Physiological basis in the assessment of myocardial mechanics using speckle-tracking echocardiography 2D. Part II.
In this paper, the authors attempt to concisely present the anatomical and pathophysiological bases as well as the principles for echocardiographic evaluation of mechanical aspects of cardiac function based on speckle tracking method. This technique uses a phenomenon involving the formation of characteristic image units, referred to as speckles or acoustic markers, which are stable during cardiac cycle, on a two-dimensional echocardiographic picture. Changes in the position of these speckles throughout the cardiac cycle, which are monitored and analyzed semi-automatically by a computer system, reflect deformation of both, cardiac ventricle as a whole as well as its individual anatomical segments. The values of strain and the strain rate, as well as the range and velocity of the movement of these markers, which are in close relationship with multiple hemodynamic parameters, can be visualized as various types of charts - linear, two- and three-dimensional - as well as numerical values, enabling deeper insight into the mechanical and hemodynamic aspects of cardiac function in health and disease. The use of information obtained based on speckle tracking echocardiography allows to understand previously unclear mechanisms of physiological and pathophysiological processes. The first part of the study discusses the formation of a two-dimensional ultrasound image and the speckles, as well as the technical aspects of tracking their movement. The second part presents in more detail the methodology of speckle-tracking echocardiography, the characteristic abnormalities of cardiac mechanics presenting in different clinical entities, and the limitations related to given clinical and technical issues.


Roles for transforming growth factor-alpha in gastric physiology and pathophysiology.
Transforming growth factor alpha (TGF alpha) is a 5.6 kd single-chain polypeptide that acts through binding to the epidermal growth factor receptor (EGFR). TGF alpha is produced in a wide range of normal as well as embryonic and neoplastic cells and tissues. TGF alpha and EGFR, but not EGF, are expressed in normal gastric mucosa. We have identified the following biological roles for TGF alpha in the stomach, using a variety of primate and rodent models: inhibition of acid secretion; stimulation of mucous cell growth; protection against ethanol- and aspirin-induced injury. This last effect is associated with a time- and dose-dependent increase in levels of insoluble gastric mucin. Based on these known biological actions of TGF alpha, we have examined TGF alpha production in Ménétrier's disease, a disorder characterized by foveolar hyperplasia, hypochlorhydria, and increased gastric mucin content. In four patients with Ménétrier's disease, there was enhanced TGF alpha immunostaining throughout the gastric mucosa. Furthermore, metallothionein (MT)-TGF alpha transgenic mice which overproduce TGF alpha in the stomach exhibit histopathological and biochemical features characteristic of and consistent with the diagnosis of Ménétrier's disease. Thus locally produced TGF alpha may mediate a number of biological processes in the stomach, and its altered production may participate in the pathogenesis of selected pathological states.


Spatial oxygen distribution and nitrous oxide emissions from soil after manure application: a novel approach using planar optodes.
The availability and spatial distribution of oxygen (O) in agricultural soil are controlling factors in the production and emission of nitrous oxide (NO) to the atmosphere, but most experiments investigating the effects of various factors on NO emissions in soil have been conducted without determining the content and distribution of O. This complicates data interpretation and leads to speculative conclusions about which nitrogen transformation processes are responsible for NO production. Using an O-specific planar optode, this paper shows how spatiotemporal O dynamics can be used to interpret data on NO emissions following a uniform or layered amendment of manure to agricultural soil. The spatial distribution of O and gas emission rates were monitored for 12 h. An anoxic layer formed rapidly around the layered manure, whereas the uniformly distributed manure led to a more widespread anoxia. Nitrous oxide emissions increased immediately after depletion of O in the manure-amended treatments. Greater understanding and improved knowledge of the spatial distribution of O is clearly beneficial and can be used to devise improved application strategies for mitigating NO emissions from manure and other fertilizers.


Children's response to adult disgust elicitors: development and acquisition.
Little is known about when or how different disgust elicitors are acquired. In Study 1, parents of children (0-18 years old) rated how their child would react to 22 disgust elicitors. Different developmental patterns were identified for core, animal, and sociomoral elicitors, with core elicitors emerging first. In Study 2, children (2-16 years old) were exposed alone and then with their parent to a range of elicitors derived from Study 1. Self-report, behavioral, and facial expression data were obtained along with measures of contagion, conservation, and contamination. Convergent evidence supported the developmental patterns reported in Study 1. Evidence for parent-child transmission was also observed, with parents of young children emoting more disgust to their offspring and showing greater behavioral avoidance. Moreover, child reactivity to animal and sociomoral elicitors and contamination correlated with parental responsiveness. Finally, young children who failed to demonstrate contagion and conservation knowledge were as reactive to core elicitors and contamination as children of the same age who demonstrated such knowledge. These findings are interpreted within an evolutionary framework in which core disgust responses are acquired early to promote avoidance of pathogens.


Pubertal timing and smoking initiation in adolescent females: differences by race.
The purpose of this study was to examine whether (a) early pubertal timing effects on smoking onset existed for both White and Black girls and (b) whether the association between pubertal timing and smoking onset was moderated by race. Participants included 264 girls (14.9 +/- 2.2 years, 164 White, and 100 Black) at the baseline report of a longitudinal study of whom 153 reported smoking and age at first cigarette. Kaplan-Meier analysis stratified by racial group showed a significant difference between the pubertal timing groups for Black girls only. After accounting for covariates using Cox regression, there was no significant interaction between pubertal timing and racial group. There was a main effect of pubertal timing indicating that late maturers were at significantly lower risk for smoking initiation compared with the early and on-time groups, but the early and on-time groups were not significantly different from each other. Results point to equal risk of early smoking onset for early and on-time maturers of both racial groups, indicating the need for smoking prevention in early adolescence for both White and Black females.


Interferon gamma production during bovine respiratory syncytial virus (BRSV) infection is diminished in calves vaccinated with formalin-inactivated BRSV.
Formalin-inactivated respiratory syncytial virus (FI-RSV) vaccination has been associated with severe disease in humans. Research in mice suggests that FI-RSV may prime for decreased interferon gamma (IFN-gamma) production at subsequent infection. Interferon-gamma production by peripheral blood mononuclear cells (PBMC) was measured following challenge of calves vaccinated with FI-BRSV to determine whether a similar mechanism is operative in a host naturally susceptible to RSV. Eight-week old male Holstein calves were administered FI-BRSV and mock challenge (V/M, n = 6); mock vaccination and BRSV challenge (M/C, n = 6) or FI-BRSV and BRSV challenge (V/C, n = 7). Vaccine was administered twice at a 2-week interval; challenge followed one month later. On days 0, 5 and 10 postchallenge (PC), PBMC were stimulated in vitro for 24 h with live BRSV, concanavalin A (positive control) or spent media (negative control). Supernatants were assayed for IFN-gamma using ELISA. Interferon-gamma production by BRSV-stimulated PBMC was increased in M/C and V/C calves as compared to V/M calves on day 5 PC (p < 0.015); and increased in M/C calves compared to V/C and V/M calves on day 10 PC (p < 0.015). Over time postchallenge, a significant increase in IFN-gamma production by BRSV-stimulated PBMC was seen in M/C calves (p < 0.025) but not in V/C calves. FI-BRSV vaccination of calves led to diminished IFN-gamma production postchallenge. Decreased IFN-gamma production may have contributed to impaired viral clearance and enhanced disease in FI-BRSV vaccinated calves.


Head-mounted eye tracking of a chimpanzee under naturalistic conditions.
This study offers a new method for examining the bodily, manual, and eye movements of a chimpanzee at the micro-level. A female chimpanzee wore a lightweight head-mounted eye tracker (60 Hz) on her head while engaging in daily interactions with the human experimenter. The eye tracker recorded her eye movements accurately while the chimpanzee freely moved her head, hands, and body. Three video cameras recorded the bodily and manual movements of the chimpanzee from multiple angles. We examined how the chimpanzee viewed the experimenter in this interactive setting and how the eye movements were related to the ongoing interactive contexts and actions. We prepared two experimentally defined contexts in each session: a face-to-face greeting phase upon the appearance of the experimenter in the experimental room, and a subsequent face-to-face task phase that included manual gestures and fruit rewards. Overall, the general viewing pattern of the chimpanzee, measured in terms of duration of individual fixations, length of individual saccades, and total viewing duration of the experimenter's face/body, was very similar to that observed in previous eye-tracking studies that used non-interactive situations, despite the differences in the experimental settings. However, the chimpanzee viewed the experimenter and the scene objects differently depending on the ongoing context and actions. The chimpanzee viewed the experimenter's face and body during the greeting phase, but viewed the experimenter's face and hands as well as the fruit reward during the task phase. These differences can be explained by the differential bodily/manual actions produced by the chimpanzee and the experimenter during each experimental phase (i.e., greeting gestures, task cueing). Additionally, the chimpanzee's viewing pattern varied depending on the identity of the experimenter (i.e., the chimpanzee's prior experience with the experimenter). These methods and results offer new possibilities for examining the natural gaze behavior of chimpanzees.


