hindlimbs of 180- to 200-g rats increased the perfusion pressure by 112-167% from 30.4 +/- 0.8 mmHg, O2 consumption by 26-68% from 6.4 +/- 0.2 mumol.g-1 x h-1, and lactate efflux by 148-380% from 5.41 +/- 0.25 mumol.g-1 x h-1. Hindlimbs of 100- to 120-g rats responded similarly to angiotensin II. Isoproterenol (1 microM) had no effect on O2 uptake or perfusion pressure but increased lactate release by 118%. Nitroprusside (0.5 mM) markedly inhibited the vasoconstrictor-mediated increases in lactate release, perfusion pressure, and O2 consumption by the hindlimb but had no effect on isoproterenol-mediated lactate efflux. Serotonin (6.7 microM) increased lactate release from the perfused mesenteric artery by 120% from 5.48 mol.g-1 x h-1. Lactate release by incubated aorta was increased by angiotensin II (50 nM), isoproterenol (1 microM), and mechanical stretch. The increase mediated by angiotensin II was blocked by glycerol trinitrate (2.2 microM), which had no effect on lactate release by isoproterenol. Neither angiotensin II (5 nM) nor vasopressin (0.5 nM) increased lactate release from incubated soleus and epitrochlearis muscles; however, lactate release was increased by isoproterenol, and this increase was unaffected by glycerol trinitrate (2.2 microM).(ABSTRACT TRUNCATED AT 250 WORDS)


Characteristics and Outcomes of Over 300,000 Patients with COVID-19 and History of Cancer in the United States and Spain.
We described the demographics, cancer subtypes, comorbidities, and outcomes of patients with a history of cancer and coronavirus disease 2019 (COVID-19). Second, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. We conducted a cohort study using eight routinely collected health care databases from Spain and the United States, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: (i) diagnosed with COVID-19, (ii) hospitalized with COVID-19, and (iii) hospitalized with influenza in 2017 to 2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes. We included 366,050 and 119,597 patients diagnosed and hospitalized with COVID-19, respectively. Prostate and breast cancers were the most frequent cancers (range: 5%-18% and 1%-14% in the diagnosed cohort, respectively). Hematologic malignancies were also frequent, with non-Hodgkin's lymphoma being among the five most common cancer subtypes in the diagnosed cohort. Overall, patients were aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 2% to 14% and from 6% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n = 67,743) had a similar distribution of cancer subtypes, sex, age, and comorbidities but lower occurrence of adverse events. Patients with a history of cancer and COVID-19 had multiple comorbidities and a high occurrence of COVID-19-related events. Hematologic malignancies were frequent. This study provides epidemiologic characteristics that can inform clinical care and etiologic studies.


The Effect of Ambient Titanium Dioxide Microparticle Exposure to the Ocular Surface on the Expression of Inflammatory Cytokines in the Eye and Cervical Lymph Nodes.
To investigate the ocular immune response following exposure to airborne titanium dioxide (TiO2) microparticles. Rats in the TiO2-exposed group (n = 10) were exposed to TiO2 particles for 2 hours twice daily for 5 days, while the controls (n = 10) were not. Corneal staining score and tear lactic dehydrogenase (LDH) activity were measured to evaluate ocular surface damage, serum immunoglobulin (Ig) G and E were assayed by using enzyme-linked immunosorbent assay, and the size of cervical lymph nodes was measured. In addition, the expression of interleukin (IL)-4, IL-17, and interferon (IFN)-γ in the anterior segment of the eyeball and cervical lymph nodes was measured by immunohistochemistry, real-time reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analysis. Median corneal staining score (3.0), tear LDH activity (0.24 optical density [OD]), and cervical lymph node size (36.9 mm2) were significantly higher in the TiO2-exposed group than in the control group (1.0, 0.13 OD, and 26.7 mm2, respectively). Serum IgG and IgE levels were found to be significantly elevated in the TiO2-exposed group (P = 0.021 and P = 0.021, respectively). Interleukin 4 expression was increased in the anterior segment of the eyeball and lymph nodes following TiO2 exposure, as measured by immunostaining, real-time RT-PCR, and Western blot. In addition, IL-17 and IFN-γ levels were also increased following TiO2 exposure compared to controls as measured by immunostaining. Exposure to airborne TiO2 induced ocular surface damage. The Type 2 helper T-cell pathway seems to play a dominant role in the ocular immune response following airborne TiO2 exposure.


Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-kB activity.
The rate of morbidity and mortality of hepatocellular carcinoma (HCC) in Taiwan has not lessened because of difficulty in treating tumor metastasis. Norcantharidin (NCTD) is currently used as an anticancer drug for hepatoma, breast cancer, and colorectal adenocarcinoma. NCTD possesses various biological anticancer activities, including apoptosis. However, detailed effects and molecular mechanisms of NCTD on metastasis are unclear. Thus, HCC cells were subjected to treatment with NCTD and then analyzed to determine the effects of NCTD on cell metastasis. Modified Boyden chamber assays revealed that NCTD treatment inhibited cell migration and invasion capacities of HCC cells substantially. Results of zymography and western blotting showed that activities and protein levels of matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (u-PA) were inhibited by NCTD. Western blot analysis showed that NCTD inhibits phosphorylation of ERK1/2. Testing of mRNA level, quantitative real-time PCR, and promoter assays evaluated the inhibitory effects of NCTD on MMP-9 and u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay for analyzing the genomic DNA sequences bound to these proteins was reactive to the transcription protein nuclear factor (NF)-kappaB, which was inhibited by NCTD. The expression of NF-kappa B was measured by western blot analysis, which revealed decreased nuclear-factor DNA-binding activity after NCTD treatment. NCTD inhibited MMP-9 and u-PA expression through the phosphorylation of ERK1/2 and NF-kappaB signaling pathway which serves as a powerful chemopreventive agent in HCC cell metastasis.


Views on clinical trial recruitment, biospecimen collection, and cancer research: population science from landscapes of the Haudenosaunee (People of the Longhouse).
Biomedical research in culturally distinct communities is often a challenge. Potential barriers to participation occur because science is presented in a format that lacks cultural acknowledgement. Investigations may also fail to showcase beneficial relevance to the communities or include them in true partnership. The history of biomedical research within Native American societies has been complicated by these issues. Historical trauma among many Native groups sometimes transcends into contemporary challenges in both recruitment to and participation particularly in biobanking research. The participants for this study included members of the Haudenosaunee, the People of the Longhouse. Native Americans, including the Haudenosaunee, endure some of the worst health disparities in the country. These include high rates of cancer, obesity, and diabetes which may be linked at least partially to genetic predisposition. Results from a Haudenosaunee urban population shared response on ways to improve recruitment strategies for biospecimen, cancer, and other health-related clinical trials. Mixed methods approaches were used, and community responses indicated the importance of creating trust through respectful partnership; promoting culturally appropriate recruitment materials; the need for a greater understanding of consenting and signature processes; the necessity for concise summary sheets; and a desire to have information that community member understand. Discussion items also include international Indigenous perspectives to biobanking and genetic-related health disparity research.


Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents.
Medication is an important element of therapeutic strategies for ADHD. While medications for ADHD are generally well-tolerated, there are common, although less severe, as well as rare but severe adverse events AEs during treatment with ADHD drugs. The aim of this review is to provide evidence- and expert-based guidance concerning the management of (AEs) with medications for ADHD. For ease of use by practitioners and clinicians, the article is organized in a simple question and answer format regarding the prevalence and management of the most common AEs. Answers were based on empirical evidence from studies (preferably meta-analyses or systematic reviews) retrieved in PubMed, Ovid, EMBASE and Web of Knowledge through 30 June 2012. When no empirical evidence was available, expert consensus of the members of the European ADHD Guidelines Group is provided. The evidence-level of the management recommendations was based on the SIGN grading system. The review covers monitoring and management strategies of loss of appetite and growth delay, cardiovascular risks, sleep disturbance, tics, substance misuse/abuse, seizures, suicidal thoughts/behaviours and psychotic symptoms. Most AEs during treatment with drugs for ADHD are manageable and most of the times it is not necessary to stop medication, so that patients with ADHD may continue to benefit from the effectiveness of pharmacological treatment.


Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement.
Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed. STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.


