Delayed hypersensitivity and acquired cellular resistance in guinea pigs infected with Listeria monocytogenes.
Randomly bred pigs of both sexes were injected intracardially with one-half of a 50% lethal dose of Listeria monocytogenes. When infected animals were skin tested with 30 mug of a water-soluble extract of sonically disrupted Listeria, both males and females had uniformly detectable levels of delayed hypersensitivity (DH) 4 days after infection. In males, cutaneous hypersensitivity to Listeria antigens reached a peak on day 5 or 6 of infection, and high levels of DH persisted through the 7th week. In females, DH reached a peak on day 6 or 7, remained at this level through the 4th week, and then dropped sharply. Cutaneous reactivity was usually higher for males than for females, and differences between the sexes were statistically significant 5, 6, and 7 weeks after infection. Low levels of DH were still present 41 weeks (females) or 46 weeks (males) after infection. Assays to determine the number of viable Listeria present in spleen homogenates indicated that bacterial multiplication occurred only during the first 24 hours of infection. The number of Listeria declined steadily thereafter, and by day 13 no bacteria could be recovered from the spleens of infected animals. Spleen assays indicated that Listeria-infected animals of both sexes were resistant to a small challenge dose of Listeria given 48 hours, 7 days, or 2 weeks after the primary infection. Resistance to re-infection was absent in females challenged at 41 weeks and in males challenged at 46 weeks.


Effect of Different Brine Injection Levels on the Drying Characteristics and Physicochemical Properties of Beef Jerky.
Meat jerky is a type of meat snack with a long shelf life, light weight, and unique sensory properties. However, meat jerky requires a long manufacturing time, resulting in high energy consumption. In this study, beef jerky was prepared by injecting different concentrations of brine at different hot-air drying times (0-800 min). When the brine injection levels were increased to 30%, the drying characteristics of beef jerky, such as drying time and effective moisture diffusivity, were significantly improved owing to the relatively high water content and the formation of porous structures. The physicochemical properties (e.g. meat color, porosity, shear force, and volatile basic nitrogen) of the beef jerky injected with 30% brine were improved owing to the shortened drying time. Scanning electron microscopy images showed that the beef jerky structure became porous and irregular during the brine injection process. Our novel processing technique for manufacturing beef jerky leads to improved quality characteristics and shortened drying times.


Natural orifice translumenal endoscopic surgery: progress in humans since white paper.
Since the first description of the concept of natural orifice translumenal endoscopic surgery (NOTES), a substantial number of clinical NOTES reports have appeared in the literature. This editorial reviews the available human data addressing research questions originally proposed by the white paper, including determining the optimal method of access for NOTES, developing safe methods of lumenal closure, suturing and anastomotic devices, advanced multitasking platforms, addressing the risk of infection, managing complications, addressing challenges with visualization, and training for NOTES procedures. An analysis of the literature reveals that so far transvaginal access and closure appear to be the most feasible techniques for NOTES, with a limited, but growing transgastric, transrectal, and transesophageal NOTES experience in humans. The theoretically increased risk of infection as a result of NOTES procedures has not been substantiated in transvaginal and transgastric procedures so far. Development of suturing and anastomotic devices and advanced platforms for NOTES has progressed slowly, with limited clinical data on their use so far. Data on the optimal management and incidence of intraoperative complications remain sparse, although possible factors contributing to complications are discussed. Finally, this editorial discusses the likely direction of future NOTES development and its possible role in clinical practice.


Mastocytosis and insect venom allergy.
To analyse the association of systemic allergic hymenoptera sting reactions with mastocytosis and elevated baseline serum tryptase and to discuss diagnosis and treatment in patients with both diseases. In recent large studies on patients with mastocytosis a much higher incidence of severe anaphylaxis following hymenoptera stings than in the normal population was documented. In patients with hymenoptera venom allergy, elevated baseline tryptase is strongly associated with severe anaphylaxis. Fatal sting reactions were reported in patients with mastocytosis, notably after stopping venom immunotherapy. During venom immunotherapy most patients with mastocytosis are protected from further sting reactions. Based on these observations immunotherapy for life is recommended for patients with mastocytosis and venom allergy. The incidence of allergic side-effects is increased in patients with mastocytosis and elevated baseline tryptase, especially in those allergic to Vespula venom. Premedication with antihistamines, or omalizumab in cases with recurrent severe side-effects, can be helpful. In all patients with anaphylaxis following hymenoptera stings, baseline serum tryptase should be determined. A value above 11.4 microg/l is often due to mastocytosis and indicates a high risk of very severe anaphylaxis following re-stings. Venom immunotherapy is safe and effective in this situation.


Attentional capture by salient distractors during visual search is determined by temporal task demands.
The question whether attentional capture by salient but task-irrelevant visual stimuli is triggered in a bottom-up fashion or depends on top-down task settings is still unresolved. Strong support for bottom-up capture was obtained in the additional singleton task, in which search arrays were visible until response onset. Equally strong evidence for top-down control of attentional capture was obtained in spatial cueing experiments in which display durations were very brief. To demonstrate the critical role of temporal task demands on salience-driven attentional capture, we measured ERP indicators of capture by task-irrelevant color singletons in search arrays that could also contain a shape target. In Experiment 1, all displays were visible until response onset. In Experiment 2, display duration was limited to 200 msec. With long display durations, color singleton distractors elicited an N2pc component that was followed by a late Pd component, suggesting that they triggered attentional capture, which was later replaced by location-specific inhibition. When search arrays were visible for only 200 msec, the distractor-elicited N2pc was eliminated and was replaced by a Pd component in the same time range, indicative of rapid suppression of capture. Results show that attentional capture by salient distractors can be inhibited for short-duration search displays, in which it would interfere with target processing. They demonstrate that salience-driven capture is not a purely bottom-up phenomenon but is subject to top-down control.


Tips and tricks to achieve osteotomy healing and prevent refracture after ulnar shortening osteotomy.
Parallel osteotomy is essential for favorable osteotomy reduction and healing and technically challenging during diaphyseal ulnar shortening osteotomy (USO). This study aimed to evaluate the advantages of guided osteotomy for parallel osteotomy and reduction osteotomies, healing over freehand osteotomy. It also aimed to identify surgical factors affecting healing after diaphyseal USO. Between June 2005 and March 2016, 136 wrists that had undergone diaphyseal USO for ulnar impaction syndrome (UIS) were evaluated. The wrists were divided into two groups according to the osteotomy technique (group 1: freehand osteotomy, 74 wrists; group 2: guided osteotomy, 62 wrists). The osteotomy reduction gap and time to osteotomy healing (union and consolidation) were compared between the groups. A multiple regression test was performed to identify the surgical factors affecting healing. The cut-off length of the reduction gap to achieve osteotomy union on time and the cut-off period to decide the failure of complete consolidation were statistically calculated. The baseline characteristics did not differ between the two groups. The osteotomy reduction gap and time to osteotomy union, and complete consolidation were shorter in group 2 than in group 1 (p = 0.002, < 0.001, 0.002). The osteotomy reduction gap was a critical surgical factor affecting both time to osteotomy union and complete consolidation (p < 0.001, < 0.001). The use of a dynamic compression plate affected only the time to complete consolidation (p < 0.001). The cut-off length of the osteotomy reduction gap to achieve osteotomy union on time was 0.85 mm. The cut-off period to decide the failure of complete consolidation was 23.5 months after osteotomy. The minimal osteotomy reduction gap was the most important for timely osteotomy healing in the healthy ulna, and guided osteotomy was beneficial for reducing the osteotomy reduction gap.


General practice patients' beliefs about their symptoms.
Patients' beliefs about symptoms are major influences on consultation and its consequences. However, little information is available about the beliefs of patients when they consult their general practitioner (GP). To describe and quantify the range of beliefs of patients about their symptoms before consultation, and to test the hypothesis that patients who attribute symptoms to stress or lifestyle would expect less benefit than others from physical medicine but more from lifestyle change and emotional support. Interviews with 100 patients attending one of two general practices were used to form a questionnaire, which was completed by 406 patients attending one of three general practices in contrasting areas of Greater London. This measured the frequency of specific beliefs about the causes of their symptoms and about effective forms of help. Patients were seen before their consultation. The most common aetiological beliefs concerned stress and lifestyle. In general, the mechanisms underlying symptoms were thought to be disturbances in bodily functioning rather than pathological processes. The most valued form of help was explanation and discussion of symptoms. Nevertheless, about half the patients expected benefit from medication and only slightly fewer from hospital investigation or treatment. Patients who attributed symptoms to stress or lifestyle were no less likely to expect help from medication or specialist referral, but they were more likely to see benefit in explanation and counselling or lifestyle change. These findings suggest hypotheses for future research into the effects that patients' attributions of their symptoms to stress and lifestyle have on their health care demands, emphasize the importance of routinely assessing patients' beliefs on consulting the GP, and provide information that can help to direct this assessment in the individual case.