Short-Term Effect of Autologous Bone Marrow Stem Cells to Treat Acute Myocardial Infarction: A Meta-Analysis of Randomized Controlled Clinical Trials.
Bone marrow stem cells (BMSCs) have been used to treat patient with ST-segment elevation myocardial infarction (STEMI) via intracoronary route. We performed a meta-analysis to evaluate the short-term efficacy and safety of this modality. Seventeen randomized controlled trials (RCTs) of BMSC-based therapy for STEMI, delivered with 9 days of reperfusion and followed up shorter than 12 months, were identified by systematic review. Intracoronary BMSC therapy resulted in an overall significant improvement in left ventricular ejection fraction (LVEF) by 2.74 % (95 % confidence interval (CI) 2.09-3.39, P < 0.00001, I(2) = 84 %) at 3-6-month follow-up and 5.1 % (95 % CI 4.16-6.03, P < 0.00001 and I(2) = 85 %) at 12 months. The left ventricular end-systolic volume (LVESV) and wall motion score index (WMSI) were also reduced at 3-6 months. At 12 months, left ventricular end-diastolic volume (LVEDV), LVESV, and WMSI were significantly reduced in BMSC group. In conclusion, intracoronary BMSC therapy at post-STEMI is safe and effective in patient with acute STEMI.


Hepatitis C viremia and genotype distribution among a sample of nonmedical prescription drug users exposed to HCV in rural Appalachia.
Research has demonstrated that hepatitis C (HCV) genotype distribution varies geographically and demographically. This exploratory study examines HCV viremia, viral concentration, and genotype distribution among anti-HCV positive, rural Appalachian nonmedical prescription drug users. The study population was randomly selected from a pool of 200 anti-HCV positive participants in a longitudinal study. Those randomly chosen were representative of the overall pool in terms of demographics, drug use, and other risk behaviors. Participants were tested serologically for HCV RNA, viral concentration, and genotype, and interview-administered questionnaires examined behavioral and demographic characteristics. Of the 81 participants, 69% tested RNA positive, 59% of which had viral loads exceeding 800,000 IU/ml. Approximately 66% of the RNA positive sample had genotype 1a; types 2b (16%) and 3a (13%) were less common. RNA positive participants were not significantly different than RNA negative participants demographically or behaviorally. Likewise, with the exception of education, genotype 1 participants were not significantly different than those with genotype 2 or 3. The prevalence of active HCV infection highlights a need for prevention and treatment in this population. However, the predominance of genotype 1 may present challenges due to its association with decreased responsiveness to drug treatment, although the novel class of direct-acting antivirals such as telaprevir and boceprevir offer new hope in this regard. The prevalence of genotype 1 may also foreshadow heightened burden of hepatocellular carcinoma and elevated healthcare expenditures. More research is needed to characterize HCV infection and genotype in this population.


Acute and chronic effects of nifedipine on plasma renin activity and plasma adrenaline and noradrenaline in controls and hypertensive patients.
1. Nifedipine, a calcium antagonist drug, was given sublingually (10 mg) to seven normal subjects and 19 patients with essential hypertension. In addition, 12 of the hypertensive subjects then received nifedipine (10 mg thrice daily) for 3 weeks. 2. Sublingual administration of nifedipine in hypertensive patients induced a prompt and sustained reduction of blood pressure, without a significant increase of heart rate; in normotensive subjects blood pressure did not change, and heart rate was significantly increased. After chronic treatment, blood pressure remained reduced and heart rate did not rise. 3. Plasma catecholamines and plasma renin activity increased significantly in normotensive subjects after acute administration. 4. After both acute and chronic administration, only plasma noradrenaline was significantly increased in hypertensive patients; in long-term treatment, it was increased in both the lying and standing positions. 5. Nifedipine is an active antihypertensive drug, which may induce some degree of sympathetic activation.


Long-term effects of cerebellar anodal transcranial direct current stimulation (tDCS) on the acquisition and extinction of conditioned eyeblink responses.
Cerebellar transcranial direct current stimulation (tDCS) has been reported to enhance the acquisition of conditioned eyeblink responses (CR), a form of associative motor learning. The aim of the present study was to determine possible long-term effects of cerebellar tDCS on the acquisition and extinction of CRs. Delay eyeblink conditioning was performed in 40 young and healthy human participants. On day 1, 100 paired CS (conditioned stimulus)-US (unconditioned stimulus) trials were applied. During the first 50 paired CS-US trials, 20 participants received anodal cerebellar tDCS, and 20 participants received sham stimulation. On days 2, 8 and 29, 50 paired CS-US trials were applied, followed by 30 CS-only extinction trials on day 29. CR acquisition was not significantly different between anodal and sham groups. During extinction, CR incidences were significantly reduced in the anodal group compared to sham, indicating reduced retention. In the anodal group, learning related increase of CR magnitude tended to be reduced, and timing of CRs tended to be delayed. The present data do not confirm previous findings of enhanced acquisition of CRs induced by anodal cerebellar tDCS. Rather, the present findings suggest a detrimental effect of anodal cerebellar tDCS on CR retention and possibly CR performance.


Preventing autoimmunity protects against the development of hypertension and renal injury.
Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production, and the prevalence of hypertension is increased markedly in this patient population compared with normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or immunoglobulin G antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti-CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-α expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein-1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation are an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus.


Multipoint temperature-independent fiber-Bragg-grating strain-sensing system employing an optical-power-detection scheme.
A temperature-independent fiber-Bragg-grating strains-sensing system, based on a novel optical-power-detection scheme, is developed and analyzed. In this system a pair of fiber Bragg gratings with reflection spectra either partially or substantially overlapping is placed side by side to form a temperature-independent strain-sensor unit. Conventional wavelength-interrogation techniques are not used here, and instead an optical-power-detection scheme is proposed to directly calibrate the measurand, i.e., the strain. Unlike the conventional approach in a multiplexed sensing system, the presented power-detection-based interrogation method does not need the fiber-Bragg-grating sensors to be spectrally separate. The only requirement is that the spectra of the two fiber Bragg gratings of each sensor unit in a multiplexed system be identical or slightly separate (slightly overlapping spectra would also work in the sensing scheme) and the source's optical power be sufficient for sensitive measurement. Based on a three-sensor-unit system, we demonstrate simple strain measurements of high linearity (+/- 0.4%), good sensitivity [2 microstrains (microS)], high thermal stability (+/- 0.8%), and zero cross talk. The effects of light source spectral flatness and fiber bending loss on measurement accuracy are also discussed.


[Adherence to the Mediterranean diet and its relation to nutritional status in older people].
the Mediterranean diet (MD) and model quality diet is associated with a reduction in mortality and an improvement in quality of life in elderly. To evaluate the relationship between nutritional status and lifestyles with the degree of adherence to the DM in elderly Methods: Sample consists of 60 subjects who attended the nursing consultation of a scepter health of Alicante with an index greater than 24.9 body mass. The frequency questionnaire food consumption MEDIS-FFQ questionnaire PREDIMED adherence to the Mediterranean diet and anthropometric assessment was used. 83.3% of the population were overweight compared to 16.7% obesity, no significant differences between sexes. The percentage of body fat was 40.3% in women and 29.5% in men (p = 0.001). 65.2% of the women had cardiovascular risk compared with 81.8% of men (p = 0.001). It was observed under compliance with dietary recommendations in whole grains, fruits and nuts. Subjects with low adherence to the DM had higher rates of obesity (OR = 1.46; 95% CI, 0.89-2.40), increased consumption of snuff (OR = 1.65; 95% CI, 1.05-2.60) and alcohol (OR = 1.53; 95% CI, 0.91-2.55), increased waist-hip ratio (OR = 2.57; 95% CI, 1.3-4.9) and higher percentage of body fat (OR = 5.3; 95% CI, 1.02-6.48). Subjects with good adherence (DM) had a lower waist-hip ratio and a lower percentage of body fat.


Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice.
Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.


[A multivariate analysis of the factors associated with the severity of chronic venous insufficiency].
Chronic Venous Insufficiency (CVI) affects a large proportion of individuals and, with the ageing of the population of Western Europe, its prevalence is expected to increase. Epidemiological data, particularly regarding risk factors, is scarce and controversial. The purpose of this study was to identify clinical factors that are associated with an increase in severity of CVI. Eighteen physicians observed 474 unselected patients with symptoms suggesting CVI. A multivariate model is forwarded in which age is a major risk factor. Other factors that are independently correlated with the severity of CVI are body weight, environmental heat, sedentariness, double heredity, high-dose oestrogen formulations, osteo-articular disease of the lower limbs, presence of troncular varices, involvement of the internal saphena, lymphedema or history of thrombophlebitis. Since most studies do not adjust for age when testing for risk factors, this may be an important reason for the multiplicity of reported factors and the lack of consistency of their results.


Clinical trial simulations in pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 analog in neonates and infants with short-bowel syndrome.
Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.


Possible health impact of phytoestrogens and xenoestrogens in food.
Plants produce estrogen-like substances, denominated phytoestrogens, which are present in many human foodstuffs. The consumption of phytoestrogens has been associated with a variety of protective effects. Their relative estrogenic potency combined with their concentrations in food and human plasma indicate biological relevance. However, their biological properties differ from those of estradiol or other endogenous estrogens in humans. For instance, their possible effects on SHBG, inhibition of steroid metabolizing enzymes, anti-proliferative and anti-angiogenetic and other side effects have been described. Furthermore, phytoestrogens can exert estrogenic and antiestrogenic activities at the same time and their potency and metabolism have not been yet elucidated in all cases. In recent decades growing evidence has accumulated on the hormone-like effects of synthetic chemicals that appeared in the environment. The possible impact of xenoestrogens, to which humans are also exposed through the food chain, needs to be further clarified as well. The molecular effects and control mechanisms of these substances, their pharmacokinetics, threshold levels and dose-response differences are issues that require further research before a full assessment of their effect on humans can be drawn. Evaluating the total exposure and impact of this estrogenic effect is very challenging because of the lack of specific knowledge in some areas and the differences in the biological activity among these substances, as pinpointed in this review.