Circular synthesized CRISPR/Cas gRNAs for functional interrogations in the coding and noncoding genome.
Current technologies used to generate CRISPR/Cas gene perturbation reagents are labor intense and require multiple ligation and cloning steps. Furthermore, increasing gRNA sequence diversity negatively affects gRNA distribution, leading to libraries of heterogeneous quality. Here, we present a rapid and cloning-free mutagenesis technology that can efficiently generate covalently-closed-circular-synthesized (3Cs) CRISPR/Cas gRNA reagents and that uncouples sequence diversity from sequence distribution. We demonstrate the fidelity and performance of 3Cs reagents by tailored targeting of all human deubiquitinating enzymes (DUBs) and identify their essentiality for cell fitness. To explore high-content screening, we aimed to generate the largest up-to-date gRNA library that can be used to interrogate the coding and noncoding human genome and simultaneously to identify genes, predicted promoter flanking regions, transcription factors and CTCF binding sites that are linked to doxorubicin resistance. Our 3Cs technology enables fast and robust generation of bias-free gene perturbation libraries with yet unmatched diversities and should be considered an alternative to established technologies.


Bicortical fixation of medial malleolar fractures: a review of 23 cases at risk for complicated bone healing.
Several methods have been described for fixation of unstable medial malleolar fractures. Certain patient populations, including the elderly, those with osteoporosis and osteopenia, and patients with diabetes mellitus, are generally known to be susceptible to complications associated with ankle fracture healing. The goal of the present retrospective investigation was to review the outcomes of a series of patients who had undergone medial malleolar fracture repair using fully threaded bicortical interfragmental compression screw fixation. Patients were included in the present series if they had undergone bicortical fixation of an unstable ankle fracture with a medial malleolar fracture component, in addition to having at least 1 of the following comorbidities: age 55 years or older, osteoporosis or osteopenia, diabetes mellitus, peripheral arterial disease, end-stage renal disease, chronic kidney disease, previous kidney transplantation, peripheral neuropathy, or current tobacco use. A total of 23 ankle fractures in 22 consecutive patients met the inclusion criteria. The mean age of the patients was 69.52 (range 45 to 89) years; 17 were female (77.27%) and 5 were male (22.73%). Of the 23 medial malleolar fractures, 21 (91.3%) achieved complete, uncomplicated healing. The mean interval to union was 62.6 (range 42 to 156) days. A total of 4 complications (17.39%) were noted, including 1 nonunion (4.35%), 1 malunion (4.35%), and 2 cases of painful retained hardware (8.7%). From our experience with this series of patients, bicortical screw fixation for medial malleolus fractures appears to be an acceptable alternative for fixation that provides a stable construct for patients at greater risk of bone healing complications.


Lipotoxicity is glucose-dependent in INS-1E cells but not in human islets and MIN6 cells.
Prolonged elevated levels of lipids have negative effects on beta-cell function and mass (lipotoxicity). To what extent exposure to high glucose concentration is important in the harmful effects of lipids (glucolipotoxicity) has been debated. We addressed beta-cell lipotoxicity by measuring apoptosis in isolated intact control human islets and insulin-secreting cell lines MIN6 and INS-1E cultured in the presence of palmitate and low (5.5 mM) or high (25 mM) glucose for 48 hours. In both cell lines and human islets palmitate induced apoptosis after culture at low glucose. Palmitate-induced apoptosis was not increased after culture at high compared to low glucose in human islets and MIN6 cells but glucose-induced rise in apoptosis was observed in INS-1E cells. The rise in apoptosis in INS-1E cells was partially reversed by inclusion of AMPK-agonist AICAR. When CPT1-inhibitor etomoxir was included during culture at low glucose palmitate-triggered apoptosis was accentuated both in the islets and the cell lines. Palmitate oxidation in human islets and the cell lines was comparable after culture at low glucose. At high glucose, palmitate oxidation was reduced by 30% in human islets and MIN6 cells but by 80% in INS-1E cells. In INS-1E cells, AICAR increased oxidation of palmitate. Presence of etomoxir at low glucose decreased palmitate oxidation both in the islets and the cell lines. In summary, lipotoxicity is evident not only in the presence of high but also low glucose concentrations. Additional effects of glucose are prominent in INS-1E but not in MIN6 cells and intact control human islets, which are able to efficiently oxidize fatty acids at high glucose and in this way avoid glucolipotoxicity.


CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition.
Checkpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S-phase arrest. Novel association between CDKN2A/p16 copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.Significance: These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors. Cancer Res; 78(3); 781-97. ©2017 AACR.