Clinical determinants of intestinal failure and death in preterm infants with surgical necrotizing enterocolitis.
We sought to investigate the clinical determinants of intestinal failure and death in preterm infants with surgical NEC. Retrospective comparison of clinical information between Group A = intestinal failure (Parenteral nutrition (PN) >90 days) and death and Group B = survivors and with PN dependence < 90 days in preterm infants with surgical NEC. Group A (n = 99/143) had a lower mean gestational age (26.4 weeks [SD3.5] vs. 29.4 [SD 3.5]; p = 0.013), lower birth weight (873 gm [SD 427g] vs. 1425 gm [894g]; p = <0.001), later age of NEC onset (22 days [SD20] vs. 16 days [SD 17]; p = 0.128), received surgery later (276 hours [SD 544] vs. 117 hours [SD 267]; p = 0.032), had cholestasis, received dopamine (80.6% vs. 58.5% ; p = 0.010) more frequently and had longer postoperative ileus time (19.8 days [SD 15.4] vs. 11.8 days [SD 6.5]; p = <0.001) and reached full feeds later (93 days [SD 45] vs. 44 [SD 22]; p = <0.001) than Group B.On multivariate logistic regression, higher birth weight was associated with lower risk (OR 0.35, 95% CI 0.15-0.82; p = 0.016) of TPN > 90 days or death. Longer length of bowel resected (OR 1.76, 95% CI 1.02-3.02; p = 0.039) and longer postoperative ileus (OR 2.87, 95% CI 1.26-6.53; p = 0.011) were also independently associated with TPN >90days or death adjusted for gestational age and antenatal steroid treatment. In preterm infants with surgical NEC, clinical factors such as lower birth weight, longer bowel loss, and postoperative ileus days were significantly and independently associated with TPN >90 days or death.


Poromechanical controls on spontaneous imbibition in earth materials.
Over the last century, the state of stress in the earth's upper crust has undergone rapid changes because of human activities associated with fluid withdrawal and injection in subsurface formations. The stress dependency of multiphase flow mechanisms in earth materials is a substantial challenge to understand, quantify, and model for many applications in groundwater hydrology, applied geophysics, CO2 subsurface storage, and the wider geoenergy field (e.g., geothermal energy, hydrogen storage, hydrocarbon recovery). Here, we conduct core-scale experiments using N2/water phases to study primary drainage followed by spontaneous imbibition in a carbonate specimen under increasing isotropic effective stress and isothermal conditions. Using X-ray computed micro-tomography images of the unconfined specimen, we introduce a novel coupling approach to reconstruct pore-deformation and simulate multiphase flow inside the deformed pore-space followed by a semi-analytical calculation of spontaneous imbibition. We show that the irreducible water saturation increases while the normalized volume of spontaneously imbibed water into the specimen decreases (46-25%) in response to an increase in effective stress (0-30 MPa), leading to higher residual gas saturations. Furthermore, the imbibition rate decreases with effective stress, which is also predicted by a numerical model, due to a decrease in water relative permeability as the pore-space becomes more confined and tortuous. This fundamental study provides new insights into the physics of multiphase fluid transport, CO2 storage capacity, and recovery of subsurface resources incorporating the impact of poromechanics.


[Increase in the maximum intensity of myocardial contractile function using glutamic acid].
In experiments on 54 isolated papillary muscles from guinea-pig hearts a rise in contraction velocity and amplitude was induced by the increment in stimulation rate. Maximal contractile indices and the rate at which they were observed were the less the greater the muscle thickness limiting oxygen supply. At any rate the relaxation velocity of thin muscles (cross sectional area 0.38 mm2) was approximately twice higher than the contraction velocity. The difference became smaller as the muscle thickness increased and completely disappeared in experiments on thick muscles (cross sectional area 1.34 mm2). Addition of glutamic acid (3.5 mM) to perfusate did not influence contraction and relaxation values at a rate of 0.5-2.0 Hz but prevented their depression at a rate of 2.5-3.5 Hz, which was typical of thick muscles. This effect seems to be related to improved energy production by myocardial cells during hypoxia or ischemia.


Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States.
Helicobacter pylori is the primary cause of peptic ulcer disease and an etiologic agent in the development of gastric cancer. H. pylori infection is curable with regimens of multiple antimicrobial agents, and antimicrobial resistance is a leading cause of treatment failure. The Helicobacter pylori Antimicrobial Resistance Monitoring Program (HARP) is a prospective, multicenter U.S. network that tracks national incidence rates of H. pylori antimicrobial resistance. Of 347 clinical H. pylori isolates collected from December 1998 through 2002, 101 (29.1%) were resistant to one antimicrobial agent, and 17 (5%) were resistant to two or more antimicrobial agents. Eighty-seven (25.1%) isolates were resistant to metronidazole, 45 (12.9%) to clarithromycin, and 3 (0.9%) to amoxicillin. On multivariate analysis, black race was the only significant risk factor (p < 0.01, hazard ratio 2.04) for infection with a resistant H. pylori strain. Formulating pretreatment screening strategies or providing alternative therapeutic regimens for high-risk populations may be important for future clinical practice.


[From the Casa de Orates to the courtroom: psychiatric expertise and legal assessment of madness in Santiago de Chile around 1860].
This article explores the position of mental health authorities in the civil justice field by studying psychiatric evaluations in cases of judicial interdiction on account of dementia in Santiago de Chile in the mid nineteenth century. It examines the legal framework that created a space for the figure of the expert and focuses on the everyday use of psychiatric evaluations, in order to explore some of the forces which legitimized their authority in the changing conditions of early psychiatry.


Measles Outbreak in a Rural Population in Bahar District, Hamadan Province, West of Iran in 2018.
Measles is in elimination phase in Iran. Following occurrence of two cases of measles in two children under six years old with the history of measles immunization in one of the villages affiliated to Bahar District, west of Hamadan Province, northwest of Iran, this study was conducted to determine the immunity status of people living in the village affected by the measles outbreak in spring of 2018. A cross-sectional (descriptive-analytical) study. Overall, 272 populations of 0-40 yr old in the village affected by outbreak were enrolled. Multistage sampling was used for choosing participants. The data collection tool was a researcher-made checklist used to collect epidemiological data including demographic characteristics and vaccination status. Blood samples were taken from them and sent to the measles reference laboratory for IgG testing. The amount of optical density (OD) greater than 0.2 was considered as positive and less than 0.1 negative, respectively. The mean age of the study population was 17.4 ±11.8 yr and the sex ratio was almost the same. Levels of antibodies against measles were positive in 63.24%, intermediate in 12.5% and negative in 24.26%. There was no significant difference between the immunity status of the subjects with gender (P=0.236) and age group (P=0.113). Pearson correlation results showed that in males there was a significant positive correlation between the age of the participants and the serum IgG level (r = 0.26, P=0.003). Measles immunity in communities is not sufficient to prevent outbreaks and small epidemics, and it is recommended that periodically, serological assessments carried out at community level and especially at high-risk groups.


Folic acid fortification of the food supply. Potential benefits and risks for the elderly population.
To estimate the potential benefits and risks of food folic acid fortification for an elderly population. Benefits are expected through the improvement of folate and homocysteine status, but there is also a risk of masking or precipitating clinical manifestations related to vitamin B12 deficiency with increasing exposure to folic acid. Cross-sectional analysis, with projected change at various levels of folic acid fortification. Participants in the Framingham Heart Study original cohort. A total of 747 subjects aged 67 to 96 years who both completed usable food frequency questionnaires and had blood concentrations of B vitamins and homocysteine measured. Projected blood folate and homocysteine concentrations and combined high folate intake and low plasma vitamin B12 concentration. Percentages of this elderly population with folate intake below 400 microg/d are projected to drop from 66% at baseline to 49% with 140 microg of folate per 100 g of cereal-grain product, to 32% with 280 microg, to 26% with 350 microg, and to 11% with 700 microg. Percentages with elevated homocysteine concentrations (>14 micromol/L) are projected to drop from 26% at baseline to 21% with 140 microg of folate per 100 g, to 17% with 280 microg, to 16% with 350 microg, and to 12% with 700 microg. Without fortification, the prevalence of combined high folate intake (>1000 microg/d) and low plasma vitamin B12 concentration (<185 pmol/L [<250 pg/mL]) was 0.1%. This is projected to increase to 0.4% with folate fortification levels of 140 to 350 microg/100 g and to 3.4% with 700 microg. The evidence suggests that, at the level of 140 microg/100 g of cereal-grain product mandated by the Food and Drug Administration, the benefits of folate fortification, through projected decreases in homocysteine level and heart disease risk, greatly outweigh the expected risks. However, quantification of the actual risks associated with vitamin B12 deficiency remains elusive. Before higher levels of folic acid fortification are implemented, further research is needed to better understand the clinical course of various forms of vitamin B12 deficiency, to measure the potential effect of high folate intake on this course, and to identify cost-effective approaches to the identification and treatment of all forms of vitamin B12 deficiency.


Selective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival in rats with C6 gliomas.
The response of brain tumors to systemic chemotherapy is limited by the blood-tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats. The Proli/NO was infused at a wide dose range (10(-2) to 10(-12) M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (BBB) permeability in response to various-sized tracers ([14C]aminoisobutyric acid, [14C]sucrose, [14C]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli/NO (10(-6) M) and carboplatin (20 mg/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli/NO and carboplatin, and no toxicity was observed. This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors.