S-layer glycan-specific loci on the chromosome of Geobacillus stearothermophilus NRS 2004/3a and dTDP-L-rhamnose biosynthesis potential of G. stearothermophilus strains.
The approximately 16.5 kb surface layer (S-layer) glycan biosynthesis (slg) gene cluster of the Gram-positive thermophile Geobacillus stearothermophilus NRS 2004/3a has been sequenced. The cluster is located immediately downstream of the S-layer structural gene sgsE and consists of 13 ORFs that have been identified by database sequence comparisons. The cluster encodes dTDP-L-rhamnose biosynthesis (rml operon), required for building up the polyrhamnan S-layer glycan, as well as for assembly and export of the elongated glycan chain, and its transfer to the S-layer protein. This is the first report of a gene cluster likely to be involved in the glycosylation of an S-layer protein. There is evidence that this cluster is transcribed as a polycistronic unit, whereas sgsE is transcribed monocistronically. To get insights into the regulatory mechanisms underlying glycosylation of the S-layer protein, the influence of growth temperature on the S-layer was investigated in seven closely related G. stearothermophilus strains, of which only strain NRS 2004/3a possessed a glycosylated S-layer. Chromosomal DNA preparations of these strains were screened for the presence of the rml operon, because L-rhamnose is a frequent constituent of S-layer glycans. From rml-positive strains, flanking regions of the operon were sequenced. Comparison with the slg gene cluster of G. stearothermophilus NRS 2004/3a revealed sequence homologies between adjacent genes. The temperature inducibility of S-layer protein glycosylation was investigated in those strains by raising the growth temperature from 55 degrees C to 67 degrees C; no change of either the protein banding pattern or the glycan staining behaviour was observed on SDS-PAGE gels, although the sgsE transcript was several-fold more abundant at 67 degrees C. Cell-free extracts of the strains were capable of converting dTDP-D-glucose to dtdp-L-rhamnose. Taken together, the results indicate that the rml locus is highly conserved among G. stearothermophilus strains, and that in the investigated rml-containing strains, dTDP-L-rhamnose is actively synthesized in vitro. However, in contrast to previous reports for G. stearothermophilus wild-type strains, an increase in growth temperature did not switch an S-layer protein phenotype to an S-layer glycoprotein phenotype, via the de novo generation of a new S-layer gene sequence.


Russian romances: emotionalism and spirituality in the writings of "Eastern Front" nurses, 1914-1918.
The nursing work of the First World War is usually associated with the trench warfare of the Western Front. Nurses were based within fairly permanent casualty clearing stations and field hospitals, and patients were moved "down the line" to base hospitals, and then to convalescent hospitals "at home." The nurses and volunteers who worked on the Eastern Front and offered their services to the letuchka or "flying columns" of the Russian medical services had a very different experience. They worked with highly mobile units, following a rapidly moving "front line." The diaries of three British (one Anglo-Russian) nurses who worked alongside Russian nursing sisterhoods in three different flying columns-Violetta Thurstan (Field Hospital and Flying Column), Florence Farmborough (With the Armies of the Tsar) and Mary Britnieva (One Woman's Story)--stand as an important corpus of nursing writing. Written in a highly romantic style, they take up similar themes around their work on the Eastern Front as a heroic journey through a dreamlike landscape. Each nurse offers a portrayal of the Russian character as fine and noble. The most important themes deal with the romance of nursing itself, in which nursing work is portrayed as both character-testing and a highly spiritual pursuit.


Thymidylate synthase inhibitors.
Folate analogues that inhibit thymidylate synthase (TS) selectively were developed based on TS and folate molecular structures and properties. The structure-activity relationship, preclinical and clinical development, and issues of potential importance in the future success of these TS inhibitors are reviewed herein. Properties of these new compounds depend mainly on the use of the reduced folate carrier (RFC) proteins for cellular entry and on intracellular polyglutamation, which augments TS inhibitory function and cellular retention. CB3717 [Zeneca (formerly ICI Pharmaceuticals), Macclesfield, United Kingdom], the first selective TS inhibitor developed, demonstrated antineoplastic activity in Phase I trials, but its development was abandoned due to nephrotoxicity. ZD1694 (Tomudex; Zeneca), a water-soluble, nonnephrotoxic quinazoline, demonstrated activity in colorectal, breast, and pancreatic cancer. Phase III trials of Tomudex in advanced colorectal cancer were completed recently. LY231514 (Eli Lilly Research Labs, Indianapolis, IN) uses the RFC and polyglutamation to exert its selective TS inhibitory action. Phase I trials of this compound have been completed. ZD9331 (Zeneca), currently in preclinical studies, was designed to obviate the use of the RFC for cellular entry. 1843U89 (Glaxo-Wellcome, Research Triangle Park, NC), currently in Phase I trial, does not require the RFC; polyglutamation of this potent TS inhibitor leads to its higher cellular retention without augmenting its TS inhibitory activity. Currently in clinical trials, AG337 (p.o. and i.v. forms) and AG331 (both by Agouron, La Jolla, CA) are lipophilic potent TS inhibitors with action independent of the RFC and polyglutamation. Multiple mechanisms through which cells may overcome TS inhibition have been described. Combining TS inhibitors with other agents that affect TS, interfere with TS gene and mRNA regulation, or inhibit salvage mechanisms of thymidylate depletion may potentially enable greater clinical utility of this class of compounds.


Trends in the prevalence and management of atrial fibrillation in general practice in England and Wales, 1994-1998: analysis of data from the general practice research database.
To determine the prevalence of atrial fibrillation in England and Wales, and examine trends in its treatment with warfarin and aspirin between 1994 and 1998. Analysis of data from the general practice research database. England and Wales. 1.4 million patients registered with 211 general practices. Age and sex specific prevalence rates of atrial fibrillation; percentage of patients with atrial fibrillation treated with oral anticoagulants or aspirin. The prevalence of atrial fibrillation in 1998 was 12.1/1000 in men and 12.7/1000 in women. Prevalence increased from less than 1/1000 in under 35 year olds to over 100/1000 in those aged 85 years and over. There was a 22% increase in the age standardised prevalence of atrial fibrillation in men and a 14% increase in women between 1994 and 1998. The percentage of patients prescribed oral anticoagulants increased from 20% to 34% in men and from 17% to 25% in women. The percentage of men with atrial fibrillation prescribed aspirin increased from 26% to 36%, and the percentage of women increased from 24% to 36%. Applying the age and sex specific prevalence and treatment rates to the population gives an estimate of around 650 000 cases of atrial fibrillation in England and Wales. The greatest number of cases occurs in the 75-84 year old age group. The number of patients in the community with identified atrial fibrillation is increasing. There has also been a pronounced increase in the percentage of patients with atrial fibrillation prescribed oral anticoagulants or aspirin.


HCC develops even in the early stage of chronic liver disease in elderly patients with HCV infection.
In recent years, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. The aim of this study was to compare the liver function and the background factors of HCC patients with hepatitis C virus (HCV) infection by generation and to examine the characteristics of this disease in the elderly. A total of 1096 patients (776 men and 320 women) diagnosed with HCV-related HCC at our institution from 1995 to 2006 were divided into 4 groups as follows: D group, 75 years of age or older; C group, 65-74 years of age; B group, 55-64 years of age; A group, 54 years of age or younger, and the liver function and other clinical characteristics were compared among these 4 groups. The average age at initial diagnosis of HCV-related HCC was 66.9 years of age. The A, B, C and D groups were comprised of 87, 363, 514 and 132 patients, respectively. The rate of Child-Pugh class A patients in the D group was significantly higher than that of the other groups (P<0.05). The average levels of ALT, TB and PT-INR in the D group were significantly lower than the levels in the other groups (P<0.05). The average Alb level in the D group was significantly higher than that in the other groups (P<0.05). In conclusion, we found that HCV-related HCC in the elderly occurred against a background of chronic liver disease with mild inflammation and fibrosis.


Do progression and remediation policies improve NCLEX-RN pass rates?
Administrators at 5 schools of nursing who implemented a progression policy based on HESI Exit Exam scores were interviewed regarding their NCLEX-RN pass rates before and after initiating the policy and methods used for remediation. Even though the methods used for remediation were quite different among the participating schools, data obtained from these interviews indicated that the schools' NCLEX-RN pass rates improved 9-41% within 2 years after implementing the progression policies.


A Rhamnose-Inducible System for Precise and Temporal Control of Gene Expression in Cyanobacteria.
Cyanobacteria are important for fundamental studies of photosynthesis and have great biotechnological potential. In order to better study and fully exploit these organisms, the limited repertoire of genetic tools and parts must be expanded. A small number of inducible promoters have been used in cyanobacteria, allowing dynamic external control of gene expression through the addition of specific inducer molecules. However, the inducible promoters used to date suffer from various drawbacks including toxicity of inducers, leaky expression in the absence of inducer and inducer photolability, the latter being particularly relevant to cyanobacteria, which, as photoautotrophs, are grown under light. Here we introduce the rhamnose-inducible rhaBAD promoter of Escherichia coli into the model freshwater cyanobacterium Synechocystis sp. PCC 6803 and demonstrate it has superior properties to previously reported cyanobacterial inducible promoter systems, such as a non-toxic, photostable, non-metabolizable inducer, a linear response to inducer concentration and crucially no basal transcription in the absence of inducer.