Long-term functional outcomes after operative treatment for intra-articular fractures of the calcaneus.
Calcaneal fractures can have long-term consequences in terms of pain and disability. Comparative studies have suggested that operative treatment of these fractures may result in better outcomes than nonoperative treatment; however, to our knowledge, the long-term outcomes of operative treatment of calcaneal fractures have not been reported for a large cohort of patients. One hundred and fifty-seven patients with calcaneal fractures were managed at our institution between January 1, 1989, and April 30, 2003. Seventy-three patients who were managed operatively for eighty-one intra-articular calcaneal fractures responded to a functional questionnaire that included the adjusted American Orthopaedic Foot and Ankle Society ankle-hindfoot scale (subjective component only), the Foot Function Index, and the calcaneal fracture scoring system at a median of 12.8 years (range, 5.0 to 18.5 years) after the injury. In our study population, the mean adjusted American Orthopaedic Foot and Ankle Society ankle-hindfoot score was 65.4 (95% confidence interval, 60.6 to 70.2), the mean Foot Function Index score was 20.5 (95% confidence interval, 16.6 to 24.4), and the mean calcaneal fracture scoring system score was 69.3 (95% confidence interval, 63.6 to 74.9). Patients who had sustained the calcaneal fracture as a result of a motor-vehicle accident rather than a fall reported significantly worse outcomes on two of three scales (p = 0.04 for the adjusted American Orthopaedic Foot and Ankle Society ankle-hindfoot scale, p = 0.05 for the Foot Function Index, and p = 0.35 for the calcaneal fracture scoring system), but this analysis was limited by the exclusion of twenty-four patients because of crush injuries (two) or unavailable documentation of the mechanism of injury (twenty-two). The long-term outcomes of operative treatment described in the present report are comparable with the long-term outcomes previously reported among smaller patient cohorts. Additional investigation is required to determine why patients with fractures that resulted from a motor-vehicle accident reported worse outcomes than patients with fractures that resulted from a fall.


Ferumoxytol-enhanced MRI for surveillance of pediatric cerebral arteriovenous malformations.
Children with intracranial arteriovenous malformations (AVMs) undergo digital DSA for lesion surveillance following their initial diagnosis. However, DSA carries risks of radiation exposure, particularly for the growing pediatric brain and over lifetime. The authors evaluated whether MRI enhanced with a blood pool ferumoxytol (Fe) contrast agent (Fe-MRI) can be used for surveillance of residual or recurrent AVMs. A retrospective cohort was assembled of children with an established AVM diagnosis who underwent surveillance by both DSA and 3-T Fe-MRI from 2014 to 2016. Two neuroradiologists blinded to the DSA results independently assessed Fe-enhanced T1-weighted spoiled gradient recalled acquisition in steady state (Fe-SPGR) scans and, if available, arterial spin labeling (ASL) perfusion scans for residual or recurrent AVMs. Diagnostic confidence was examined using a Likert scale. Sensitivity, specificity, and intermodality reliability were determined using DSA studies as the gold standard. Radiation exposure related to DSA was calculated as total dose area product (TDAP) and effective dose. Fifteen patients were included in this study (mean age 10 years, range 3-15 years). The mean time between the first surveillance DSA and Fe-MRI studies was 17 days (SD 47). Intermodality agreement was excellent between Fe-SPGR and DSA (κ = 1.00) but poor between ASL and DSA (κ = 0.53; 95% CI 0.18-0.89). The sensitivity and specificity for detecting residual AVMs using Fe-SPGR were 100% and 100%, and using ASL they were 72% and 100%, respectively. Radiologists reported overall high diagnostic confidence using Fe-SPGR. On average, patients received two surveillance DSA studies over the study period, which on average equated to a TDAP of 117.2 Gy×cm2 (95% CI 77.2-157.4 Gy×cm2) and an effective dose of 7.8 mSv (95% CI 4.4-8.8 mSv). Fe-MRI performed similarly to DSA for the surveillance of residual AVMs. Future multicenter studies could further investigate the efficacy of Fe-MRI as a noninvasive alternative to DSA for monitoring AVMs in children.