BODY-Q patient-reported outcomes measure (PROM) to assess sleeve gastrectomy vs. Roux-en-Y gastric bypass: eating behavior, eating-related distress, and eating-related symptoms.
Post-operative changes in eating behavior, eating-related distress and eating-related symptoms play an important role in the lives of bariatric surgery patients. However, there are no studies that assess these outcomes using a specifically designed patient-reported outcome measure (PROM) for patients undergoing bariatric surgery. We use our newly developed and validated scales as part of the well-established BODY-Q PROMs to compare laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass patients (LRYGB). We analyzed data from an international multi-center prospective cohort study of patients over 18 who underwent bariatric surgery. We used multivariable linear regression models to assess the difference between LRYGB and LSG for the new BODY-Q scales, which include eating behavior, eating-related distress and eating-related symptoms. All analyses were corrected for significant confounding variables. Out of 1420 patients, 920 underwent LRYGB and 500 underwent LSG. The LRYGB group had a higher percentage total weight loss (p < 0.001). There was no significant difference in eating behavior (e.g., stop eating before feeling full, avoiding unhealthy snacks, etc.) or eating-related distress (e.g., feeling ashamed or out of control after eating). Patients who underwent LSG scored significantly better on the post-prandial eating-related symptoms scale (e.g., vomiting, reflux; p < 0.001). Symptoms more prevalent in the LRYGB patients were related to dumping syndrome whereas symptoms more prevalent in LSG patients were related to reflux. Patients who underwent LRYGB had a significantly better weight loss after surgery, but they scored worse on post-prandial symptoms in comparison to LSG patients. This information may be relevant for patients in the pre-operative counseling setting, as it may influence their decision for surgical procedure selection.


Anesthetic-protein interaction: surface potential of bovine serum albumin estimated by a pH-sensitive dye.
It is often contended that inhalation anesthetics act on proteins via perturbation of lipid membranes. However, direct interaction between anesthetics and water-soluble proteins also has been demonstrated. We postulate that the anesthetic action is directed to the interface between water and macromolecules, irrespective of lipid membranes or proteins. The present study deals with anesthetic effects upon interfacial properties of a water-soluble, crystalline delipidated bovine serum albumin. A pH-indicator dye, bromothymol blue, was used to probe the surface potential of the protein. When a pH-indicator dye binds to a macromolecule, the pH, indicated by the color of the dye, differs from the bulk pH measured by a pH meter. This is because the pH of the microscopic area, where the dye is adsorbed, differs from the bulk due to the surface electrostatic potential that interacts with hydrogen ions (electrostatic terms), and the physical property that affects the color of the dye at the bound region is different from the bulk (nonelectrostatic terms). The mismatch between the bulk pH and the color of the bound pH indicator can be used to probe the property of the dye binding site. By screening the electrostatic effects with high ionic strength, the anesthetic effects upon the nonelectrostatic term were shown to be negligible under the present experimental conditions; the pH-color mismatch was mainly caused by the anesthetic effect upon the electrostatic potential of the macromolecular surface interacting with the dye. Accordingly, the surface potential of the dye binding site was estimated from the mismatch. It was found that inhalation anesthetics decreased the surface potential. The partial pressures of diethylether, enflurane, and methoxyflurane that decreased the surface potential by 10 mV were 2.1 X 10(-2), 1.7 X 10(-2), and 0.17 X 10(-2) bar, respectively, which were in agreement with the minimal alveolar concentrations of these anesthetics to achieve surgical anesthesia.


An alternative to post hoc model modification in confirmatory factor analysis: The Bayesian lasso.
As a commonly used tool for operationalizing measurement models, confirmatory factor analysis (CFA) requires strong assumptions that can lead to a poor fit of the model to real data. The post hoc modification model approach attempts to improve CFA fit through the use of modification indexes for identifying significant correlated residual error terms. We analyzed a 28-item emotion measure collected for n = 175 participants. The post hoc modification approach indicated that 90 item-pair errors were significantly correlated, which demonstrated the challenge in using a modification index, as the error terms must be individually modified as a sequence. Additionally, the post hoc modification approach cannot guarantee a positive definite covariance matrix for the error terms. We propose a method that enables the entire inverse residual covariance matrix to be modeled as a sparse positive definite matrix that contains only a few off-diagonal elements bounded away from zero. This method circumvents the problem of having to handle correlated residual terms sequentially. By assigning a Lasso prior to the inverse covariance matrix, this Bayesian method achieves model parsimony as well as an identifiable model. Both simulated and real data sets were analyzed to evaluate the validity, robustness, and practical usefulness of the proposed procedure. (PsycINFO Database Record


Arterial pulse wave reflection as feedback.
Traditionally, input impedance (Z(in)) has been used to characterize the global dynamic properties of an arterial system independent of properties of the heart. Defined as the relationship of pressure and flow at the entrance of an arterial system, it describes the ability of an arterial system to dynamically impede blood flow. Recently, a new description has been developed that also characterizes the arterial system independent of properties of the heart. Apparent arterial compliance (C(app)) is defined as the dynamic relationship of input pressure and volume stored in an arterial system, and describes the ability of the arterial system to dynamically store blood. Both Z(in) and C(app) are influenced by pulse wave propagation and reflection. However, the functional form of Capp lends itself to describing the arterial system in terms of negative feedback. Pulse wave reflection decreases the pulsatile volume stored (gain) at low frequencies, but increases the range of frequencies (bandwidth) in which the pulsatile volume is determined by total arterial compliance. This paper illustrates, by simple analytical formula, large-scale arterial system modeling, and direct analysis of data, how this conceptualization of reflection offers a new means to interpret changes in arterial system dynamics resulting from changes in arterial compliance.


The effect of pain on involuntary and voluntary capture of attention.
There is converging evidence for the notion that pain affects a broad range of attentional domains. This study investigated the influence of pain on the involuntary capture of attention as indexed by the P3a component in the event-related potential derived from the electroencephalogram. Participants performed in an auditory oddball task in a pain-free and a pain condition during which they submerged a hand in cold water. Novel, infrequent and unexpected auditory stimuli were presented randomly in a series of frequent standard and infrequent target tones. P3a and P3b amplitudes were observed to novel, unexpected and target-related stimuli, respectively. Both electrophysiological components were characterized by reduced amplitudes in the pain compared with the pain-free condition. Hit rate and reaction time to target stimuli did not differ between the two conditions presumably because the experimental task was not difficult enough to exceed attentional capacities under pain conditions. These results indicate that voluntary attention serving the maintenance and control of ongoing information processing (reflected by the P3b amplitude) is impaired by pain. In addition, the involuntary capture of attention and orientation to novel, unexpected information (measured by the P3a) is also impaired by pain. Thus, neurophysiological measures examined in this study support the theoretical positions proposing that pain can reduce attentional processing capacity. These findings have potentially important implications at the theoretical level for our understanding of the interplay of pain and cognition, and at the therapeutic level for the clinical treatment of individuals experiencing ongoing pain.


Inability to transmit scrapie by transfection of mouse embryo cells in vitro.
Infectivity of nucleic acid from highly infectious mouse scrapie brains was studied by transfecting the nucleic acid in vitro prior to inoculation into animals. Foetal mouse brain and whole mouse embryo cultures were chosen as the cells used for the transfection. As an internal control, infectious nucleic acid was recovered from bacteriophage phi X174 and whole virus particles were obtained when cultures were transfected with herpes simplex virus DNA. In contrast, none of the animals inoculated with nucleic acid preparations derived from scrapie-infected tissues developed scrapie disease either with or without transfection procedures. These findings (i) show transfection techniques fail to elicit evidence of a scrapie-specific infectious nucleic acid and (ii) confirm the observation that scrapie is not a viroid.


Craniocervical arterial dissection in children: clinical and radiographic presentation and outcome.
Craniocervical arterial dissection is a recognized cause of arterial ischemic stroke in children. Whether children with craniocervical arterial dissection have dissection characteristics different from those of adults is unclear. A retrospective review of children, 1 month to 18 years of age, with dissection from two Canadian pediatric ischemic stroke registry centers was conducted. From 213 patients with arterial ischemic stroke, 16 (7.5%) were identified with dissection, 37.5% had warning symptoms, and 50% had a history of head or neck trauma. The clinical presentation included headache (44%), altered consciousness (25%), seizures (12.5%), and focal deficits (87.5%). Dissection involved extracranial vessels in 75% and anterior circulation in 56%. Follow-up included complete recovery in 43%, mild to moderate deficits in 44%, and severe deficits in 13%. Fourteen (87.5%) children received antithrombotic treatment. Follow-up angiography showed resolution of abnormalities in 60% of vessels. Total occlusion had the worst outcome for recanalization. In conclusion, the etiology of arterial dissection in the majority of children appears to be either trauma or idiopathic. Long-term angiography shows variable outcomes, depending on the initial findings. The relationship of angiographic outcomes with recurrent strokes requires further study in pediatric dissection. (J Child Neurol 2006;21:8-16).


Alpha-fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma.
Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human sodium iodide symporter (NIS) gene transfer using a mouse alpha-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1-6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1-6 cell line showed a 10-fold increase in iodide accumulation, while HepG2 cells accumulated (125)I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1-6 and 93% of HepG2 cells were killed by (131)I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total (123)I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq(-1) (131)I. After administration of a therapeutic (131)I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of (131)I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.


Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy.
Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7). Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide.Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.