Prevalence and prognosis of atrial septal aneurysm in high risk fetuses without structural heart defects.
The aim of this study was to evaluate the prevalence and prognostic implications of the association between atrial septal aneurysm (ASA) and fetal arrhythmias in a population of high risk fetuses. One thousand three hundred and two fetal echocardiograms performed during high risk pregnancies from the 17th to the 41st week of gestation were retrospectively evaluated for the presence of ASA and/or arrhythmias. An ASA was defined as redundant tissue extending at least halfway across the left atrium. Patients with an ASA were distinguished in two subgroups according to whether there was (subgroup 1) or was not (subgroup 2) cyclical contact of the atrial septum with the left atrial wall or with the mitral valve. Arrhythmias were documented during mono/two-dimensional echocardiography and Doppler evaluation. Out of 1223 patients considered for the study, 93 (7.6%) fetuses had an ASA; among these 93 fetuses, 33 (36%) had premature atrial beats (p < 0.001). Ten of these patients were included in subgroup 1, and 7 of them (70%) exhibited premature atrial beats (p = 0.016 vs subgroup 2). No arrhythmias other than premature atrial beats were observed in these patients. None of them received any therapy during observation. All of them developed a regular sinus rhythm within 3 months of life. On the basis of these data, we can speculate that, if accurately searched for, ASA is often present (7.6%) and is likely to represent a mechanical stimulus for the generation of premature atrial beats. Indeed, our data show an important correlation between the degree of bulging and the presence of arrhythmias, supporting the hypothesis of a mechanical stimulus. However, the observed arrhythmias did not appear to be prone to degeneration. In conclusion, ASA observed during fetal life is often associated with premature atrial beats, which are apparently in direct relation with the degree of bulging of the atrial septum. On the other hand, an ASA almost invariably disappears at birth and is not associated with major arrhythmias.


Generality in multispecies responses to ocean acidification revealed through multiple hypothesis testing.
Decades of research have demonstrated that many calcifying species are negatively affected by ocean acidification, a major anthropogenic threat in marine ecosystems. However, even closely related species may exhibit different responses to ocean acidification and less is known about the drivers that shape such variation in different species. Here, we examine the drivers of physiological performance under ocean acidification in a group of five species of turf-forming coralline algae. Specifically, quantitating the relative weight of evidence for each of ten hypotheses, we show that variation in coralline calcification and photosynthesis was best explained by allometric traits. Across ocean acidification conditions, larger individuals (measured as noncalcified mass) had higher net calcification and photosynthesis rates. Importantly, our approach was able to not only identify the aspect of size that drove the performance of coralline algae, but also determined that responses to ocean acidification were not dependent on species identity, evolutionary relatedness, habitat, shape, or structural composition. In fact, we found that failure to test multiple, alternative hypotheses would underestimate the generality of physiological performances, leading to the conclusion that each species had different baseline performance under ocean acidification. Testing among alternative hypotheses is an essential step toward determining the generalizability of experiments across taxa and identifying common drivers of species responses to global change.


An integrated approach to NMR spin relaxation in flexible biomolecules: application to beta-D-glucopyranosyl-(1-->6)-alpha-D-mannopyranosyl-OMe.
The description of the reorientational dynamics of flexible molecules is a challenging task, in particular when the rates of internal and global motions are comparable. The commonly used simple mode-decoupling models are based on the assumption of statistical independence between these motions. This assumption is not valid when the time scale separation between their rates is small, a situation that was found to arise in oligosaccharides in the context of certain internal motions. To make possible the interpretation of NMR spin relaxation data from such molecules, we developed a comprehensive approach generally applicable to flexible rotators with one internal degree of freedom. This approach integrates a stochastic description of coupled global tumbling and internal torsional motion, quantum chemical calculations of the local potential and the local geometry at the site of the restricted torsion, and hydrodynamics-based calculations of the diffusive properties. The method is applied to the disaccharide beta-D-Glcp-(1-->6)-alpha-D-[6-(13)C]-Manp-OMe dissolved in a DMSO-d(6)/D(2)O cryosolvent. The experimental NMR relaxation parameters, associated with the (13)CH(2) probe residing at the glycosidic linkage, include (13)C T(1) and T(2) and (13)C-{(1)H} nuclear Overhauser enhancement (NOE) as well as longitudinal and transverse dipole-dipole cross-correlated relaxation rates, acquired in the temperature range of 253-293 K. These data are predicted successfully by the new theory with only the H-C-H angle allowed to vary. Previous attempts to fit these data using mode-decoupling models failed.


The ghosts in the computer: the role of agency and animacy attributions in "ghost controls".
Three studies evaluated the role of 4-year-old children's agency- and animacy-attributions when learning from a computerized ghost control (GC). In GCs, participants observe events occurring without an apparent agent, as if executed by a "ghost" or unobserved causal forces. Using a touch-screen, children in Experiment 1 responded to three pictures in a specific order under three learning conditions: (i) trial-and-error (Baseline), (ii) imitation and (iii) Ghost Control. Before testing in the GC, children were read one of three scripts that determined agency attributions. Post-test assessments confirmed that all children attributed agency to the computer and learned in all GCs. In Experiment 2, children were not trained on the computer prior to testing, and no scripts were used. Three different GCs, varying in number of agency cues, were used. Children failed to learn in these GCs, yet attributed agency and animacy to the computer. Experiment 3 evaluated whether children could learn from a human model in the absence of training under conditions where the information presented by the model and the computer was either consistent or inconsistent. Children evidenced learning in both of these conditions. Overall, learning in social conditions (Exp. 3) was significantly better than learning in GCs (Exp. 2). These results, together with other published research, suggest that children privilege social over non-social sources of information and are generally more adept at learning novel tasks from a human than from a computer or GC.


Inhibition by natural dietary substances of gastrointestinal absorption of starch and sucrose in rats 2. Subchronic studies.
Acute oral consumption of various natural inhibitors of amylase (bean and hibiscus extracts) and sucrase (L-arabinose) reduce absorption of starch and sucrose respectively in rats and pigs measured by lessened appearance of circulating glucose levels. The present subchronic study was designed to determine whether these selected inhibitors of gastrointestinal starch and sucrose absorption (so-called "carb blockers") remain effective with continued use and to assess their metabolic influences after prolonged intake. Sprague-Dawley rats were gavaged twice daily over nine weeks with either water or an equal volume of water containing a formula that included bean and hibiscus extracts and L-arabinose. To estimate CHO absorption, control and treated Sprague-Dawley rats were gavaged with either water alone or an equal volume of water containing glucose, rice starch, sucrose, or combined rice starch and sucrose. Circulating glucose was measured at timed intervals over four hours. The ability to decrease starch and sucrose absorption use. No toxic effects (hepatic, renal, hematologic) were evident. Blood chemistries revealed significantly lower circulating glucose levels and a trend toward decreased HbA1C in the nondiabetic rats receiving the natural formulation compared to control. Subchronic administration of enzyme inhibitors was also associated with many metabolic changes including lowered systolic blood pressure and altered fluid-electrolyte balance. We postulate that proper intake of natural amylase and sucrase inhibitors may be useful in the prevention and treatment of many chronic disorders associated with perturbations in glucose-insulin homeostasis secondary to the rapid absorption of refined CHO.


Inhibitory effect of progesterone on sexual receptivity in female rats: a temporal relationship to estrogen administration.
The inhibitory effect of progesterone (P) injected at various times on female sexual behavior was investigated in estradiol benzoate (EB) treated ovariectomized rats. Four behavioral tests were carried out at two-week intervals. All females received 5 micrograms/kg b.w. EB and 0.5 mg P 44 hr after the EB. In the P-control group, an additional 5 mg P was administered at the same time as the injection of EB in four tests. Instead of P, oil was given concurrently with EB in the Oil control group. In the experimental groups, female rats were treated with 5 mg P from 1 to 40 hr before (PB group) or after (PA group) the EB-injection. A sexual behavioral test was started 4 hr after 0.5 mg P. The results show that low levels of lordosis and soliciting behavior were observed in the P group, compared to the Oil-control group. In the PB groups, lordosis quotient (LQ) was low when P was given from 1 to 24 hr before EB. Moreover, animals in which P was given 27-40 hr before EB showed lower LQ than Oil-control animals, but higher LQ than rats in the P-control group. In the PA groups, when P was administered from 1 to 24 hr after EB, low levels of lordosis response were observed, whereas animals which received P 27-40 hr after EB showed a high score of LQ, being comparable to that in the Oil control. These results suggest that the period of 24 hr before and after EB injection is a critical period for inhibitory action of P on female sexual behavior in female rats.


REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.
Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.


The role of rituximab and chemotherapy in aggressive B-cell lymphoma: A preliminary report of dose-adjusted EPOCH-R.
Accumulating evidence suggests that the ability to activate apoptotic pathways may be an important determinant of chemotherapy sensitivity and presents a potentially important new therapeutic strategy. Monoclonal antibodies against the CD20 antigen directly induce apoptosis and may serve to modulate the threshold for chemotherapy-induced apoptosis. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), a monoclonal antibody against CD20, was combined with dose-adjusted EPOCH (infusional etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) chemotherapy and tested in 38 untreated or relapsed poor-prognosis aggressive lymphomas. Twenty-three patients were untreated. Of these patients, all had large B-cell histologies, a median age of 52 years, Eastern Cooperative Oncology Group performance status ≥ 2 in 30%, and high-intermediate or high International Prognostic Index scores in 61%. Fifteen patients had relapsed or refractory lymphomas. These patients had received a median of two (range, one to four) prior regimens, 67% had aggressive histologies, and 60% had high-intermediate or high International Prognostic Index scores. Complete remissions were achieved in 85% and 64% of untreated and previously treated patients, respectively; additionally 42% of patients with disease refractory before therapy achieved complete remission. At a median follow-up of 12 months, progression-free and overall survival in the previously untreated group was 85% and 79%, respectively, and no patient in complete remission has relapsed. These results suggest that rituximab may modulate the sensitivity of B-cell lymphomas to chemotherapy. Semin Oncol 29 (suppl 2):41-47. This is a US government work. There are no restrictions on its use.


