Differences in brain function and changes with intervention in children with poor spelling and reading abilities.
Previous fMRI studies in English-speaking samples suggested that specific interventions may alter brain function in language-relevant networks in children with reading and spelling difficulties, but this research strongly focused on reading impaired individuals. Only few studies so far investigated characteristics of brain activation associated with poor spelling ability and whether a specific spelling intervention may also be associated with distinct changes in brain activity patterns. We here investigated such effects of a morpheme-based spelling intervention on brain function in 20 children with comparatively poor spelling and reading abilities using repeated fMRI. Relative to 10 matched controls, children with comparatively poor spelling and reading abilities showed increased activation in frontal medial and right hemispheric regions and decreased activation in left occipito-temporal regions prior to the intervention, during processing of a lexical decision task. After five weeks of intervention, spelling and reading comprehension significantly improved in the training group, along with increased activation in the left temporal, parahippocampal and hippocampal regions. Conversely, the waiting group showed increases in right posterior regions. Our findings could indicate an increased left temporal activation associated with the recollection of the new learnt morpheme-based strategy related to successful training.


The regulatory role of PDE4B in the progression of inflammatory function study.
Inflammation is a response of the body to external stimuli (eg. chemical irritants, bacteria, viruses, etc.), and when the stimuli are persistent, they tend to trigger chronic inflammation. The presence of chronic inflammation is an important component of the tumor microenvironment produced by a variety of inflammatory cells (eg. macrophages, neutrophils, leukocytes, etc.). The relationship between chronic inflammation and cancer development has been widely accepted, and chronic inflammation has been associated with the development of many cancers, including chronic bronchitis and lung cancer, cystitis inducing bladder cancer. Moreover, chronic colorectitis is more likely to develop into colorectal cancer. Therefore, the specific relationship and cellular mechanisms between inflammation and cancer are a hot topic of research. Recent studies have identified phosphodiesterase 4B (PDE4B), a member of the phosphodiesterase (PDEs) protein family, as a major cyclic AMP (cAMP) metabolizing enzyme in inflammatory cells, and the therapeutic role of PDE4B as chronic inflammation, cancer. In this review, we will present the tumors associated with chronic inflammation, and PDE4B potential clinical application.


A cost analysis of an emergency computerized tomography teleradiology system.
We carried out a cost analysis of a teleradiology system for emergency computerized tomography (CT) examinations. Teleradiology was implemented by connecting two spiral CT scanners in the University Hospital in Innsbruck and the Regional Hospital in Zwettl. It enabled the remote hospital in Zwettl to get fast and competent reports of emergency CT examinations when there was no specialist radiologist available. In 13 months' use for routine night and weekend service, the system proved fast and reliable. During the study period 121 emergency examinations of 116 patients were transmitted from Zwettl to Innsbruck. The fixed costs of teleradiology were for the ISDN connection and amounted to DM230 plus DM696/year rental. The average cost of one emergency CT examination by teleradiology was DM372 (range 308-453). One possible alternative, transporting the films by taxi for reporting elsewhere, was cheaper (estimated cost DM156), but would have been much slower. Another alternative, transporting the patient to the nearest central hospital for scanning, was much more expensive: DM524 by road or DM4667 by helicopter ambulance.


[Minimally invasive surgical treatment for venous leg ulcer].
To evaluate therapeutic effects of endovenous laser treatment (ELT) and subfascial endoscopic perforator surgery (SEPS) in the treatment of venous leg ulcer (VLU). ELT and SEPS were performed in 10 patients with VLU (involving 10 legs). Among them, external valvuloplasty was performed in 4 legs with deep venous valve insufficiency. Ulcer of the 10 legs healed within 10-60 days after the operation, and follow-up study ranging from 2 to 8 months with the average of 6 months revealed no recurrences. ELT combined with SEPS provides an effective approach for VLU treatment with minimal invasion, and when combined with external valvuloplasty, this approach may effectively reduce ulcer recurrence.