Pharmaceutico-analytical Study of Kushtae Shangarf Prepared with Jozbua (Myristica fragrans Houtt.) and Phitkari (Alum).
Kushta of Shangarf (KS) is in therapeutic use since long time in Unani and Ayurvedic medicine. It requires extensive assessment with respect to its safety and processing because of the presence of mercury. KS prepared with Shangarf (HgS), Phitkari (alum), and Jozbua (Myristica fragrans Houtt.) was selected for the study. It is indicated as tonic, increases blood production, and improves complexion of face. Preparation of KS by classical and contemporary method and its comparative physicochemical analysis was attempted in this work. Kushta was prepared by incinerating the drugs kept inside Buta in Bhatti with 24kg of Uple (cow-dung cakes) and also in muffle furnace. Samples obtained were evaluated by Unani specifications (test), powder characterizations, loss on drying, pH, ash value, solubility, particle size, and qualitative estimation of organic and inorganic constituents, X-ray diffraction (XRD), quantitative estimation by inductively coupled plasma-mass spectrometry and inductively coupled plasma-optical emission spectrometry, and so on. Physicochemical standards set in were comparable in KS prepared by classical method (KSCM) and in KS prepared by muffle furnace method (KSMFM), except water-soluble ash and solubility in water were found slightly more in KSMFM. XRD study revealed the presence of aluminum oxide phase and absence of mercury in both the samples. Quantitative estimation of elements in both the samples in decreasing order are as follows: sulfur > aluminum > calcium > iron > arsenic. Arsenic was found more than iron in KSCM at parts per million level. Preliminary understanding suggests that muffle furnace method could be a better option with respect to safety and ease of preparation. Shangarf incinerated above 900°C with Phitkari and Jaiphal did not show presence of mercury in both the samples, indicating KS prepared by incinerating at higher temperature can be safer than unroasted preparation. Studied formulation can be recommended or used for its indications without the concern of mercury toxicity.


Atmospheric pressure thermal dissociation of phospho- and sulfopeptides.
Several phospho- and sulfopeptides were subjected to atmospheric pressure thermal dissociation (APTD), which was effected by passing peptide ions generated by electrosonic spray ionization (ESSI) through a heated coiled metal tube. Sequence informative fragment ions including a-, b-, c-, and y-types of ions were observed with increased relative intensities under APTD compared with collision-induced dissociation (CID), performed inside the ion trap. A certain degree of preservation of phosphate and sulfate ester moieties was observed for some fragments ions under APTD. The neutral fragments generated outside the mass spectrometer were further analyzed via on-line corona discharge to provide rich and complementary sequence information to that provided by the fragment ions directly obtained from APTD, although complete losses of the modification groups were noted. Improved primary sequence information for phospho- and sulfopeptides was typically obtained by analyzing both ionic and neutral fragments from APTD compared with fragment ions from CID alone. Localization of the modification sites of phospho- and sulfopeptides was achieved by combining the structural information acquired from APTD and CID.


Molecular and cellular analysis of a novel HBA2 mutation (HBA2: c.94A > G) shows activation of a cryptic splice site and generation of a premature termination codon.
In this study, we describe the clinical features and provide experimental analyses of a novel point mutation affecting the penultimate nucleotide of the first exon of the HBA2 (HBA2: c.94A > G) gene identified in a 26-year-old female who also carries a heterozygous Hb E (HBB: c.79G > A) variant. The aim of the study was to investigate the impact of this point mutation on the transcriptional activity of the HBA2 gene using a combination of an initial in silico prediction followed by in vitro mutagenesis and transcriptional activity assessment. The analyses revealed that the HBA2: c.94A > G point mutation causes the activation of a cryptic splice site located 49 bp upstream of the exon1-intron1 boundary in both HBA2 long and short isoforms, thus generating a frameshift and a premature termination codon between codons 48 and 49 in the second exon. A rapid degradation of the aberrantly spliced transcripts by the nonsense mediated decay (NMD) surveillance system is highly indicative of an α-thalassemia (α-thal) phenotype. However, the abnormal mRNA may not be entirely degraded since the proband presents a slight splenomegaly that could be the sign of extra vascular hemolysis.


Immune cell transcriptome datasets reveal novel leukocyte subset-specific genes and genes associated with allergic processes.
The precise function of various resting and activated leukocyte subsets remains unclear. For instance, mast cells, basophils, and eosinophils play important roles in allergic inflammation but also participate in other immunologic responses. One strategy to understand leukocyte subset function is to define the expression and function of subset-restricted molecules. To use a microarray dataset and bioinformatics strategies to identify novel leukocyte markers as well as genes associated with allergic or innate responses. By using Affymetrix microarrays, we generated an immune transcriptome dataset composed of gene profiles from all of the major leukocyte subsets, including rare enigmatic subsets such as mast cells, basophils, and plasma cells. We also assessed whether analysis of genes expressed commonly by certain groups of leukocytes, such as allergic leukocytes, might identify genes associated with particular responses. Transcripts highly restricted to a single leukocyte subset were readily identified (>2000 subset-specific transcripts), many of which have not been associated previously with leukocyte functions. Transcripts expressed exclusively by allergy-related leukocytes revealed well known as well as novel molecules, many of which presumably contribute to allergic responses. Likewise, Nearest Neighbor Analysis of genes coexpressed with Toll-like receptors identified genes of potential relevance for innate immunity. Gene profiles from all of the major human leukocyte subsets provide a powerful means to identify genes associated with single leukocyte subsets, or different types of immune response. A comprehensive dataset of gene expression profiles of human leukocytes should provide new targets or biomarkers for human inflammatory diseases.


Double-strand breaks stimulate alternative mechanisms of recombination repair.
To test the double-strand break repair model, we used HO nuclease to introduce double-strand breaks at several sites along a yeast chromosome containing duplicated DNA. Depending on the configuration of the double-strand break and recombining markers, different spectra of recombinant products were observed. Different repair kinetics and recombinant products were observed when a double-strand break was introduced in unique or duplicated DNA. The results of this study suggest that double-strand breaks in yeast stimulate recombination by several mechanisms, and we propose an alternative mechanism for double-strand break-induced gene conversion that does not depend on direct participation of the broken ends.


An Overview of the Activities of Cefiderocol Against Sensitive and Multidrug- Resistant (MDR) Bacteria.
The need for new therapeutics and drug delivery systems has become necessary owing to the public health concern associated with the emergence of multidrug-resistant microorganisms. Among the newly discovered therapeutic agents is cefiderocol, which was discovered by Shionogi Company, Japan as an injectable siderophore cephalosporin. Just like the other β-lactam antibiotics, cefiderocol exhibits antibacterial activity via cell wall synthesis inhibition, especially in Gram negative bacteria (GNB); it binds to the penicillin-binding proteins, but its unique attribute is that it crosses the periplasmic space of bacteria owing to its siderophore-like attribute; it also resists the activity of β-lactamases. Among all the synthesized compounds with the modified C-7 side chain, cefiderocol (3) presented the best and well-balanced activity against multi-drug resistant (MDR) Gram negative bacteria, including those that are resistant to carbapenem. İn this article, an overview of the recent studies on cefiderocol was presented.


[Pilot experience with radio-knife "Surgitron"].
A new radiosurgical knife Surgitron is described in terms of its application in ENT operations. Surgical procedures, indications, operative regimes are detailed. Advantages and disadvantages of the device design are outlined. The device is functionally and cosmetically effective. Thus, it holds promise in surgery.


Tenosynovial Giant Cell Tumor in the Dermis of the External Auditory Meatus.
A 26-year-old African American woman with a history of a recurring "oozing papule" in the right ear presented to the emergency department in July 2010 with a 2-month history of an enlarging, painful growth in the right ear canal. Physical examination revealed a 1-cm round cystic lesion along the right, anterior external auditory canal wall, just medial to the tragus. Initial diagnosis was an infected cyst of the external ear canal. The patient was instructed to follow-up with an ear, nose, and throat (ENT) office. Two months following the emergency department visit, inspection by ENT revealed a 3- to 4-mm round, firm subcutaneous nodule that did not extend into the ear canal or cartilage. According to the patient, this lesion had recurred with several infections. The lesion was biopsied in the outpatient setting and demonstrated ulceration with marked acute and chronic inflammation in addition to granulation tissue. Two months later, the lesion was surgically excised. The final diagnosis of giant cell tumor, tenosynovial type with lesion-free margins, and no involvement of the cartilage was made (Figures 1-3). No further treatment was recommended. Gross examination of the excised lesion revealed tan to white soft tissue measuring 1.0×0.7×0.3 cm. Results from factor XIII A immunostain was negative, confirming that the lesion did not represent an unusual variant of fibrous histiocytoma (Figure 4). To date, recurrence of this lesion has not been appreciated.


Sex-Specific Genetic Variants are Associated With Coronary Endothelial Dysfunction.
Endothelial dysfunction is an early stage of atherosclerosis. Single-nucleotide polymorphisms (SNPs) have been associated with vascular dysfunction, cardiac events, and coronary artery remodeling. We aimed to detect SNPs associated with endothelial dysfunction and determine whether these associations are sex specific. Six hundred forty-three subjects without significant obstructive coronary artery disease underwent invasive coronary endothelial function assessment. We collected data from 1536 SNPs that had previously been associated with vasoreactivity, angiogenesis, inflammation, artery calcification, atherosclerotic risk factors, insulin resistance, hormone levels, blood coagulability, or with coronary heart disease. Coronary vascular reactivity was assessed by the percent change in coronary artery diameter ≤ -20% after an intracoronary bolus injection of acetylcholine on invasive coronary physiology study. SNPs significantly associated with coronary epicardial endothelial dysfunction were ADORA1, KCNQ1, and DNAJC4 in the whole cohort, LPA, MYBPH, ADORA3, and PON1 in women and KIF6 and NFKB1 in men (P<0.01). We have identified several significant SNPs that are associated with an increased risk of coronary endothelial dysfunction. These associations appear to be sex specific and may explain gender-related differences in development of atherosclerosis.