Sequence-specific antibodies to connexins block intercellular calcium signaling through gap junctions.
Mechanical stimulation of a single cell in primary airway epithelial cell cultures induces an intercellular Ca2+ wave that has been proposed to be mediated via gap junctions. To investigate directly the role of gap junctions in this multicellular response, the effects of intracellularly-loaded sequence-specific connexin (gap junction) antibodies on the propagation of intercellular Ca2+ waves were evaluated. Electroporation of antibodies to the cytosolic loop (Des 1, generated to amino acids 102-112 + 116-124; and Des 5, amino acids 108-119), or to the carboxyl tail (Gap 9, amino acids 264-283) of connexin 32 inhibited the propagation of intercellular Ca2+ waves. The inhibitory effect of Des 1 antibody was competitively reversed by the co-loading of a peptide derived from a similar cytosolic loop sequence (Des 5 peptide). Conversely, the inhibitory effects on intercellular Ca2+ wave propagation of Gap 9 antibody was not altered by co-loading with the Des 5 peptide. Antibodies raised to peptide sequences within the extracellular loop (Gap 11, amino acids 151-187), or the cytoplasmically located amino terminus (Gap 10, amino acids 1-21) of connexin 32 did not inhibit mechanically-induced intercellular communication. Also ineffective in perturbing intercellular communication were antibodies raised to peptide sequences of the cytosolic loops of connexin 43 (Gap 15, amino acids 131-142) or connexin 26 (Des 3, amino acids 106-119). These data suggest that mechanically-induced Ca2+ waves in airway cell cultures are propagated through gap junctions made up of connexin 32 proteins.


Histopathological changes in the liver of rabbits exposed to high nitrate ingestion in drinking water.
In India, especially in Rajasthan, people drink water which contains high level of nitrates and the possibility of finding concentrations of up to 500 mg of nitrate ions per litre of water is not unusual. Excessive use of nitrate fertilisers and herbicides results in accumulation of nitrate in plants and methemoglobinaemia in cattle as consequences of nitrate poisoning. The ingested nitrate is converted to nitrite in the digestive system and it is absorbed in blood, thus causing methemoglobinaemia. Methaemoglobinaemia is not restricted to infants alone, but it is prevalent in higher age groups also. Therefore, an experimental study was conducted on 10 rabbits which were between three and a half months to four months of age, which had weights which ranged from 1.310 kg to 1.720 kg. Five groups A, B, C,D and E were formed, with two rabbits in each group. The control Group A was given water orally, which had 45 mg/litres of nitrate. Groups B to E (experimental groups) were administered water orally, which had concentrations of 100mg/litre, 200mg/litre, 400mg/litre and 500mg/litre of nitrate respectively, for 120 days. During experimental period, the differences in general behaviour of rabbits were noted. After this, rabbits were anaesthetised and sacrificed according to guidelines of ICMR and their livers were removed and processed for making paraffin sections,.Hematoxyllin and eosin staining was done for microscopic observations. During experimental period, the animals were found to be lethargic on 75(th) day. Quantity of intake of food and water was not altered in the rabbits which were undergoing experiments in different groups. Rabbits of all groups i.e. A to E showed a continuous increase in heart rate (up to 218/minute in Group E) and respiration rate (up to 84/minute in Group E) respectively. The microscopic study showed mild necrosis of hepatocytes, with infiltration of inflammatory cells in between hepatocytes. In higher groups, the liver showed bridging necrosis and portal triditis. Dilatations of central vein with eosinophilic degeneration were observed in Group E only.


Sibling structure, distributive norms, and negotiation for mothers-in-law's assistance in rural South China.
Recent studies of parent-adult child relations using a network family approach have paid increasing attention to within-family differences and the role of in-laws in parent-adult child exchanges. However, the effect of sibling structure on the allocation of childcare and household help provided by older women, the negotiation process among in-laws and the underlying principle(s) have been under-examined. Based on ethnographic and interview data collected from 28 women in rural South China, this article examines the effect of sibling structure on mothers-in-law's assistance in the context of economic reform, and the role of cultural norms and daughters-in-law in the negotiation process using a family network perspective. Since the late 1970s, the sibling order of husbands and the presence of their unmarried brothers have negatively affected the bargaining power of young married women and their access to childcare assistance from their mothers-in-law. In terms of household help, sibling size and the equity principle have prevented mothers-in-law in larger extended families from providing assistance during both the pre-reform and reform periods. Although the equity norm is a pivotal moral resource for daughters-in-law in negotiating parental support, other competing norms, particularly parents' obligations to their unmarried adult sons, may set limits on their claims and bargaining power. FINDINGS demonstrate that the distribution of childcare and household help provided by mothers-in-law are results of intra- and intergenerational negotiation among daughters- and mothers-in-law, rather than simply a dyadic parent-child relationship. Competing norms and daughters-in-law also play important roles in the negotiation for parental help.


Intake of Japanese and Chinese teas reduces risk of Parkinson's disease.
Studies that have addressed the association between the intake of coffee or caffeine and Parkinson's disease (PD) were conducted mainly in Western countries. Little is known about this relationship in an Asian population. Therefore, we performed an assessment of the association of the intake of coffee, other caffeine-containing beverages, and caffeine with the risk of PD in Japan. The study involved 249 PD cases and 368 control subjects. Information on dietary factors was obtained through a self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, educational level, pack-years of smoking, body mass index, the dietary glycemic index, and intake of cholesterol, vitamin E, β-carotene, vitamin B(6,) alcohol, and iron. Intake of coffee, black tea, and Japanese and Chinese teas was significantly inversely associated with the risk of PD: the adjusted odds ratios in comparison of the highest with the lowest quartile were 0.52, 0.58, and 0.59, respectively (95% confidence intervals = 0.30-0.90, 0.35-0.97, and 0.35-0.995, respectively). A clear inverse dose-response relationship between total caffeine intake and PD risk was observed. We confirmed that the intake of coffee and caffeine reduced the risk of PD. Furthermore, this is the first study to show a significant inverse relationship between the intake of Japanese and Chinese teas and the risk of PD.


Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage.
The mechanisms by which nitric oxide modulates microvascular albumin exchange were investigated by monitoring leukocyte-endothelial cell adhesion and fluorescein isothiocyanate-albumin leakage in rat mesenteric venules exposed to NG-nitro-L-arginine methyl ester (L-NAME). L-NAME elicited an initial rapid increase followed by a slower rate of albumin accumulation in the interstitial space. The initial phase of albumin leakage preceded the L-NAME-induced leukocyte adherence and emigration, whereas the magnitude of the albumin leakage observed in the later phase of L-NAME exposure was highly correlated with the number of adherent and emigrated leukocytes in the same segment of venule. Monoclonal antibodies (MAbs) directed against adhesion molecules CD11/CD18, ICAM-1, or P-selectin, but not a nonbinding MAb, attenuated the albumin leakage induced by L-NAME. WEB2086, a platelet activating factor antagonist, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) reduced the leukocyte adherence and emigration as well as the increased albumin leakage. Only 8-br-cGMP and the P-selectin MAb attenuated the platelet-leukocyte aggregation elicited by L-NAME. Phalloidin, which promotes endothelial junctional integrity, inhibited both the early and late phases of albumin leakage. Overall, these findings suggest that the increased albumin leakage observed in postcapillary venules after inhibition of nitric oxide production involves a mechanism that includes a role for cGMP, platelet activating factor, leukocyte-endothelial cell adhesion, and the endothelial cell cytoskeleton.


Paget's disease of the breast: a clinical perspective.
Paget's disease of the breast is a rare disorder of the nipple-areola complex often associated with an underlying in situ or invasive carcinoma. Eczematoid changes of the nipple-areola complex and persistent soreness or itching should raise suspicion of this disease. The histogenesis of Paget's disease of the breast continues to be debated and is important when considering treatment options. The epidermotropic theory suggests that Paget's cells are ductal carcinoma cells that have migrated from an underlying carcinoma of the breast parenchyma to the epidermis of the nipple. The in situ transformation theory has been proposed to explain the development of this disorder in patients in whom an underlying mammary carcinoma is not found or when there is an underlying carcinoma anatomically remote from the nipple-areola complex. Paget's cells are believed to arise as malignant cells in the epidermis of the nipple independent from any other pathologic process within the breast parenchyma. The current standard treatment of biopsy-proven Paget's disease involves mastectomy, although some studies have proposed the use of breast conservation therapy for patients in whom an underlying breast cancer cannot be located. We propose a treatment algorithm for patients presenting with Paget's disease of the breast.