Adaptation and Implementation of a Transitional Care Protocol for Patients Undergoing Complex Abdominal Surgery.
Transitional care protocols are effective at reducing readmission for medical patients, yet no evidence-based protocols exist for surgical patients. A transitional care protocol was adapted to meet the needs of patients discharged to home after major abdominal surgery. The Coordinated-Transitional Care (C-TraC) protocol, initially designed for medical patients, was used as the initial framework for the development of a surgery-specific protocol (sC-TraC). Adaptation was accomplished using a modification of the Replicating Effective Programs (REP) model, which has four phases: (1) preconditions, (2) preimplementation, (3) implementation, and (4) maintenance and evolution. A random sample of five patients each month was selected to complete a phone survey regarding patient satisfaction. Preimplementation planning allowed for integration with current systems, avoided duplication of processes, and defined goals for the protocol. The adapted protocol specifically addressed surgical issues such as nutrition, fever, ostomy output, dehydration, drain character/output, and wound appearance. After protocol launch, the rapid iterative adaptation process led to changes in phone call timing, inclusion and exclusion criteria, and discharge instructions. Survey responders reported 100% overall satisfaction with the transitional care program. The adaptable nature of sC-TraC may allow for low-resource hospitals, such as rural or inner-city medical centers, to use the methodology provided in this study for implementation of local phone-based transitional care protocols. In addition, as the C-TraC program has begun to disseminate nationally across US Department of Veterans Affairs (VA) hospitals and rural health settings, sC-TraC may be implemented using the existing transitional care infrastructure in place at these hospitals.


Evaluation of Factors Affecting Size and Size Distribution of Chitosan-Electrosprayed Nanoparticles.
Size and size distribution of polymeric nanoparticles have important effect on their properties for pharmaceutical application. In this study, Chitosan nanoparticles were prepared by electrospray method (electrohydrodynamic atomization) and parameters that simultaneously affect size and/or size distribution of chitosan nanoparticles were optimized. Effect of formulation/processing three independent formulation/processing parameters, namely concentration, flow rate and applied voltage was investigated on particle size and size distribution of generated nanoparticles using a Box-Behnken experimental design. All the studied factors showed important effects on average size and size distribution of nanoparticles. A decrease in size and size distribution was obtainable with decreasing flow rate and concentration and increasing applied voltage. Eventually, a sample with minimum size and polydispersity was obtained with polymer concentration, flow rate and applied voltage values of 0.5 %w/v, 0.05 ml/hr and 15 kV, respectively. The experimentally prepared nanoparticles, expected having lowest size and size distribution values had a size of 105 nm, size distribution of 36 and Zeta potential of 59.3 mV. Results showed that optimum condition for production of chitosan nanoparticles with the minimum size and narrow size distribution was a minimum value for flow rate and highest value for applied voltage along with an optimum chitosan concentration.


[Anesthetic Management of a 69-year-old Patient with Eisenmenger Syndrome for Abdominoperineal Resection].
Although life expectancy of the patients with Eisenmenger syndrome (ES) is currently reported to be lower than 40 years, life span of the patients with ES may be extended because of development of medical care. According to recently reported middle-aged patients with ES undergoing non-cardiac surgeries, per-operative mortality and morbidity of the patients with ES undergoing non-cardiac surgeries may be lower than previously thought, and even elderly patients may be able to undergo major surgeries such as laparotomies for cancers. We described the anesthetic management of a 69-year-old patient with ES who had undergone abdominoperineal resection. In the anesthetic management it is important to maintain adequate blood volumne and systemic vascular resistance and this avoids increases of right-to-left shunt. Perioperative monitoring of pulmonary arterial pressure was useful for hemodynamic management. Good pain control and management of body temperature were also needed for a perioperative course with no adverse events. The appropriate anesthetic management of the 69-year-old patient with ES for abdominoperineal resection resulted in the successful perioperative course.


[Clinical effects of Fu Fang Ya Tong Ding on gingivitis and pericoronitis].
To evaluate the clinical effects of Fu Fang Ya Tong Ding on treatment of gingivitis and pericoronitis. 120 clinical patients with gingivitis or pericoronitis were randomly divided into 3 groups (40 patients in each group). After routine rinse treatment for all patients, patients in the test group were treated with Fu Fang Ya Tong Ding, patients in the positive group were treated with iodine glycerol, while that time patients in the negative group received no treatment anymore. Ten minutes after treatment, visual analogue scale (VAS) was used to record the severity of pain for each patient. 3 days and 7 days later, pain and inflammation degree were also recorded by pain three-degree scoring method and index of gingivitis. The total treatment effects were evaluated under a comprehensive clinical treatment standard. 10 minutes after treatment, 40.0% of patients in the test group had almost no pain, while no obvious reduction of pain was found in the control group. 3 days, 7 days after the treatment, 92.5%, 95.0% of patients in the test group had no pain, and 55.0%, 90.0% of patients in the positive group had no pain. In the negative group, there were 47.5% of patients which pain was still remained in 7 days. 7 days after treatment, gingival index in the test group reduced by 25.0% and 42.8% compared with the positive and negative groups (P<0.05). 3 days after treatment, 62.5%, 45.0% and 30.0% patients separately in the test, positive and negative groups manifested good effects under the comprehensive clinical treatment standard; after 7 days, 97.5%, 92.5% and 77.5% patients in the 3 groups manifested good effect. The group using Fu Fang Ya Tong Ding had better effects than groups using iodine glycerol or only applying routine rinsing treatment group (P<0.05). Fu Fang Ya Tong Ding can treat gingivitis and pericoronitis through significantly reducing inflammation and pain.


Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols.
The immune-enhancing effects of selenium (Se) supplementation make it a promising complementary and alternative medicine modality for boosting immunity, although mechanisms by which Se influences immunity are unclear. Mice fed low (0.08 mg/kg), medium (0.25 mg/kg), or high (1.0 mg/kg) Se diets for 8 wk were challenged with peptide/adjuvant. Antigen-specific CD4(+) T cell responses were increased in the high Se group compared with the low and medium Se groups. T cell receptor signaling in ex vivo CD4(+) T cells increased with increasing dietary Se, with all 3 groups differing from one another in terms of calcium mobilization, oxidative burst, translocation of nuclear factor of activated T cells, and proliferation. The high Se diet increased expression of interleukin (IL)-2 and the high affinity chain of the IL-2 receptor compared with the low and medium Se diets. The high Se diet skewed the T helper (Th)1/Th2 balance toward a Th1 phenotype, leading to higher interferon-gamma and CD40 ligand levels compared with the low and medium Se diets. Prior to CD4(+) T cell activation, levels of reactive oxygen species did not differ among the groups, but the low Se diet decreased free thiols compared with the medium and high Se diets. Addition of exogenous free thiols eliminated differences in CD4(+) T cell activation among the dietary groups. Overall, these data suggest that dietary Se levels modulate free thiol levels and specific signaling events during CD4(+) T cell activation, which influence their proliferation and differentiation.


Effectiveness of integrated Aedes albopictus management in southern Switzerland.
The exotic invasive tiger mosquito, Aedes albopictus, appeared in southern Switzerland in 2003. The spread of the mosquito has been surveyed constantly since then, and an integrated vector management (IVM) has been implemented to control its numbers. The control measures focus on the aquatic phase of the mosquito with removal of breeding sites and applications of larvicides in public areas whereas private areas are reached through extensive public information campaigns. Here, we evaluated the efficacy of the IVM. Since all the municipalities with Ae. albopictus in southern Switzerland are currently implementing the IVM, Italian municipalities just across the Swiss-Italian border, where Ae. albopictus is present but no coordinated intervention programme is in place, served as control. Ovitraps and adult female traps were used to measure mosquito abundance in 2019. Generalised mixed-effects models were used to model the numbers of Ae. albopictus eggs and adult females collected. These numbers of Ae. albopictus eggs were compared to the numbers of eggs collected in 2012 and 2013 in a previous assessment of the IVM, using a hurdle model. Mean numbers of Ae. albopictus eggs and adult females in 2019 were consistently higher in the municipalities not following an IVM programme. In these municipalities, there were about four times (3.8) more eggs than in the municipalities implementing an IVM programme. Also, the numbers of eggs and adult females increased steadily from the beginning of the Ae. albopictus reproductive season, reaching a peak in August. In contrast, the increase in numbers of Ae. albopictus was much more contained in the municipalities implementing an IVM programme, without reaching an evident peak. Comparison with data from 2012 and 2013 indicates that the gap between intervention and non-intervention areas may have almost doubled in the past 6 years. The results of the survey strongly support the efficacy of the IVM programme implemented in southern Switzerland compared to municipalities without defined control measures. With the constant implementation of an IVM, it appears possible to contain the numbers of Ae. albopictus at a manageable level, reducing the nuisance for the human population and the risk of arbovirus epidemics.


Visual deficit interventions in adult stroke and brain injury: a systematic review.
Visual deficits after cerebral injury are common. The variability in the types of injury sustained as well as their impact on function in the environment have produced multiple approaches at corrective intervention. To assess the effectiveness of these vision interventions, an extensive literature search was completed. The analysis of this review revealed some success with visual neglect disorders, but not enough evidence to comment definitively on interventions for hemianopsia, quadrantonopsia, diplopia, or convergence insufficiency. A lack of follow-up also limited efforts to assess the durability of documented gains. Additional research is necessary to clarify, quantify, and measure treatment outcomes for acquired visual dysfunction as well as to link laboratory testing to improvement in actual functioning for individuals in their environment.