The importance of acknowledging clinical uncertainty in the diagnosis of epilepsy and non-epileptic events.
Failure to recognise diagnostic uncertainty between the epilepsies and non-epileptic events may be a factor in high rates of misdiagnosis. To explore the results of acknowledging diagnostic uncertainty in a cohort of children presenting with paroxysmal events. Children (29 days-16th birthday) with new presentations of paroxysmal disorders were ascertained through outpatients, admissions, and accident and emergency over a two year period in a district hospital with a catchment population of 500,000. Cases were classified by diagnosis at entry and 6-30 months later. A random selection of cases was independently assessed. A total of 684 cases were ascertained. Attacks were initially classified as febrile seizures (n = 212), acute symptomatic epileptic seizures (n = 5), epilepsies (n = 83), unclassified (possible epilepsy) (n = 90), isolated epileptic seizures (n = 51), and non-epileptic events (n = 243). Case review enabled reclassification of 61 of those initially unclassified--31 to an epilepsy and 27 to non-epileptic events. In 29 the final diagnosis was never clarified. These were 23 cases with confusing or absent histories and six with short lived seizure clusters. Prognosis for these 29 cases was good; 75% had been discharged. None were on long term medication. The diagnosis in the 131 cases confirmed as epilepsy was stable. Independent review of a random sample showed full concordance with one neurologist and 20% uncertainty with another. In addition to definite epilepsy or non-epileptic events it is helpful to recognise a group of cases where the diagnosis is uncertain-unclassified paroxysmal events. Reassessment of these cases enables accurate diagnosis and may prevent a hasty and incorrect diagnosis of epilepsy.


Effect of the radiation intensity, water turbidity and exposure time on the survival of Cryptosporidium during simulated solar disinfection of drinking water.
The solar disinfection (SODIS) technique is a highly effective process that makes use of solar energy to inactivate pathogenic microorganisms in drinking water in developing countries. The pathogenic protozoan parasite Cryptosporidium parvum is often found in surface waters and is associated with waterborne outbreaks of cryptosporidiosis. In the present study, a complete multi-factorial mathematical model was used to investigate the combined effects of the intensity of solar radiation (200, 600 and 900W/m(2) in the 320nm to 10microm range), water turbidity (5, 100 and 300 NTU) and exposure time (4, 8 and 12h) on the viability and infectivity of C. parvum oocysts during simulated SODIS procedures at a constant temperature of 30 degrees C. All three factors had significant effects (p<0.05) on C. parvum survival, as did the interactions of water turbidity with radiation intensity and radiation intensity with exposure time. However, the parameter with the greatest effect was the intensity of radiation; levels > or =600W/m(2) and times of exposure between 8 and 12h were required to reduce the oocyst infectivity in water samples with different degrees of turbidity.


CB2 receptors in reproduction.
Cannabinoids have been always identified as harmful drugs because of their negative effects on male and female reproduction. The discovery of the 'endocannabinoid system (ECS)', composed of bioactive lipids (endocannabinoids), their receptors and their metabolic enzymes, and the generation of mouse models missing cannabinoid receptors or other elements of the ECS, has enabled a wealth of information on the significance of endocannabinoid signalling in multiple reproductive events: Sertoli cell survival, spermatogenesis, placentation, fertilization, preimplantation embryo development, implantation and postimplantation embryonic growth. These studies have also opened new perspectives in clinical applications, pointing to the ECS as a new target for correcting infertility and for improving reproductive health in humans. This review will focus on the involvement of type-2 cannabinoid (CB2) receptors in reproductive biology, covering both the male and female sides. It will also discuss the potential relevance of the immunological activity of CB2 at the maternal/foetal interface, as well as the distinctiveness of CB2 versus type-1 cannabinoid (CB1) receptors that might be exploited for a receptor subtype-specific regulation of fertility. In this context, the different signalling pathways triggered by CB1 and CB2 (especially those controlling the intracellular tone of nitric oxide), the different activation of CB1 and CB2 by endogenous agonists (like anandamide and 2-arachidonoylglycerol) and the different localization of CB1 and CB2 within membrane subdomains, termed 'lipid rafts', will be discussed. It is hoped that CB2-dependent endocannabinoid signalling might become a useful target for correcting infertility, in both men and women.


A dyadic approach for a remote physical activity intervention in adults with Alzheimer's disease and their caregivers: Rationale and design for an 18-month randomized trial.
Adults with Alzheimer's disease and related dementia (ADRD) and their caregivers represent a sizeable and underserved segment of the population with low levels of moderate physical activity (MPA). Options for increasing MPA in community dwelling adults with ADRD and their caregivers are limited. A home-based physical activity intervention delivered remotely via video conferencing to groups of adults with ADRD and their caregivers (RGV), represents a potentially effective approach for increasing MPA in this group. We will conduct an 18-month randomized trial (6 mos. Active intervention, 6 mos. Maintenance, 6 mos. no contact) to compare the effectiveness of the RGV approach with usual care, enhanced with caregiver support (EUC), for increasing MPA in 100 community dwelling adults with ADRD and their caregiver. The primary aim is to compare MPA (min/wk.), assessed by accelerometer, across the 6-mo. active intervention in adults with ADRD randomized to RGV or EUC. Secondarily, we will compare adults with ADRD and their caregivers randomized to RGV or ECU on the following outcomes across 18 mos.: MPA (min/wk.), sedentary time (min/wk.), percentage meeting 150 min/wk. MPA goal, functional fitness, activities of daily living, quality of life, residential transitions, cognitive function, and caregiver burden. Additionally, we will evaluate the influence of age, sex, BMI, attendance (exercise/support sessions), use of recorded sessions, self-monitoring, peer interactions during group sessions, caregiver support, type and quality of dyadic relationship, and number of caregivers on changes in MPA in adults with ADRD and their caregiver across 18 mos.


[Study of the effect of parotitis vaccine on DNA repair in human lymphocytes].
The effect of parotitis vaccine virus (strain L-3) on the DNA repair synthesis induced by 4-nitroquinoline-1-oxide has been studied. The efficiency of the repair synthesis depends on individual properties of the human body, viral multiplicity and concentration of the mutagen. A two-fold increase in DNA repair synthesis was obtained after infection of cells with low viral multiplicity (0.001 HADU50 per cell) and using 2.5 x 10(-7) M concentration of the mutagen A ten-fold increase in mutagen concentration affecting the infected cells was accompanied by the inhibition of DNA repair synthesis. Lymphocytes from children studied 7 days after vaccination by the attenuated virus did not reveal any changes in DNA repair synthesis as compared with the cells from nonvaccinated children.


Do biological measures mediate the relationship between education and health: A comparative study.
Despite a myriad of studies examining the relationship between socioeconomic status and health outcomes, few have assessed the extent to which biological markers of chronic disease account for social disparities in health. Studies that have examined this issue have generally been based on surveys in wealthy countries that include a small set of clinical markers of cardiovascular disease. The availability of recent data from nationally representative surveys of older adults in Costa Rica and Taiwan that collected a rich set of biomarkers comparable to those in a recent US survey permits us to explore these associations across diverse populations. Similar regression models were estimated on three data sets - the Social Environment and Biomarkers of Aging Study in Taiwan, the Costa Rican Study on Longevity and Healthy Aging, and the Health and Retirement Study in the USA - in order to assess (1) the strength of the associations between educational attainment and a broad range of biomarkers; and (2) the extent to which these biomarkers account for the relationships between education and two measures of health status (self-rated health, functional limitations) in older populations. The estimates suggest non-systematic and weak associations between education and high risk biomarker values in Taiwan and Costa Rica, in contrast to generally negative and significant associations in the US, especially among women. The results also reveal negligible or modest contributions of the biomarkers to educational disparities in the health outcomes. The findings are generally consistent with previous research suggesting stronger associations between socioeconomic status and health in wealthy countries than in middle-income countries and may reflect higher levels of social stratification in the US. With access to an increasing number of longitudinal biosocial surveys, researchers may be better able to distinguish true variations in the relationship between socioeconomic status and health across different settings from methodological differences.


The anticardiolipin syndrome. A new way to slice an old pie, or a new pie to slice?
Students of systemic lupus erythematosus have long been confused by the paradoxical association of atypical clinical features such as recurrent thrombosis and spontaneous abortion with the lupus anticoagulant and biologic false-positive VDRL reaction. The recent development of sensitive, solid-phase immunoassays for quantitating the autoantibody response to phospholipids holds the promise of illuminating the basis for this seeming enigma. It is now apparent that antiphospholipids antibodies such as anticardiolipin might well play a role in mediating the elements of this paradox. In addition, other cutaneous vascular conditions as diverse as livedo reticularis and Degos' disease might also be related to this type of autoimmune response.


Estrogen Modulates Corneal Nociception and Maintains Corneal Homeostasis in Rat Eye.
To evaluate the role of estrogen in corneal nociception, its influence on lacrimal secretion, and development of dry eye. Ovariectomy was performed in normal healthy female rats (OVX). Estrogen replacement was performed in a population of these rats (OVX+E). Tests for dry eye and corneal sensitivity were performed and compared with rats in proestrus (PRO) as controls. Gene expression of neuropeptides such as substance P, calcitonin gene receptor-like protein (CGRP), estrogen receptor α, TRPV1, and TRPM8 was evaluated in the cornea and trigeminal ganglion. Expression of substance P and CGRP in the cornea was also examined by immunohistochemistry. The response of the cornea to capsaicin and menthol was evaluated to identify the activity of receptors TRPV1 and TRPM8, respectively. There was a significant decrease in tear formation (4.2 ± 0.6 mm/min vs. 6.6 ± 0.42 mm/min), corneal sensitivity (2.2 ± 0.17 cm vs. 6 ± 0 cm), and increase in fluorescein staining in corneas after ovariectomy compared with controls. There was a significant decrease in gene expression of CGRP, substance P, TRPV1, and TRPM8 in the ovarioectomized cornea. A significant decrease in tear formation (3.17 ± 0.30 mm/min vs. 7.17 ± 0.87 mm/min) and eye wipe response (10.5 ± 1.99 wipes vs. 18.33 ± 1.05 wipes) after treatment with menthol and capsaicin in OVX rats was observed. Estrogen replacement significantly enhanced tear formation (4.02 ± 0.6 mm/min vs. 6.7 ± 0.80 mm/min), corneal sensitivity (2.2 ± 0.17 cm vs. 3.2 ± 0.17 cm), and response to capsaicin (10.5 ± 1.99 eye wipes vs. 24.5 ± 0.92 wipes) and menthol (3.17 ± 0.30 mm/min vs. 6.5 ± 0.22 mm/min) and increased expression of neuropeptides, TRPV1 and TRPM8. This study demonstrates the role of estrogen in corneal nociception and its deficiency as a cause of dry eye.