Vitamin A Supplementation Programs and Country-Level Evidence of Vitamin A Deficiency.
Vitamin A supplementation (VAS) programs targeted at children aged 6-59 months are implemented in many countries. By improving immune function, vitamin A (VA) reduces mortality associated with measles, diarrhea, and other illnesses. There is currently a debate regarding the relevance of VAS, but amidst the debate, researchers acknowledge that the majority of nationally-representative data on VA status is outdated. To address this data gap and contribute to the debate, we examined data from 82 countries implementing VAS programs, identified other VA programs, and assessed the recentness of national VA deficiency (VAD) data. We found that two-thirds of the countries explored either have no VAD data or data that were >10 years old (i.e., measured before 2006), which included twenty countries with VAS coverage ≥70%. Fifty-one VAS programs were implemented in parallel with at least one other VA intervention, and of these, 27 countries either had no VAD data or data collected in 2005 or earlier. To fill these gaps in VAD data, countries implementing VAS and other VA interventions should measure VA status in children at least every 10 years. At the same time, the coverage of VA interventions can also be measured. We identified three countries that have scaled down VAS, but given the lack of VA deficiency data, this would be a premature undertaking in most countries without appropriate status assessment. While the global debate about VAS is important, more attention should be directed towards individual countries where programmatic decisions are made.


Self-Assembly and Stabilization of Hybrid Cowpea Chlorotic Mottle Virus Particles under Nearly Physiological Conditions.
Capsids of the cowpea chlorotic mottle virus (CCMV) hold great promise for use as nanocarriers in vivo. A major drawback, however, is the lack of stability of the empty wild-type virus particles under physiological conditions. Herein, the assembly behavior and stability under nearly physiological conditions of protein-based block copolymers composed of the CCMV capsid protein and two hydrophobic elastin-like polypeptides are reported. UV/Vis spectroscopy studies, dynamic light-scattering analysis, and TEM measurements demonstrate that both hybrid variants form stable capsids at pH 7.5, physiological NaCl concentration, and 37 °C. The more hydrophobic variant also remains stable in a cell culture medium. These engineered, hybrid CCMV capsid particles can therefore be regarded as suitable candidates for in vivo applications.


Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.
Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.


Silencing of Mcl-1 overcomes resistance of melanoma cells against TRAIL-armed oncolytic adenovirus by enhancement of apoptosis.
Arming of oncolytic viruses with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown as a viable approach to increase the antitumor efficacy in melanoma. However, melanoma cells may be partially or completely resistant to TRAIL or develop TRAIL resistance, thus counteracting the antitumor efficiency of TRAIL-armed oncolytic viruses. Recently, we found that TRAIL resistance in melanoma cells can be overcome by inhibition of antiapoptotic Bcl-2 protein myeloid cell leukemia 1 (Mcl-1). Here, we investigated whether the cytotoxicity of AdV-TRAIL, an oncolytic adenovirus, which expresses TRAIL after induction by doxycycline (Dox), can be improved in melanoma cells by silencing of Mcl-1. Two melanoma cell lines, the TRAIL-resistant MeWo and the TRAIL-sensitive Mel-HO were investigated. Treatment of both cell lines with AdV-TRAIL resulted in a decrease of cell viability, which was caused by an increase of apoptosis and necrosis. The proapoptotic effects were dependent on induction of TRAIL by Dox and were more pronounced in Mel-HO than in MeWo cells. SiRNA-mediated silencing of Mcl-1 resulted in a further significant decrease of cell viability and a further increase of apoptosis and necrosis in AdV-TRAIL-infected MeWo and Mel-HO cells. However, while in absolute terms, the effects were more pronounced in Mel-HO cells, in relative terms, they were stronger in MeWo cells. These results show that silencing of Mcl-1 represents a suitable approach to increase the cytotoxicity of a TRAIL-armed oncolytic adenovirus in melanoma cells. KEY MESSAGES: • Cytotoxicity of TRAIL-expressing adenovirus can be enhanced by silencing of Mcl-1. • The effect occurs in TRAIL-sensitive and TRAIL-resistant melanoma cells. • Increase of apoptosis is the main mechanism induced by Mcl-1 silencing.


Temporal and geographic patterns of hypoglycemia among hospitalized patients with diabetes mellitus.
Hypoglycemia is often cited as a barrier to achieving inpatient glycemic targets. We sought to characterize hypoglycemic events in our institution by work-shift cycle and by specific treatment area. Capillary (bedside) and blood (laboratory) glucose values of <70 mg/dl for patients with either a known diagnosis of diabetes or with evidence of hyperglycemia were abstracted from our laboratory database for hospitalizations between October 1, 2007, and February 3, 2008. Hypoglycemic events were analyzed by 12 h nursing work-shift cycles (day shift, 07:00 to 18:59; night shift, 19:00 to 06:59) and by the six medical, surgical, and intensive care areas in the hospital (designated areas 1 to 6). We identified 206 individual patients with either diabetes or hyperglycemia (mean age, 67 years; 56% men; 83% white) who had 423 hypoglycemic events. There were 78% more hypoglycemic events during the night shift (n = 271 events in 128 individual patients) than during the day shift (n = 152 events in 96 individual patients). Most of the night-shift hypoglycemic measurements were detected between 04:00 and 04:59 or 06:00 and 06:59. The mean hypoglycemic level was comparable between shifts (p = .79) and across the six inpatient areas. The number of hypoglycemic events per person increased with lengths of hospital stay >5 days. The prevalence of hypoglycemia varied across patient care areas within the hospital, with most (28%) detected in one area of the hospital. There are temporal and geographic patterns in the occurrence of hypoglycemia among patients with diabetes or hyperglycemia in our hospital. Further study should focus on the reasons underlying these variations so that specific interventions can address the risk of hypoglycemia during peak times and places.


Mood Homeostasis, Low Mood, and History of Depression in 2 Large Population Samples.
Existing therapeutic options are insufficient to tackle the disease burden of depression, and new treatments are sorely needed. Defining new psychotherapeutic targets is challenging given the paucity of coherent mechanistic explanations for depression. To assess whether mood homeostasis (ie, the stabilization of one's mood by engaging in mood-modifying activities) is a possible new therapeutic target by testing the hypothesis that people with low (vs high) mean mood and people with (vs without) a history of depression have impaired mood homeostasis. The quantitative association between mood and daily activities was computed in 2 large case-control studies based on the 58sec data set (collected from December 1, 2012, to May 31, 2014, and analyzed from April 1 to 30, 2019), and the World Health Organization Study on Global Aging and Adult Health (WHO SAGE) data set (collected from January 1, 2007, to December 31, 2010, and analyzed from June 1 to 30, 2019). The 58sec data set consists of self-enrolled participants from high-income countries. The WHO SAGE data set consists of nationally representative participants in low- and middle-income countries recruited via cluster sampling. The main outcome (defined before data analysis) was the difference in mood homeostasis between people with high vs low mean mood (58sec data) and between people with vs without a history of depression (WHO SAGE data). A total of 28 212 participants from the 58sec data set (65.8% female; mean [SD] age, 28.1 [9.0] years) and 30 116 from the WHO SAGE data set (57.0% female; mean [SD] age, 57.8 [14.7] years) were included, for an overall study population of 58 328 participants. Mood homeostasis was significantly lower in people with low (vs high) mean mood (0.63 [95% CI, 0.45 to 0.79] vs 0.96 [95% CI, 0.96 to 0.98]; P < .001) and in people with (vs without) a history of depression (0.03 [95% CI, -0.26 to 0.24] vs 0.68 [95% CI, 0.55 to 0.75]; P < .001). In dynamic simulations, lower mood homeostasis led to more depressive episodes (11.8% vs 3.8% yearly risk; P < .001) that lasted longer (4.19 vs 2.90 weeks; P = .006). In this study, mood homeostasis appeared to have been impaired in people with low mood and in those with a history of depression. Mood homeostasis may therefore provide new insights to guide the development of treatments for depression.


Achieving better quality of care for low-income populations: the roles of health insurance and the medical home in reducing health inequities.
In the United States, uninsured and low-income adults experience substantial health and health care inequities when compared with insured and higher-income individuals. A new analysis of the Commonwealth Fund 2010 Biennial Health Insurance Survey demonstrates that when low-income adults have both health insurance and a medical home, they are less likely to report cost-related access problems, more likely to be up-to-date with preventive screenings, and report greater satisfaction with the quality of their care. Moreover, the gaps in health care between them and higher-income populations are significantly reduced. The Affordable Care Act includes numerous provisions that will significantly expand health insurance coverage, especially to low-income patients, as well as provisions to promote medical homes. Along with supporting the full implementation of coverage expansions, it will be important for public and private stakeholders to create opportunities that enhance access to medical homes for vulnerable populations.


[Fatal outcome after postexposure rabies vaccination in a patient with Parkinson's disease].
In Serbia and Montenegro postexposure rabies vaccination is performed using five doses of rabies vaccine with a potency of 2.5 I.U. It is given on 0, 3rd, 7th, 14th and 28th day, combined with human rabies immunoglobulin with the first dose. Modern rabies vaccines produced in cell cultures rarely cause neurologic complications, among which Guillain-Barre syndrome and parkinsonism. The authors report a case of a 78-year-old woman with a documented five-year history of Parkinson's disease, who was bitten by a rabid cat. Twelve hours later, when the rabies infection of the cat was confirmed by an immunofluorescence test, the patient received the first dose of rabies vaccine Verorab (Aventis), a cell culture vaccine, together with the human rabies immunoglobulin produced in Belgrade. After the third dose of rabies vaccine, the symptoms of Parkinson's disease progressed and vaccination was interrupted. However, one month later, the patient died with predominantly neurological symptoms. As the patient died at the time when incubation of rabies might have been expected, autopsy and rabies diagnostics were performed. AUTOPSY AND PATHOHISTOLOGIC FINDINGS: The autopsy and pathohistologic findings from the specimens treated with routine hematoxylin and eosin staining, together with immunofluorescence test, excluded rabies as a cause of death and revealed neurodegenerative changes typical for Parkinson's disease. Using two different fluorescent rabies antibodies, we performed a direct immunofluorescence antibody tests, but no rabies antigens were detected. However, in histologic slides of the brain stem, large intracytoplasmic inclusions were found in some neurons, identified as Lewy bodies characteristic for Parkinson's disease. Parkinson's disease, with its complications, was the cause of death of the patient bitten by a rabid cat. Furthermore, the coincidence of the progression of Parkinson's disease symptoms, at the time of postexposure rabies vaccination, points to the vaccine as a possible contributing factor to aggravation of the disease and lethal outcome.