Selective ablation of virion host shutoff protein RNase activity attenuates herpes simplex virus 2 in mice.
The virion host shutoff (vhs) protein of herpes simplex virus (HSV) has endoribonuclease activity and rapidly reduces protein synthesis in infected cells through mRNA degradation. Herpes simplex virus 1 (HSV-1) and HSV-2 vhs mutants are highly attenuated in vivo, but replication and virulence are largely restored to HSV-2 vhs mutants in the absence of a type I interferon (IFN) response. The role of vhs in pathogenesis and the hindrance of the type I IFN response have classically been examined with viruses that completely lack vhs or express a truncated vhs protein. To determine whether RNase activity is the principal mechanism of vhs-mediated type I IFN resistance and virulence, we constructed a HSV-2 point mutant that synthesizes full-length vhs protein lacking RNase activity (RNase(-) virus). Wild-type and mutant HSV-2 vhs proteins coimmunoprecipitated with VP16 and VP22. vhs protein bearing the point mutation was packaged into the virion as efficiently as the wild-type vhs protein. Like a mutant encoding truncated vhs, the RNase(-) virus showed IFN-dependent replication that was restricted compared with that of the wild-type virus. The RNase(-) virus was highly attenuated in wild-type mice infected intravaginally, with reduced mucosal replication, disease severity, and spread to the nervous system comparable to those of the vhs truncation mutant. Surprisingly, in alpha/beta interferon (IFN-alpha/beta) receptor knockout mice, the vhs RNase mutant was more attenuated than the vhs truncation mutant in terms of disease severity and virus titer in vaginal swabs and central nervous system samples, suggesting that non-enzymatically active vhs protein interferes with efficient virus replication. Our results indicate that vhs enzymatic activity plays a complex role in vhs-mediated type I IFN resistance during HSV-2 infection.


CGGBP1 mitigates cytosine methylation at repetitive DNA sequences.
CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.


Medication adherence and subjective weight perception in patients with first-episode psychotic disorder.
Medication adherence is critical to the management of psychotic disorder. Different factors associated with medication adherence have been investigated in previous studies. However, the association with subjective weight perception, which is related to the weight gain side effect of antipsychotics, has not been thoroughly investigated. Subjective weight perception may not equal objective weight status. This study tests the hypothesis that medication adherence is related to subjective weight perception in a group of patients with first-episode psychotic disorder who have taken antipsychotics for one year. This study recruited 160 participants with one-year histories of first-episode psychotic disorder and measured their actual and perceived weights, amount of weight gain in the past year, body size satisfaction and medication adherence levels. The associations between medication adherence and both the actual and perceived weight status were analyzed controlling for other confounding factors including insight, drug attitude, illness severity and other medication side effects. Stepwise multiple regression analysis found that the participants' perceived weight status, negative attitude toward their drugs and insight were the major factors associated with poor medication adherence. Of the participants who perceived themselves as being overweight, 86% believed that antipsychotics were responsible. Among those who had such beliefs, 72% had reduced their antipsychotic dosages on their own. About half of the participants had gained more than 7% of their baseline weight and 43.1% of the participants were found to be overweight after one year of treatment with antipsychotics. The results of this study indicate that medication adherence is associated with perceived weight status. Healthcare professionals should be aware of this relationship and address this issue early in the management of patients. Apart from weight management programs, education on a correct weight perception should be carried out with the promotion of proper drug attitudes and better insight for the improvement of medication adherence in the early course of psychotic disorder.


The European clinical research response to optimise treatment of patients with COVID-19: lessons learned, future perspective, and recommendations.
Clinicians have worked feverishly to treat patients with COVID-19 while also carrying out clinical research studies. We discuss how the clinical research community responded to the pandemic in Europe, what lessons were learned, and provide recommendations for future clinical research response during pandemics. We focused on two platform trials: RECOVERY and REMAP-CAP. Both trials were able to enrol patients very rapidly during the beginning of the pandemic because of pre-established structures and procedures, and because they share simple execution and flexibility to adjust when evidence emergences. However, contracting, regulatory hurdles, and competition with (often inadequately designed or underpowered) national trials was a major challenge in several EU countries. We recommend the creation of structures and partnerships that facilitate prioritisation of clinical research, simplification of clinical trial delivery, development of digital models and procedures for data collection and sharing, development of a mechanism to rapidly leverage pandemic funding and to connect EU funding with national funding, and investment in clinical trial networks, platform trials, and master protocols. Finally, the future pandemic clinical research response of the EU should be embedded in the global response. We believe that globally connected clinical trial networks will be essential to respond more effectively to future infectious diseases outbreaks.


Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients.
To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) of elderly (≥65 years of age) nonvalvular atrial fibrillation (NVAF) patients initiating apixaban vs. rivaroxaban, dabigatran, or warfarin. NVAF patients with Medicare Advantage coverage in the US initiating oral anticoagulants (OACs, index event) were identified from the Humana database (1 January 2013-30 September 2015) and grouped into cohorts depending on OAC initiated. Propensity score matching (PSM), 1:1, was conducted among patients treated with apixaban vs. each other OAC, separately. Rates of S/SE and MB were evaluated in the follow-up. Cox regressions were used to compare the risk of S/SE and MB between apixaban and each of the other OACs during the follow-up. The matched pairs of apixaban vs. rivaroxaban (n = 13,620), apixaban vs. dabigatran (n = 4654), and apixaban vs. warfarin (n = 14,214) were well balanced for key patient characteristics. Adjusted risks for S/SE (hazard ratio [HR] vs. rivaroxaban: 0.72, p = .003; vs. warfarin: 0.65, p < .001) and MB (HR vs. rivaroxaban: 0.49, p < .001; vs. warfarin: 0.53, p < .001) were significantly lower during the follow-up for patients treated with apixaban vs. rivaroxaban and warfarin. Adjusted risks for S/SE (HR: 0.78, p = .27) and MB (HR: 0.82, p = .23) of NVAF patients treated with apixaban vs. dabigatran trended to be lower, but did not reach statistical significance. In the real-world setting after controlling for differences in patient characteristics, apixaban is associated with significantly lower risk of S/SE and MB than rivaroxaban and warfarin, and a trend towards better outcomes vs. dabigatran among elderly NVAF patients in the US.


Orchestration of protein acetylation as a toggle for cellular defense and virus replication.
Emerging evidence highlights protein acetylation, a prevalent lysine posttranslational modification, as a regulatory mechanism and promising therapeutic target in human viral infections. However, how infections dynamically alter global cellular acetylation or whether viral proteins are acetylated remains virtually unexplored. Here, we establish acetylation as a highly-regulated molecular toggle of protein function integral to the herpesvirus human cytomegalovirus (HCMV) replication. We offer temporal resolution of cellular and viral acetylations. By interrogating dynamic protein acetylation with both protein abundance and subcellular localization, we discover finely tuned spatial acetylations across infection time. We determine that lamin acetylation at the nuclear periphery protects against virus production by inhibiting capsid nuclear egress. Further studies within infectious viral particles identify numerous acetylations, including on the viral transcriptional activator pUL26, which we show represses virus production. Altogether, this study provides specific insights into functions of cellular and viral protein acetylations and a valuable resource of dynamic acetylation events.


Vertical sleeve gastrectomy improves ventilatory drive through a leptin-dependent mechanism.
Obesity hypoventilation syndrome (OHS) is a serious disorder characterized by daytime hypercapnia, disordered breathing, and a reduction in chemosensitivity. Vertical sleeve gastrectomy (VSG), a bariatric surgical procedure resulting in weight loss and weight-independent improvements in glucose metabolism, has been observed to substantially improve sleep-disordered breathing. However, it is unclear if the ventilatory effects of VSG are secondary to weight loss or the marked change in metabolic physiology. Using preclinical mouse models, we found that VSG leads to an improvement in the hypercapnic ventilatory response (HCVR) and reductions in circulating leptin levels independent of reductions in body mass, fat mass, and caloric intake. In the absence of leptin, VSG continues to improve body mass, fat mass, and glucose tolerance in ob/ob mice but no longer affects HCVR. However, the HCVR of ob/ob mice can be returned to wild-type levels with leptin treatment. These data demonstrate that VSG improves chemosensitivity and ventilatory drive via a leptin-dependent mechanism. Clinically, these data downgrade the relative contribution of physical, mechanical load in the pathogenesis of OHS, and instead point to physiological components of obesity, including alterations in leptin signaling, as key drivers in OHS.