Antioxidant activity of enzymatic extracts from Stellaria dichotoma.
The antioxidant properties of enzymatic extracts from Stellaria dichotoma were evaluated using seven carbohydrases (Promozyme, Celluclast, Maltogenase, Viscozyme, Termamyl, Dextrozyme, and AMG 300L) and five proteases (Protamex, Flavourzyme, Neutrase, pancreatic trypsin, and Alcalase) (all from Novo Co., Novozyme Nordisk, Bagsvaerd, Denmark) for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, hydroxyl radical, and alkyl radical scavenging activity using an electron spin resonance spectrometer. The DPPH radical scavenging activities of pancreatic trypsin and Celluclast extracts from S. dichotoma were the highest among various protease and carbohydrate extracts, and the 50% inhibitory concentration (IC(50)) values were 10.45 and 13.80 microg/mL, respectively. The Flavourzyme and Promozyme extracts of S. dichotoma showed the highest hydroxyl radical scavenging activities among the tested protease and carbohydrase extracts, with IC(50) values of 1.51 and 1.23 microg/mL, respectively. The S. dichotoma enzymatic extracts also exhibited alkyl radical scavenging activity in a dose-dependent manner. In addition, the ability of the enzymatic extracts to inhibit the oxidative damage of DNA was assessed in vitro by measuring the conversion of supercoiled pBR322 plasmid DNA to the open circular form. It was found that the enzymatic extracts could significantly and dose-dependently protect against hydroxyl radical-induced DNA damage. These results indicate that enzymatic extracts of S. dichotoma possess potent antioxidant activity.


The significance of antral follicle size prior to stimulation in predicting ovarian response in a multiple dose GnRH antagonist protocol.
Prediction of ovarian responses prior to stimulation is not only useful for patient counseling, but also important in tailoring the optimal dosage of gonadotrophin for individual patients. By prospectively study of 214 women undergoing in vitro fertilization and embryo transfer (IVF-ET) treatment, we obtained data supporting that antral follicle size could be an additional valuable predictive marker other than the antral follicle count (AFC) in predicting ovarian response. Our studies revealed that AFC achieved the best predictive value in relation to the number of oocyte obtained, followed by antral follicle size, basal follicle stimulating hormone (FSH) and body mass index (BMI). Unlike AFC, antral follicle size was noted to be negatively correlated with the dosage (R = -0.493) and duration (R = -0.465) of rFSH stimulation. Antral follicle size was also found with higher negative regression coefficient (B = -0.661) as compared with that of basal FSH concentration (B = -0.326) and BMI (b = -0.281). More importantly, women with antral follicle size 6-7 mm showed significantly higher AFC, oocytes retrieved, fertilized oocytes and grade I/II embryos along with much lower transfer cycle cancellation rate (7.5% vs. 16-17%). Together, our data suggest that basal antral follicle size could be a valued predictive marker in women with IVF-ET treatment, in which women with antral follicle size 6-7 mm are likely predisposed to better IVF-ET outcomes.


Ontogeny and localization of the cells produce IL-2 in healthy animals.
IL-2 is a growth factor for activated T cells and is required for maintenance of naturally arising regulatory T cells (nTregs). Mice defective in IL-2/IL-2 receptor signaling pathways have impaired nTregs and suffer from lymphoproliferative disorders, suggesting that IL-2 is present and functional in healthy animals. However, the cellular source of IL-2 is currently unknown. To determine which cells produce IL-2 in healthy animals, we established mice carrying cre gene knock in at the il-2 locus (termed IL-2(cre)). When IL-2(cre) mice were crossed with EGFP reporter mice, EGFP was exclusively expressed by a fraction of CD4 T cells present in both lymphoid and non-lymphoid tissues. Live imaging of IL-2(cre) mice that carry the luciferase reporter showed concentrated localization of luciferase(+) cells in Peyer's patches. These cells were not observed in new born mice but appeared within 3days after birth. Reduction of antigen receptor repertoire by transgene expression reduced their number, indicating that recognition of environmental antigens is necessary for generation of these IL-2 producers in healthy animals. A substantial fraction of EGFP(+) cells also produce IL-10 and IFN-γ, a characteristic profile of type 1 regulatory T cells (Tr1). The data suggest that a group of Tr1 cells have addition roles in immune homeostasis by producing IL-2 along with other cytokines and help maintaining Tregs.