The three-dimensional structure of canine parvovirus and its functional implications.
The three-dimensional atomic structure of a single-stranded DNA virus has been determined. Infectious virions of canine parvovirus contain 60 protein subunits that are predominantly VP-2. The central structural motif of VP-2 has the same topology (an eight-stranded antiparallel beta barrel) as has been found in many other icosahedral viruses but represents only about one-third of the capsid protein. There is a 22 angstrom (A) long protrusion on the threefold axes, a 15 A deep canyon circulating about each of the five cylindrical structures at the fivefold axes, and a 15 A deep depression at the twofold axes. By analogy with rhinoviruses, the canyon may be the site of receptor attachment. Residues related to the antigenic properties of the virus are found on the threefold protrusions. Some of the amino termini of VP-2 run to the exterior in full but not empty virions, which is consistent with the observation that some VP-2 polypeptides in full particles can be cleaved by trypsin. Eleven nucleotides are seen in each of 60 symmetry-related pockets on the interior surface of the capsid and together account for 13 percent of the genome.


Aggression and Harm-Avoidant Trait Impede Recovery From Internet Gaming Disorder.
Background: Relatively little is known about which neuropsychological factors promote recovery from Internet gaming disorder (IGD). Methods: With informed consents, a cohort study was conducted in Seoul metropolitan area, South Korea, to investigate the course of IGD in youths. At baseline, we assessed psychosocial measures and gaming related measures such as Young's Internet Addiction Test (IAT) and the Aggression Questionnaire. The Balloon Analog Risk Task was also performed to study risk-taking behavior. A total of 60 subjects demonstrating three or greater criteria in the diagnostic interviews on IGD and the IAT score of 50 or above were included. After brief parental coaching at baseline, the participants were followed up at 3 and 6 months (n = 31). The baseline characteristics were compared between the non-improved group (<10% improvement in IAT score) and the improved group (≥30% improvement in IAT score) using Mann-Whitney U-test or chi-squared tests with a two-tailed statistical significance of 0.05. Results: The non-improved group and the improved group did not demonstrate significant differences regarding demographics or the IAT scores at baseline. However, the IAT scores were significantly higher in the non-improved group at both 3 and 6 months. The non-improved group was also more likely to display higher aggression and harm avoidance than the improved group at baseline. Discussion: Youths with excessive gaming problems should be evaluated for aggression and harm avoidance since they contributed to a worse prognosis. For those with high aggression or harm avoidance, more active therapeutic interventions should be considered.


TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis.
The present study was undertaken to validate whether TNF-α and calreticulin (CRT) serve as dual signaling to activate nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and HUVECs. The effect of human antigen R (HuR) in NLRP3 inflammasome activation was also explored in RA FLS. Immunofluorescence was used to determine the expression of NLRP3 and adaptor protein apoptosis associated speck-like protein containing a CARD (ASC) in RA synovial tissue and HuR location in RA FLS. Western blot and quantitative real-time PCR were employed to measure the priming effect of NLRP3 inflammasome in cells and HuR expression in synovial tissue. The concentrations of IL-1β and IL-18 were detected by enzyme linked immunosorbent assay. Immunohistochemistry was used to visualize the expression of HuR in synovial tissue. HuR knockdown in RA FLS was achieved by siRNA-mediated gene silencing. Higher expression of NLRP3 and ASC in RA synovial tissue than those in osteoarthritis was detected. The staining of NLRP3, ASC and cleaved IL-1β were observed in FLS and vascular endothelial cells in RA synovium. Expression of NLRP3 and pro-IL-1β in RA FLS and HUVECs treated with TNF-α was increased. The pro-IL-18 expression was also enhanced in HUVECs, but not in RA FLS. TNF-α/CRT dual stimulation of cells gave rise to caspase-1 p20 expression and the secretion of IL-1β. The secreted IL-18 was also elevated in HUVECs but not in RA FLS. HuR expression was significantly elevated in RA synovial tissue. TNF-α initiated the nucleocytoplasmic shuttling of HuR in both FLS and HUVECs. The knockdown of HuR in FLS incubated with TNF-α led to reduced caspase-1 p20 protein expression and further resulted in decreased secretion of IL-1β in the presence of CRT. TNF-α/CRT dual signaling induced NLRP3 inflammasome activation, which could be suppressed by HuR knockdown presumably due to the block of HuR translocating from nucleus to cytoplasma.


Positive and Negative Experiences of Social Support and Risk of Dementia in Later Life: An Investigation Using the English Longitudinal Study of Ageing.
Having a network of close relationships may reduce the risk of developing dementia. However, social exchange theory suggests that social interaction entails both rewards and costs. The effects of quality of close social relationships in later life on the risk of developing dementia are not well understood. To investigate the effects of positive and negative experiences of social support within key relationships (spouse or partner, children, other immediate family, and friends) on the risk of developing dementia in later life. We analyzed 10-year follow up data (2003/4 to 2012/13) in a cohort of 10,055 dementia free (at baseline) core participants aged 50 years and over from the English Longitudinal Study of Ageing (ELSA). Incidence of dementia was identified from participant or informant reported physician diagnosed dementia or overall score of informant-completed IQCODE questionnaire. Effects of positive and negative experiences of social support measured at baseline on risk of developing dementia were investigated using proportional hazards regression accommodating interval censoring of time-to-dementia. There were 340 (3.4%) incident dementia cases during the follow-up. Positive social support from children significantly reduced the risk of dementia (hazard ratio, HR = 0.83, p = 0.042, 95% CI: 0.69 to 0.99). Negative support from other immediate family (HR = 1.26, p = 0.011, CI: 1.05 to 1.50); combined negative scores from spouse and children (HR = 1.23, p = 0.046, CI: 1.004 to 1.51); spouse, children, and other family (HR = 1.27, p = 0.021, CI = 1.04 to 1.56); other family & friends (HR = 1.25, p = 0.033, CI: 1.02 to 1.55); and the overall negative scores (HR = 1.31, p = 0.019, CI: 1.05 to 1.64) all were significantly associated with increased risk of dementia. Positive social support from children is associated with reduced risk of developing dementia whereas experiences of negative social support from children and other immediate family increase the risk. Further research is needed to better understand the causal mechanisms that drive these associations.


High-speed confocal fluorescence lifetime imaging microscopy (FLIM) with the analog mean delay (AMD) method.
We demonstrate a high-speed confocal fluorescence lifetime imaging microscopy (FLIM) whose accuracy and photon economy are as good as that of a time-correlated single photon counting (TCSPC). It is based on a new lifetime determination scheme, the analog mean delay (AMD) method. Due to the technical advantages of multiple fluorescence photon detection capability, accurate lifetime determination scheme and high photon detection efficiency, the AMD method can be the most effective method for high-speed confocal FLIM. The feasibility of real-time confocal FLIM with the AMD method has been demonstrated by observing the dynamic reaction of calcium channels in a RBL-2H3 cell with respect to 4αPDD stimulus. We have achieved the photon detection rate of 125 times faster than a conventional TCSPC based system in this experiment.


Lovastatin 5-year safety and efficacy study. Lovastatin Study Groups I through IV.
Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used to treat hypercholesterolemia. They have a good short- to medium-term safety profile, but long-term safety data are limited. Seven hundred forty-five patients with severe hypercholesterolemia (mean baseline plasma cholesterol level on diet, 9.3 mmol/L [360 mg/dL]) were treated with lovastatin for a median duration of 5.2 years. Their mean age at baseline was 50 years, 68% were male, 60% had familial hypercholesterolemia, and 42% had a history of coronary heart disease. Seventy-seven percent of patients had titrations of lovastatin to 80 mg/d, and 58% took other lipid-lowering agents, usually bile acid sequestrants, concomitantly. The mean changes at 5 years in total, low-density lipoprotein, and high-density lipoprotein cholesterol were -35%, -44%, and +14%, respectively. Eighty percent of patients completed the study, 13% were unavailable for follow-up, 4% were discontinued due to adverse events unlikely to be related to lovastatin, and 3% (21) were discontinued because of drug-attributable adverse events: marked but asymptomatic increase in aminotransferase values (10 patients), gastrointestinal disturbance (three patients), rash (two patients), myalgia (one patient), myopathy (two patients), arthralgia (one patient), insomnia (one patient), and weight gain (one patient). Sixteen patients died during the study, all of coronary disease. Of these, 14 had coronary heart disease at baseline. There were no deaths attributable to trauma, suicide, or homicide, and there were only 14 cases of cancer (vs 21 expected). There was no evidence for an adverse effect on the lens. Lovastatin is a generally well-tolerated and effective drug during long-term use.