Neuroprotective Effects of Platonin, a Therapeutic Immunomodulating Medicine, on Traumatic Brain Injury in Mice after Controlled Cortical Impact.
Traumatic brain injury (TBI) is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied by neuroinflammation, microglial activation, and additional cell death subsequently occur. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers, and some types of acute inflammation. In the present study, the neuroprotective effects of platonin against TBI were explored in a controlled cortical impact (CCI) injury model in mice. Treatment with platonin (200 µg/kg) significantly reduced the neurological severity score, general locomotor activity, and anxiety-related behavior, and improved the rotarod performance of CCI-injured mice. In addition, platonin reduced lesion volumes, the expression of cleaved caspase-3, and microglial activation in TBI-insulted brains. Platonin also suppressed messenger (m)RNA levels of caspase-3, caspase-1, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β. On the other hand, free radical production after TBI was obviously attenuated in platonin-treated mice. Treatment with platonin exhibited prominent neuroprotective properties against TBI in a CCI mouse model through its anti-inflammatory, anti-apoptotic, and anti-free radical capabilities. This evidence collectively indicates that platonin may be a potential therapeutic medicine for use with TBIs.


Serenoa Repens, lycopene and selenium: a triple therapeutic approach to manage benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is a major health concern that is likely to have an increasing impact in line with the gradual aging of the population. BPH is characterized by smooth muscle and epithelial proliferation primarily within the prostatic transition zone that can cause a variety of problems for patients, the most frequent are the lower urinary tract symptoms. BPH is thought to involve in disruption of dihydrotestosterone (DHT)-supported homeostasis between cell proliferation and cell death, and, as a result, proliferative processes predominate and apoptotic processes are inhibited. Phytotherapeutic supplements, mainly based on Saw Palmetto-derived Serenoa Repens (SeR), are numerous and used frequently. Serenoa Repens reduces inflammation and decreases in vivo the androgenic support to prostatic cell growth. Furthermore, SeR stimulates the apoptotic machinery; however, data supporting efficacy is limited, making treatment recommendations difficult. Besides SeR, selenium (Se), an essential trace element mainly functioning through selenoproteins and able to promote an optimal antioxidant/oxidant balance, and lycopene (Ly), a dietary carotenoid synthesized by plants, fruits, and microorganisms with a strong antioxidant activity, has been shown to exert beneficial effects in prostate disease. SeR is frequently associated with Ly and Se, in order to increase its therapeutic activity in benign prostatic hyperplasia (BPH). It has been shown that the Ly-Se-SeR association has a greater and enhanced antiinflammatory activity that might be of particular interest in the treatment of BPH. The Ly-Se-SeR association is also more effective than SeR alone in reducing prostate weight and hyperplasia, in augmenting the pro-apoptotic Bax and caspase-9 and blunting the anti-apoptotic Bcl-2 mRNA. In addition, Ly-Se-SeR more efficiently suppresses the EGF and Vascular Endothelial Growth Factor (VEGF) expressions in hyperplastic prostates. Therefore, SeR particularly when combined with Se and Ly may have a greater potential for the management of benign prostate hyperplasia.


Vitamin K status is associated with childhood bone mineral content.
In adult bone, vitamin K contributes to bone health, probably through its role as co-factor in the carboxylation of osteocalcin. In children, the significance of vitamin K in bone-mass acquisition is less well known. The objective of this longitudinal study was to determine whether biochemical indicators of vitamin K status are related to (gains in) bone mineral content (BMC) and markers of bone metabolism in peripubertal children. In 307 healthy children (mean age 11.2 years), BMC of the total body, lumbar spine and femoral neck was determined at baseline and 2 years later. Vitamin K status (ratio of undercarboxylated (ucOC) to carboxylated (cOC) fractions of osteocalcin; UCR) was also measured at both time points. Markers of bone metabolism, sex steroids, vitamin D status and growth hormones were measured at baseline only. Large variations in the levels of the UCR were found at both time-points, indicating a substantial interindividual difference in vitamin K status. Improvement of vitamin K status over 2 years (n 281 children) was associated with a marked increase in total body BMC (r -49.1, P<0.001). The UCR was associated with pubertal stage, markers of bone metabolism, sex hormones and vitamin D status. A better vitamin K status was associated with more pronounced increase in bone mass in healthy peripubertal children. In order to determine the significance of these findings for childhood bone health, additional paediatric studies are needed.