Anabolic role of lysyl oxidase like-2 in cartilage of knee and temporomandibular joints with osteoarthritis.
Lysyl oxidase like-2 (LOXL2) is a copper-dependent amine oxidase. Our previous studies showed that LOXL2 is elevated during mouse fracture healing. The goal of this study was to evaluate the potential of LOXL2 to act as an anabolic agent in cartilage affected by osteoarthritis (OA). LOXL2 was visualized in tissues from human knee and hip joints and temporomandibular joints (TMJ) by immunofluorescence. The activity of LOXL2 in human articular and TMJ chondrocytes was assessed by cell-based assays, microarray analysis, and RT-qPCR, and LOXL2-mediated activation of NF-κB and extracellular signal-related kinase (ERK) signaling pathways was measured by western blotting. To examine LOXL2-induced effect in vivo, we implanted Matrigel-imbedded human chondrocytes into nude mice and exposed them to exogenous LOXL2 for 6 weeks. Finally, LOXL2-induced effects on collagen type 2 α1 (COL2A1) and phospho-SMAD2/3 were evaluated by immunofluorescence analysis. LOXL2 staining was detected in damaged regions of human TMJ, hip and knee joints affected by OA. Stimulation with transforming growth factor (TGF)-β1 upregulated LOXL2 expression, while pro-inflammatory cytokines IL-1β and TNF-α downregulated LOXL2, in human chondrocytes. Viral transduction of LOXL2 in OA chondrocytes increased the mRNA levels of chondroitin sulfate proteoglycan (CSPG4), aggrecan (ACAN), sex determining region Y-box containing gene 9 (SOX9), and COL2A1 but reduced the levels of extracellular matrix (ECM)-degrading enzymes matrix metalloproteinase (MMP)1, MMP3, and MMP13. Further, forced expression of LOXL2 promoted chondrogenic lineage-specific gene expression, increased the expression of COL2A1 in the presence of TNF-α, and inhibited chondrocyte apoptosis. LOXL2 expression also inhibited IL-1β-induced phospho-NF-κB/p65 and TGF-β1-induced ERK1/2 phosphorylation. Matrigel constructs of human chondrocytes from the knee joint and TMJ implanted in nude mice showed anabolic responses after LOXL2 transduction, including increased expression of SOX9, ACAN, and COL2A1. Finally, immunofluorescence staining revealed co-localization of LOXL2 with SOX9 in the nuclei of cells in the implants, decreased phospho-SMAD2/3, and increased COL2A1 staining. Our results suggest that although LOXL2 is upregulated in cartilage affected by OA, this may be a protective response that promotes anabolism while inhibiting specific catabolic responses in the pathophysiology of OA.


Crucial Role of microRNAs as New Targets for Amelogenesis Disorders Detection.
Amelogenesis imperfecta (AI) refers to a heterogeneous group of conditions with multiple factors which contribute to the hypomineralisation of enamel. Preventive measures are necessary to predict this pathology. Prospects for preventive medicine are closely related to the search for new informative methods for diagnosing a human disease. MicroRNAs are prominent for the non-invasive diagnostic platform. The aim of the review is to review the heterogeneous factors involved in amelogenesis and to select the microRNA panel associated with the AI type. We used DIANA Tools (algorithms, databases and software) for interpreting and archiving data in a systematic framework ranging from the analysis of expression regulation from deep sequencing data to the annotation of miRNA regulatory elements and targets (https://dianalab. e-ce.uth.gr/). In our study, based on a gene panel associated with the AI types, twenty-four miRNAs were identified for the hypoplastic type (supplement), thirty-five for hypocalcified and forty-- nine for hypomaturation AI. The selection strategy included the microRNA search with multiple targets using the AI type's gene panel. Key proteins, calcium-dependent and genetic factors were analysed to reveal their role in amelogenesis. The role of extracellular non-coding RNA sequences with multiple regulatory functions seems to be the most attractive. We chose the list of microRNAs associated with the AI genes. We found four microRNAs (hsa-miR-27a-3p, hsa-miR-375, hsa-miR-16-5p and hsamiR- 146a-5p) for the gene panel, associated with the hypoplastic type of AI; five microRNAs (hsa- miR-29c-3p, hsa-miR-124-3p, hsa-miR-1343-3p, hsa-miR-335-5p, and hsa-miR-16-5p - for hypocalcified type of AI, and seven ones (hsa-miR-124-3p, hsa-miR-147a, hsa-miR-16-5p, hsamiR- 429, hsa-let-7b-5p, hsa-miR-146a-5p, hsa-miR-335-5p) - for hypomaturation. It was revealed that hsa-miR-16-5p is included in three panels specific for both hypoplastic, hypocalcified, and hypomaturation types. Hsa-miR-146a-5p is associated with hypoplastic and hypomaturation type of AI, which is associated with the peculiarities of the inflammatory response immune response. In turn, hsa-miR-335-5p associated with hypocalcified and hypomaturation type of AI. Liquid biopsy approaches are a promising way to reduce the economic cost of treatment for these patients in modern healthcare. Unique data exist about the role of microRNA in regulating amelogenesis. The list of microRNAs that are associated with AI genes and classified by AI types has been uncovered. The target gene analysis showed the variety of functions of selected microRNAs, which explains the multiple heterogeneous mechanisms in amelogenesis. Predisposition to mineralisation problems is a programmed event. Many factors determine the manifestation of this problem. Additionally, it is necessary to remember the variable nature of the changes, which reduces the prediction accuracy. Therefore, models based on liquid biopsy and microRNAs make it possible to take into account these factors and their influence on the mineralisation. The found data needs further investigation.


[Morpho-functional iterative surgery in a patient with von Recklinghausen disease].
Neurofibromatosis 1 is an autosomal dominant disease with an estimated incidence 1:2500 to 1:3000 live newborns. The disease presents with multiple cutaneous and non cutaneous lesions. NF1 occurs with equal frequency in males and females and has been identified in all ethnic group. The morbidity and the mortality caused by NF1 are the result of complications that may involve any of the body systems. This disease has been linked with mutations of the NF1 gene which encodes tumor suppressor neurofibromin. At least half of patients with NF1 will have only cutaneous involvement that is not considered to be a major medical problem, even though it can be a source of psychologic burden as a result of cosmetic disfigurement. The cardinal features of the disorder are cafè-au-lait spots, axillary freckling, cutaneous neurofibromas and Lisch nodules, but there are a lot of wide variety of complications affecting almost every system of the body, including the eyes (optic glioma), the nervous system (intracranial tumors), the skeleton (short stature, scoliosis), the endocrine and cardiovascular system (hypertension). Manifestations of NF1 vary at different times in an individual's life. Substantial variability exists among affected members of a single family. This variability confounds clinical management and the severity of the disease cannot be predicted. We present a case in young woman 24 years-old treated by reiterative plastic surgery.


2011 and 2012 Early Careers Achievement Awards: use of genomic biology to study companion animal intestinal microbiota.
Although dogs and cats are quite different than many livestock species in that they have evolved by eating diets high in fat and protein and low in carbohydrates, the gastrointestinal microbiota still play a key role in the gut and overall host health of these species. Early experiments in this field used culture-based techniques to evaluate the effects of dietary ingredients, such as fibers and prebiotics, on microbiota and indices of gut health (e.g., fecal scores, pH, fermentative end products). Such studies, however, were limited in scope and lacked precision as it pertained to the microbiota. The DNA-based techniques that have become available over the past decade have greatly upgraded research capabilities and have provided a more encompassing view of the canine and feline gastrointestinal microbiomes. High-throughput sequencing techniques that are much cheaper and faster than Sanger sequencing have been a key development in this progress. Sequence data not only allow for the identification of all microbial taxa but also provide information regarding functional capacity when a shotgun sequencing approach is used. The few canine and feline studies that have used 454 pyrosequencing have identified the predominant microbial taxa and metabolic functions present in healthy populations, differences between healthy and diseased dog and cat populations, and the effects of diet (e.g., dietary fibers, prebiotics, protein to carbohydrate ratio) on gastrointestinal microbiota. Although these studies have provided a foundation from which to work, more research is needed to increase our general understanding of the gastro-intestinal microbiome, how it impacts host health, how its composition and activity may be altered by age, genetic, or environmental factors, and test whether specific pathogens or disease signatures can be identified and used in diagnosis and/or treatment of disease.