Classic Hodgkin lymphoma and Castleman disease: an entity appears to be emerging.
Hodgkin lymphoma is a B cell neoplasm characterized by Hodgkin and Reed-Sternberg (HRS) cells in an inflammatory background. Classic Hodgkin lymphoma (CHL) accounts for approximately 90% of all cases of HL and four types are recognized in the World Health Organization (WHO) classification: lymphocyte-rich, nodular sclerosis, mixed cellularity, and lymphocyte depleted. Castleman disease (CD) is a designation used for a heterogeneous group of diseases that involve lymph nodes. Histologically, there are hyaline vascular and plasma cell variants, the latter including human herpes virus 8 (HHV8)-positive and HHV8-negative subsets. In this study, we describe three men, 45-57 years of age, one HIV-positive, who had coexistent CHL and CD. All patients had the interfollicular variant of CHL and HHV8-negative plasma cell variant CD. Immunohistochemical analysis supported the diagnosis of CHL; the HRS cells were positive for CD15, CD30, and PAX-5 (dim). In two cases, the HRS cells and the plasma cells of CD expressed interleukin-6 (IL-6). Our review of the literature identified 34 cases of coexistent CHL and CD reported previously. In aggregate, about two-thirds of all cases of CHL have been the interfollicular variant and around 90% of CD cases were plasma cell variant, HHV8-negative in the subset of cases tested. We suggest that interfollicular variant CHL and plasma cell variant CD may be a distinct entity with a common pathogenesis, possibly related to IL-6 dysregulation. The few cases in the literature describing other forms of CHL and hyaline vascular variant CD are different from the entity reported here, with a different pathogenesis, likely similar to focal Castleman-like changes that have been described in association with various types of non-Hodgkin lymphoma.


Can Clinical Evaluation Predict Return to Sport after Acute Hamstring Injuries? A Systematic Review.
The current literature on the value of clinical evaluation for predicting time to return to sport (RTS) after acute hamstring injuries has not been systematically summarised. The aim of this study was to systematically review the literature on the prognostic value of clinical findings (patient history and physical examination) for time to RTS after acute hamstring injuries in athletes. The databases PubMed, EMBASE, SPORTDiscus and Cochrane Library were searched between October 2014 and August 2015. Studies evaluating patient history and/or physical assessment findings as possible predictors for time to RTS (described in days or weeks) following acute hamstring injuries in athletes were eligible for inclusion. Two authors independently screened the search results and assessed risk of bias using the modified Quality in Prognosis Studies (QUIPS) tool for quality appraisal of prognosis studies. We used a best-evidence synthesis to determine the level of evidence. Sixteen studies were included, of which one study had a low risk of bias and 15 had a high risk of bias. Moderate evidence for an association with time to RTS was found for three clinical findings (visual analogue scale; pain at time of injury, self-predicted time to RTS and clinician predicted time to RTS). There was limited evidence for an association with time to RTS for seven clinical findings (muscle pain during everyday activities, popping sound at injury, forced to stop within 5 min, visual bruising at the site of injury, width (cm) of tenderness to palpation, pain on trunk flexion and pain on active knee flexion initially after injury). The remaining clinical findings revealed either conflicting evidence or limited evidence for an association with time to RTS. There is at present no strong evidence that any clinical finding at baseline provides a valuable prognosis for time to RTS after an acute hamstring injury. There is moderate evidence that visual analogue scale pain at time of injury and predictions for time to RTS by the patient and the clinician are associated with time to RTS. The methodological quality of the current literature is characterised by a substantial risk of bias and reporting of RTS definitions and criteria for RTS were inconsistent. We provide recommendations that can guide the design of future studies.


Transcriptional regulation of the p67phox gene: role of AP-1 in concert with myeloid-specific transcription factors.
We have investigated the myeloid-specific transcriptional regulation of p67(phox), an essential component of phagocyte respiratory burst NADPH oxidase. Analysis was carried out on the p67(phox) 5'-flanking region from -3669 to -4 (relative to ATG), including the first exon and intron and part of the second exon. The construct extending from -985 to -4 produced the highest luciferase activity in myeloid HL-60 cells but was not active in HeLa or Jurkat cells, indicating myeloid-specific expression. Four active elements were identified: Sp1/Sp3 at -694, PU.1 at -289, AP-1 at -210, and PU.1/HAF1 at -182, the latter three being in the first intron. These cis elements bound their cognate transacting factors both in vitro and in vivo. Mutation of the Sp1, PU.1, or PU.1/HAF1 site each decreased promoter activity by 35-50%. Mutations in all three sites reduced promoter activity by 90%. However, mutation of the AP-1 site alone nearly abolished promoter activity. The AP-1 site bound Jun and Fos proteins from HL-60 cell nuclear extract. Co-expression with Jun B in AP-1-deficient cells increased promoter activity by 3-fold. These data show that full p67(phox) promoter activity requires cooperation between myeloid-specific and nonmyeloid transcription factors, with AP-1 being the most critical for function.


Separase: a universal trigger for sister chromatid disjunction but not chromosome cycle progression.
Separase is a protease whose liberation from its inhibitory chaperone Securin triggers sister chromatid disjunction at anaphase onset in yeast by cleaving cohesin's kleisin subunit. We have created conditional knockout alleles of the mouse Separase and Securin genes. Deletion of both copies of Separase but not Securin causes embryonic lethality. Loss of Securin reduces Separase activity because deletion of just one copy of the Separase gene is lethal to embryos lacking Securin. In embryonic fibroblasts, Separase depletion blocks sister chromatid separation but does not prevent other aspects of mitosis, cytokinesis, or chromosome replication. Thus, fibroblasts lacking Separase become highly polyploid. Hepatocytes stimulated to proliferate in vivo by hepatectomy also become unusually large and polyploid in the absence of Separase but are able to regenerate functional livers. Separase depletion in bone marrow causes aplasia and the presumed death of hematopoietic cells other than erythrocytes. Destruction of sister chromatid cohesion by Separase may be a universal feature of mitosis in eukaryotic cells.


Anti-Mullerian hormone trend evaluation after laparoscopic surgery of monolateral endometrioma using a new dual wavelengths laser system (DWLS) for hemostasis.
Operative laparoscopy is the gold standard in the treatment of endometriotic ovarian cysts. Excisional surgery is the best technique to prevent recurrences and improve symptoms but it may result in ovarian reserve damage due to the removal of healthy ovarian cortex. The aim of this study was to assess the impact on ovarian reserve of the use of dual wavelengths laser system (DWLS) hemostasis after stripping technique of monolateral endometrioma, by dosing the anti-Mullerian hormone (AMH). This prospective study was conducted at the Institute of Obstetrics and Gynecology, University of Foggia, from December 2013 to January 2015. Forty-five women underwent excision of monolateral endometriotic ovarian cyst by stripping without using a bipolar coagulation and performing hemostasis with a DWLS. The AMH serum levels were estimated before the surgery (T0), 4-6 weeks (T1) and 6-9 months (T2) after surgery. Our results suggest that an appropriate surgical technique with the use of laser hemostasis does not determine a significant reduction of ovarian reserve. Laser hemostasis could prevent follicular reserve loss after ovarian endometrioma surgery.


Effects of Chikungunya virus immunity on Mayaro virus disease and epidemic potential.
Mayaro virus (MAYV) causes an acute febrile illness similar to that produced by chikungunya virus (CHIKV), an evolutionary relative in the Semliki Forest virus complex of alphaviruses. MAYV emergence is typically sporadic, but recent isolations and outbreaks indicate that the virus remains a public health concern. Given the close phylogenetic and antigenic relationship between CHIKV and MAYV, and widespread distribution of CHIKV, we hypothesized that prior CHIKV immunity may affect MAYV pathogenesis and/or influence its emergence potential. We pre-exposed immunocompetent C57BL/6 and immunocompromised A129 or IFNAR mice to wild-type CHIKV, two CHIKV vaccines, or a live-attenuated MAYV vaccine, and challenged with MAYV. We observed strong cross-protection against MAYV for mice pre-exposed to wild-type CHIKV, and moderately but significantly reduced cross-protection from CHIKV-vaccinated animals. Immunity to other alphavirus or flavivirus controls provided no protection against MAYV disease or viremia. Mechanistic studies suggested that neutralizing antibodies alone can mediate this protection, with T-cells having no significant effect on diminishing disease. Finally, human sera obtained from naturally acquired CHIKV infection cross-neutralized MAYV at high titers in vitro. Altogether, our data suggest that CHIKV infection can confer cross-protective effects against MAYV, and the resultant reduction in viremia may limit the emergence potential of MAYV.


Demes: a standard format for demographic models.
Understanding the demographic history of populations is a key goal in population genetics, and with improving methods and data, ever more complex models are being proposed and tested. Demographic models of current interest typically consist of a set of discrete populations, their sizes and growth rates, and continuous and pulse migrations between those populations over a number of epochs, which can require dozens of parameters to fully describe. There is currently no standard format to define such models, significantly hampering progress in the field. In particular, the important task of translating the model descriptions in published work into input suitable for population genetic simulators is labor intensive and error prone. We propose the Demes data model and file format, built on widely used technologies, to alleviate these issues. Demes provide a well-defined and unambiguous model of populations and their properties that is straightforward to implement in software, and a text file format that is designed for simplicity and clarity. We provide thoroughly tested implementations of Demes parsers in multiple languages including Python and C, and showcase initial support in several simulators and inference methods. An introduction to the file format and a detailed specification are available at https://popsim-consortium.github.io/demes-spec-docs/.


Depth from focus based on combinatorial optimization.
Depth from focus (DFF) is a technique to estimate the depth and 3D shape of an object from a sequence of images obtained at different focus settings. The DFF is presented as a combinatorial optimization problem. After the estimate of the initial depth map solution of an object, the algorithm updates the depth map iteratively from the specially defined neighborhood. The results of the proposed DFF algorithm have shown significant improvements in both the accuracy of the depth map estimation and the computational complexity, with respect to the existing DFF methods.