No effect of triheptanoin on exercise performance in McArdle disease.
To study if treatment with triheptanoin, a 7-carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and glycogen-dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease. Double-blind, placebo-controlled, crossover study in patients with McArdle disease completing two treatment periods of 14 days each with a triheptanoin or placebo diet (1 g/kg/day). Primary outcome was change in mean heart rate during 20 min submaximal exercise on a cycle ergometer. Secondary outcomes were change in peak workload and oxygen uptake along with changes in blood metabolites and respiratory quotients. Nineteen of 22 patients completed the trial. Malate levels rose on triheptanoin treatment versus placebo (8.0 ± SD2.3 vs. 5.5 ± SD1.8 µmol/L, P < 0.001), but dropped from rest to exercise (P < 0.001). There was no difference in exercise heart rates between triheptanoin (120 ± SD16 bpm) and placebo (121 ± SD16 bpm) treatments. Compared with placebo, triheptanoin did not change the submaximal respiratory quotient (0.82 ± SD0.05 vs. 0.84 ± SD0.03), peak workload (105 ± SD38 vs. 102 ± SD31 Watts), or peak oxygen uptake (1938 ± SD499 vs. 1977 ± SD380 mL/min). Despite increased resting plasma malate with triheptanoin, the increase was insufficient to generate a normal TCA turnover during exercise and the treatment has no effect on exercise capacity or oxidative metabolism in patients with McArdle disease.


Adding adefovir vs. switching to entecavir for lamivudine-resistant chronic hepatitis B (ACE study): a 2-year follow-up randomized controlled trial.
Management of lamivudine-resistant chronic hepatitis B (CHB) remains challenging, as inappropriate choice of treatment may cause multidrug resistance. Until now, randomized trials directly comparing adding adefovir and switching to entecavir monotherapy have not been reported. This multicentre prospective randomized study was designed to compare the efficacy of these two strategies. Two hundred and nineteen lamivudine-resistant CHB patients were randomized to either adefovir-lamivudine combination group or entecavir monotherapy group (n = 110 vs. 109), and followed up for 24 months. One hundred and eighty patients completed this study. At month 24, virological response rate [hepatitis B virus (HBV) DNA <60 IU/ml] was higher in the adefovir-lamivudine combination group compared with entecavir group (56.7% vs. 40%, P = 0.025), although biochemical and serological response rates were not significantly different. Genotypic resistance (9.2% vs. 24.6%, P = 0.005) and combined viral breakthrough (2.0% vs. 17.6%, P < 0.001) were more frequent in the entecavir group. However, by subgroup analysis, virological response rates were not significantly different between the two therapies in HBeAg-positive patients (44.9% vs. 35.7%, P = 0.268) or in patients with high baseline HBV DNA (≥7 log IU/ml) (40.7% vs. 31.3%, P = 0.320) at month 24. This study showed that adefovir-lamivudine combination provides significantly higher antiviral efficacy and the lower resistance rate compared with the entecavir monotherapy in the management of lamivudine-resistant CHB. However, it had limited efficacy in HBeAg-positive patients or in patients with high baseline HBV DNA.


The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.
The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.


FragSAD: A database of diversity and species abundance distributions from habitat fragments.
Habitat destruction is the single greatest anthropogenic threat to biodiversity. Decades of research on this issue have led to the accumulation of hundreds of data sets comparing species assemblages in larger, intact, habitats to smaller, more fragmented, habitats. Despite this, little synthesis or consensus has been achieved, primarily because of non-standardized sampling methodology and analyses of notoriously scale-dependent response variables (i.e., species richness). To be able to compare and contrast the results of habitat fragmentation on species' assemblages, it is necessary to have the underlying data on species abundances and sampling intensity, so that standardization can be achieved. To accomplish this, we systematically searched the literature for studies where abundances of species in assemblages (of any taxa) were sampled from many habitat patches that varied in size. From these, we extracted data from several studies, and contacted authors of studies where appropriate data were collected but not published, giving us 117 studies that compared species assemblages among habitat fragments that varied in area. Less than one-half (41) of studies came from tropical forests of Central and South America, but there were many studies from temperate forests and grasslands from all continents except Antarctica. Fifty-four of the studies were on invertebrates (mostly insects), but there were several studies on plants (15), birds (16), mammals (19), and reptiles and amphibians (13). We also collected qualitative information on the length of time since fragmentation. With data on total and relative abundances (and identities) of species, sampling effort, and affiliated meta-data about the study sites, these data can be used to more definitively test hypotheses about the role of habitat fragmentation in altering patterns of biodiversity. There are no copyright restrictions. Please cite this data paper and the associated Dryad data set if the data are used in publications.