Association of sympathovagal imbalance with cardiovascular risks in patients with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is associated with cardiovascular risks like obesity, insulin resistance, dyslipidemia that can lead to sympathovagal imbalance (SVI). The study was designed to assess the cardiovascular risk in PCOS and link of metabolic derangements to SVI. Thirty-five newly diagnosed PCOS patients and 32 age-matched controls were recruited. Waist-hip ratio, body mass index (BMI), basal cardiovascular parameters such as basal heart rate (BHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and rate pressure product (RPP) were recorded. Autonomic functions were assessed using short-term heart rate variability (HRV) analysis, heart rate and blood pressure response to standing (30:15 ratio), deep breathing (E:I ratio) and isometric handgrip (ΔDBPihg). Fasting plasma glucose, insulin, lipid profile and testosterone were assayed. Insulin resistance (HOMA-IR) and lipid risk factors were calculated. The cases had increased BHR, BMI, SBP, DBP, MAP and RPP. The ratio of low-frequency to high-frequency (LF-HF) of HRV, the marker of SVI was significantly increased in cases. 30:15 ratio and ΔDBPihg were increased and E:I ratio was decreased in the cases. HOMA-IR, lipid risk factors and testosterone were significantly elevated in cases. There was a significant correlation of LF-HF with BMI, BHR, RPP, insulin resistance and lipid risk factors. On regression analysis, insulin resistance and lipid risk factors had independent association with LF-HF. PCOS patients have SVI, decreased HRV and increased RPP and the potential cardiovascular risks. The insulin resistance and dyslipidemia contribute to SVI and cardiovascular risks in PCOS patients.


Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors.
Mucocutaneous keratinocytes and bronchial epithelial cells express nicotinic acetylcholine receptors (nAChRs). Emerging evidence indicates that nAChRs can be stimulated also by the tobacco-derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) that can induce tumors in laboratory animals. Nitrosamines may disturb the delicate balance between cell proliferation, growth arrest, and apoptosis. A novel paradigm of cell regulation via nAChR has been discovered in studies of SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein)-1 and -2. Experimental results suggest that SLURP-1 and -2 regulate keratinocyte proliferation, apoptosis, and differentiation. Most importantly, SLURPs and professional nicotinic antagonists can abolish, in part, the abilities of NNK and NNN to cause tumorigenic transformation of immortalized keratinocytes. Learning the pharmacology of the nitrosamine vs. SLURP action on epithelial cells may help develop an effective anti-cancer treatment and prevention programs wherein hazardous effects of tobacco products are anticipated, or even abolished, by a pharmacologic ligand of the specific nicotinic receptor acting as an antidote.


Variation between populations and local adaptation in acanthocephalan-induced parasite manipulation.
Many trophically transmitted parasites manipulate their intermediate host phenotype, resulting in higher transmission to the final host. However, it is not known if manipulation is a fixed adaptation of the parasite or a dynamic process upon which selection still acts. In particular, local adaptation has never been tested in manipulating parasites. In this study, using experimental infections between six populations of the acanthocephalan parasite Pomphorhynchus laevis and its amphipod host Gammarus pulex, we investigated whether a manipulative parasite may be locally adapted to its host. We compared adaptation patterns for infectivity and manipulative ability. We first found a negative effect of all parasite infections on host survival. Both parasite and host origins influenced infection success. We found a tendency for higher infectivity in sympatric versus allopatric combinations, but detailed analyses revealed significant differences for two populations only. Conversely, no pattern of local adaptation was found for behavioral manipulation, but manipulation ability varied among parasite origins. This suggests that parasites may adapt their investment in behavioral manipulation according to some of their host's characteristics. In addition, all naturally infected host populations were less sensitive to parasite manipulation compared to a naive host population, suggesting that hosts may evolve a general resistance to manipulation.


Fibrinolysis in multisystem trauma patients.
Changes in the fibrinolytic system may lead to coagulation disorders in acute trauma patients. This study examined fibrin degradation by measuring D-dimer crosslinked fibrin degradation products (indicates hypercoagulability), plasminogen activators (fibrinolysis), and antithrombin III in 42 adult trauma patients and correlated these data with injury severity, types of injury, complications, and clinical tests of coagulation. Hypercoagulability and suppression of fibrinolysis were seen in most patients and were not correlated with severity of injury. These changes appeared most severe in patients with nervous system injury. Several patients with less severe injuries but evidence of hypercoagulability developed clinical evidence of pathologic thrombosis. Latex agglutination of D-dimer provides a rapid test of fibrinolysis that may be clinically useful in the management of trauma patients who cannot be easily studied for thrombosis.


Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study.
The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. Boehringer Ingelheim.


Adherence to Measuring What Matters: Description of an Inpatient Palliative Care Service of an Urban Teaching Hospital.
Benefits of palliative care have been extensively described; however, reports on adherence to national quality indicators are limited. This study focuses on describing the characteristics of patients who were seen at an urban academic hospital and their care team's adherence to 5 out of 10 Measuring What Matters (MWM) quality indicators. Retrospective chart review Setting/Subjects: Patients seen by inpatient palliative care service from January 2014 to December 2015 in an urban academic hospital. Patient age, gender, ethnicity, disease category, discharge end point, life-sustaining preferences, surrogate decision-maker documentation, and initial palliative assessment were analyzed using descriptive, parametric, and nonparametric statistics. During two years, 1272 patients were seen by the inpatient palliative care service. Fifty-one percent of patients were male, with an average age of 68 years. The majority were Caucasian (57%) and African American (41%). Life-limiting illnesses included were cancer, complex chronic illnesses, and gastrointestinal illness. Adherence to comprehensive palliative care assessment was measured at 64%; initial visit assessment for physical symptoms was 38%; code status preference was 99%; care consistent with preference in vulnerable elders was 99%; and surrogate documentation was noted at 33%. Compared to hospital patients discharged without hospice, patients discharged with hospice care had consults with higher adherence to comprehensive assessment and surrogate documentation quality standards (p < 0.05). Adherence to MWM measures was variable. Subjects discharged with hospice services were more likely to receive comprehensive assessment within 5 days of admission and surrogate documentation compared to those subjects without hospice care.


Gene association analysis of an osteopontin polymorphism and ketosis resistance in dairy cattle.
The aim of this study was to identify the c.495C > T polymorphism within exon 1 of the osteopontin gene (OPN), and to analyze its association with susceptibility to ketosis in Polish Holstein-Friesian (HF) cows. The study utilized blood samples from 977 HF cows, for the determination of β-hydroxybutyric acid (BHB) and for DNA isolation. The c.495C > T polymorphism of the bovine osteopontin gene was determined by PCR-RFLP. The CT genotype (0.50) was deemed the most common, while TT (0.08) was the rarest genotype. Cows with ketosis most often had the CC genotype, while cows with the TT genotype had the lowest incidence of ketosis. To confirm the relationship between the genotype and ketosis in cows, a weight of evidence (WoE) was generated. A very strong effect of the TT genotype on resistance to ketosis was demonstrated. The distribution of the ROC curve shows that the probability of resistance to ketosis is > 75% if cows have the TT genotype of the OPN gene (cutoff value is 0.758). Results suggest that TT genotype at the c.495C > T locus of the OPN gene might be effective way to detect the cows with risk of ketosis.


The maternal erotic transference.
After reviewing literature on gender and erotic transferences, which have often been treated as primarily problematic, this paper offers a positive and transformational view of aspects of what is called the maternal erotic transference (MET). Rooted in mother and baby's earliest sensual contacts, it manifests in concrete transferences to the real parts of the body of the therapist; its expressions are typically inhibited as preverbal and/or defended against out of shame and fear of humiliation. Analysts of both genders who have access to their own maternal erotic countertransferences and their patients' matching transferences may enable their patients' acceptance of and immersion in the maternal erotic transference in its loving and sado-masochistic permutations and thus foster the making of a sense of wholeness, and connectedness to living. Experienced thus, MET may herald the transition in the analysis from a dyadic to a triadic oedipal phase animated by accessible pre-oedipal aggressivity and sensuality.


Structural changes accompanying enzymatic activation of human Hageman factor.
The structure of Hageman factor, isolated from human plasma, was analyzed before and after enzymatic activation. The purified molecule is a single polypeptide chain of 80,000 molecular weight (mol wt) sedimenting at 4.5S. An amino acid analysis has been performed. The concentration of Hageman factor in normal human plasma was found to be 29 mug/ml with variation between individuals ranging from 15 to 47 mug/ml. Treatment of the molecule with kallikrein, plasmin, or trypsin resulted in cleavage at two primary sites, yielding fragments of 52,000, 40,000, and 28,000 mol wt. No further changes occurred in the fragments with subsequent reduction. Prekallikrein-activating ability was associated exclusively with the 28,000 moiety.


Quantum-inspired encoding enhances stochastic sampling of soft matter systems.
Quantum advantage in solving physical problems is still hard to assess due to hardware limitations. However, algorithms designed for quantum computers may engender transformative frameworks for modeling and simulating paradigmatically hard systems. Here, we show that the quadratic unconstrained binary optimization encoding enables tackling classical many-body systems that are challenging for conventional Monte Carlo. Specifically, in self-assembled melts of rigid lattice ring polymers, the combination of high density, chain stiffness, and topological constraints results in divergent autocorrelation times for real-space Monte Carlo. Our quantum-inspired encoding overcomes this problem and enables sampling melts of lattice rings with fixed curvature and compactness, unveiling counterintuitive topological effects. Tackling the same problems with the D-Wave quantum annealer leads to substantial performance improvements and advantageous scaling of sampling computational cost with the size of the self-assembled ring melts.


Efficacy of Guardian Cap Soft-Shell Padding on Head Impact Kinematics in American Football: Pilot Findings.
Sport-related concussion prevention strategies in collision sports are a primary interest for sporting organizations and policy makers. After-market soft-shell padding purports to augment the protective capabilities of standard football helmets and to reduce head impact severity. We compared head impact kinematics [peak linear acceleration (PLA) and peak rotational acceleration (PRA)] in athletes wearing Guardian Cap soft-shell padding to teammates without soft-shell padding. Ten Division I college football players were enrolled [soft-shell padding (SHELL) included four defensive linemen and one tight end; non-soft-shell (CONTROL) included two offensive linemen, two defensive linemen, and one tight end]. Participants wore helmets equipped with the Head Impact Telemetry System to quantify PLA (g) and PRA (rad/s2) during 14 practices. Two-way ANOVAs were conducted to compare log-transformed PLA and PRA between groups across helmet location and gameplay characteristics. In total, 968 video-confirmed head impacts between SHELL (n = 421) and CONTROL (n = 547) were analyzed. We observed a Group x Stance interaction for PRA (F1,963 = 7.21; p = 0.007) indicating greater PRA by SHELL during 2-point stance and lower PRA during 3- or 4-point stances compared to CONTROL. There were no between-group main effects. Protective soft-shell padding did not reduce head impact kinematic outcomes among college football athletes.


Irinotecan combined with bolus 5-fluorouracil and folinic acid for metastatic colorectal cancer: is this really a dangerous treatment?
Rothenberg et al called for caution in the palliative use of irinotecan, 5-fluorouracil (5-FU) bolus and leucovorin (IFL schedule), because of early treatment related deaths in C89803 and N9741 studies. The objective of our multicenter phase II study was to evaluate the efficacy and safety of the combination of 5-FU bolus, folinic acid (FA) and irinotecan as first-line chemotherapy for metastatic colorectal cancer. From December 1999 to June 2002 138 patients (pts) were treated. The chemotherapy regimen was as follows: irinotecan 125 mg/m2 i.v. over 90 min and 5-FU 500 mg/m2 preceded by FA 20 mg/m2, both given by bolus, weekly, for 4 weeks every 6 weeks. Treatment continued until disease progression or unacceptable toxicity. Total number of administered cycles was 404. Average dose intensity was 75%. 47 out of 131 evaluable pts achieved a complete (n = 6) or partial (n = 41) response, leading to an overall response rate (RR) of 36% [95% confidence interval (CI) 24% to 48%], stable disease was registered in 50 (38%). The estimated median time to progression and survival were 6.5 months (95% CI 5.2-9.4) and 16.6 months (95% CI 15.1-19.3) respectively. Two-year survival was 35%. Toxicity was well manageable. In 18 (13.8%) pts the chemotherapy was stopped because of toxicity. Treatment related death was not observed. Close clinical monitoring, early recognition of toxicity, immediate therapeutic intervention are recommended for pts receiving IFL. In our experience this regimen has manageable toxicity and appropriate level of dose intensity and seems to be a good option for first-line therapy in metastatic colorectal cancer.


The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6.
Adenosine is an endogenous metabolite produced during hypoxia or inflammation. Previously implicated as an anti-inflammatory mediator in CD4(+) T cell regulation, we report that adenosine acts via dendritic cell (DC) A(2B) adenosine receptor (A(2B)AR) to promote the development of Th17 cells. Mouse naive CD4(+) T cells cocultured with DCs in the presence of adenosine or the stable adenosine mimetic 5'-(N-ethylcarboximado) adenosine resulted in the differentiation of IL-17- and IL-22-secreting cells and elevation of mRNA that encode signature Th17-associated molecules, such as IL-23R and RORγt. The observed response was similar when DCs were generated from bone marrow or isolated from small intestine lamina propria. Experiments using adenosine receptor antagonists and cells from A(2B)AR(-/-) or A(2A)AR(-/-)/A(2B)AR(-/-) mice indicated that the DC A(2B)AR promoted the effect. IL-6, stimulated in a cAMP-independent manner, is an important mediator in this pathway. Hence, in addition to previously noted direct effects of adenosine receptors on regulatory T cell development and function, these data indicated that adenosine also acts indirectly to modulate CD4(+) T cell differentiation and suggested a mechanism for putative proinflammatory effects of A(2B)AR.


Yeast Autolysis in Sparkling Wine Aging: Use of Killer and Sensitive Saccharomyces cerevisiae Strains in Co-Culture.
Sparkling wines produced by traditional method owe their characteristics to secondary fermentation and maturation that occur during a slow ageing in bottles. Yeast autolysis plays an important role during the sparkling wine aging. Using a combination of killer and sensitive yeasts is possible to accelerate yeast autolysis and reduce maturing time. killer and sensitive Saccharomyces cerevisiae strains, separately and in co-cultures, were inoculated in base wine and bottled on pilot-plant scale. Commercial Saccaromyces bayanus strain was also investigated. Protein free amino acid and polysaccharides contents and sensory analysis were determined on the wine samples at 3, 6 and 9 months of aging. Yeast autolysis that occurs during the production of sparkling wines, obtained with co-cultures of killer and sensitive strains, has influenced free amino acids, total protein and polysaccharides content after 3 months aging time: sparkling wines, produced without the use of these yeasts, have reached the same results only after 9 months aging time. These results demonstrate that killer and sensitive yeasts in co-culture can accelerate the onset of autolysis in enological conditions, and has a positive effect on the quality of the aroma and flavor of sparkling wine. This paper offers an interesting biotechnological method to reduce production time of sparkling wine with economical benefits for the producers. We revised all patents relating to sparkling wine considering only those of interest for our study.


Comprehensive vs. Assisted Management of Mood and Pain Symptoms (CAMMPS) trial: Study design and sample characteristics.
Pain is the most common presenting somatic symptom in medical outpatients, and depression and anxiety are the two most common mental disorders. They frequently co-occur, are under-treated, and result in substantial disability and reduced health-related quality of life. The Comprehensive vs. Assisted Management of Mood and Pain Symptoms (CAMMPS) study is a randomized comparative effectiveness trial designed to test the relative effectiveness of a lower-resource vs. a higher-resource technology-assisted intervention for the management of patients suffering from pain plus anxiety and/or depression. CAMMPS has enrolled 294 primary care patients with chronic pain plus comorbid anxiety and/or depression and randomized them to either: 1) Assisted Symptom Management (ASM) consisting of automated symptom monitoring by interactive voice recording or Internet and prompted pain and mood self-management; or 2) Comprehensive Symptom Management (CSM) which combines ASM with optimized medication management delivered by a nurse-physician specialist team and facilitated mental health care. Outcomes are assessed at baseline, 1, 3, 6, and 12months. The primary outcome is a composite pain-anxiety-depression (PAD) severity score. Secondary outcomes include individual pain, anxiety, and depression scores, health-related quality of life, disability, healthcare utilization, and treatment satisfaction. CAMMPS provides an integrated approach to PAD symptoms rather than fragmented care of single symptoms; coordinated symptom management in partnership with primary care clinicians and psychologists embedded in primary care; efficient use of health information technology; attention to physical and psychological symptom comorbidity; and the coupling of self-management with optimized medication management and facilitated mental health care. clinicaltrials.gov Identifier: NCT01757301.


UV Irradiation of Vaccinia Virus-Infected Cells Impairs Cellular Functions, Introduces Lesions into the Viral Genome, and Uncovers Repair Capabilities for the Viral Replication Machinery.
Vaccinia virus (VV), the prototypic poxvirus, encodes a repertoire of proteins responsible for the metabolism of its large dsDNA genome. Previous work has furthered our understanding of how poxviruses replicate and recombine their genomes, but little is known about whether the poxvirus genome undergoes DNA repair. Our studies here are aimed at understanding how VV responds to exogenous DNA damage introduced by UV irradiation. Irradiation of cells prior to infection decreased protein synthesis and led to an ∼12-fold reduction in viral yield. On top of these cell-specific insults, irradiation of VV infections at 4 h postinfection (hpi) introduced both cyclobutene pyrimidine dimer (CPD) and 6,4-photoproduct (6,4-PP) lesions into the viral genome led to a nearly complete halt to further DNA synthesis and to a further reduction in viral yield (∼35-fold). DNA lesions persisted throughout infection and were indeed present in the genomes encapsidated into nascent virions. Depletion of several cellular proteins that mediate nucleotide excision repair (XP-A, -F, and -G) did not render viral infections hypersensitive to UV. We next investigated whether viral proteins were involved in combatting DNA damage. Infections performed with a virus lacking the A50 DNA ligase were moderately hypersensitive to UV irradiation (∼3-fold). More strikingly, when the DNA polymerase inhibitor cytosine arabinoside (araC) was added to wild-type infections at the time of UV irradiation (4 hpi), an even greater hypersensitivity to UV irradiation was seen (∼11-fold). Virions produced under the latter condition contained elevated levels of CPD adducts, strongly suggesting that the viral polymerase contributes to the repair of UV lesions introduced into the viral genome. IMPORTANCE Poxviruses remain of significant interest because of their continuing clinical relevance, their utility for the development of vaccines and oncolytic therapies, and their illustration of fundamental principles of viral replication and virus/cell interactions. These viruses are unique in that they replicate exclusively in the cytoplasm of infected mammalian cells, providing novel challenges for DNA viruses. How poxviruses replicate, recombine, and possibly repair their genomes is still only partially understood. Using UV irradiation as a form of exogenous DNA damage, we have examined how vaccinia virus metabolizes its genome following insult. We show that even UV irradiation of cells prior to infection diminishes viral yield, while UV irradiation during infection damages the genome, causes a halt in DNA accumulation, and reduces the viral yield more severely. Furthermore, we show that viral proteins, but not the cellular machinery, contribute to a partial repair of the viral genome following UV irradiation.