Octaphlorethol A, a novel phenolic compound isolated from Ishige foliacea, protects against streptozotocin-induced pancreatic β cell damage by reducing oxidative stress and apoptosis.
Pancreatic β cells are extremely sensitive to oxidative stress, which probably has an important role in β cell damage in diabetes. The protective effect of octaphlorethol A (OPA), a novel phenolic compound isolated from Ishige foliacea, against streptozotocin (STZ)-induced pancreatic β cell damage was investigated using a rat insulinoma cell line (RINm5F pancreatic β cells). Pretreatment with OPA decreased the death of STZ-treated pancreatic β cells at concentrations of 12.5 μg/ml or 50 μg/ml, and reduced the generation of thiobarbituric acid reactive substances and intracellular reactive oxygen species in a dose-dependent manner in STZ-treated pancreatic β cells. In addition, the OPA pretreatment increased the activities of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase in STZ-treated pancreatic β cells. Moreover, OPA treatment elevated the level of insulin, which was reduced by STZ treatment, and protected pancreatic β cells against damage under STZ-treated conditions. These effects were mediated by suppressing apoptosis and were associated with increased anti-apoptotic Bcl-xL expression and reduced pro-apoptotic Bax and cleaved caspase-3 expression. These findings indicate that OPA may be useful as a potential pharmaceutical agent to protect against pancreatic β cell damage caused by oxidative stress associated with diabetes.


Psychohistorical Hypotheses on Japan's History of Hostility Towards China.
The accelerating tensions and military posturing between Japan and China have created a serious crisis with a danger of a catastrophic war. The purpose of this paper is to summarize the events of the current crisis, and to put it in the context of Japan's long history of hostility to China and repeated attempts at conquest. The historical record shows that Japan has attacked China at least seven times, even though China has never attacked Japan. The irrationality of Japan's behavior is demonstrated by the repetition of this hostile behavior despite the enormous human and economic costs that Japan has suffered because of it. The irrationality of Japan's militarism suggests that psychological explanations may be required to understand this phenomenon. Several hypotheses are proposed, including 1) projected paranoid aggression, 2) collective Zeigarnik compulsion, 3) perceived weakness exciting aggression, 4) national inferiority feelings, 5) cultural narcissism, and 6) Oedipal-like hatred of a parent culture.


Identical excimer laser PTK treatments in rabbits result in two distinct haze responses.
To obtain objective light-scattering measurements to test a hypothesis that identical PTK treatments cause distinct low- and high-level light-scattering responses in rabbit corneas. An excimer laser was used to produce identical 6-mm diameter phototherapeutic keratectomy treatments (PTK) in 32 pigmented rabbits. Eyes were treated by performing a 40-microm epithelial ablation, followed by a 100-mum stromal PTK. Objective scattering measurements were made before treatment, weekly up to 5 weeks, and then biweekly to 9 weeks. Confocal microscopy was performed on several corneas at 4 and 7 weeks. Mean scattering levels split into distinct low- and high-scattering groups 2 weeks after treatment and remained distinct until week 7 (P < 0.003). Scattering in the low group reached a broad peak that lasted from weeks 2 to 4 at approximately 3 times the pretreatment level. Scattering in the high group peaked at 3 weeks at approximately 12 times the pretreatment level. Scattering levels diminished after reaching their peaks. Confocal images showed a band of highly reflective material in the anterior stroma that extended much deeper in corneas from the high group. The reflective band in the highly scattering corneas obscured the posterior stroma from view for up to 5 weeks. Quantitative scattering data obtained with the scatterometer suggest that identical PTK treatments indeed result in distinct low- and high-level light-scattering responses in rabbits.


Sclareol induces cell cycle arrest and ROS-mediated apoptosis and ferroptosis in lung adenocarcinoma cells.
Sclareol (SC) has shown significant anticancer activity against breast and colon cancers among others. However, its ability to precipitate similar anticancer effects in lung cancer has yet to be investigated. To address this issue, SC-treated lung adenocarcinoma cells (A549) were assessed for viability and functional competence as well as the expression of genes related to apoptosis and cell cycling. Our results demonstrated that SC treatment inhibited A549 cell clonogenic features and reduced their migration and invasion potential in a dose-dependent manner. Mechanistically, SC treatment downregulated the expression of cyclin D1 and survivin and upregulated that of p21 and p16, which was associated with a significant increase in the percentage of SubG0 cells. SC treatment is also associated with the induction of both the extrinsic and intrinsic apoptotic pathways, as evidenced by the increased expression and splitting of PARP1 and procaspases 3 and 9 and the reduced expression of antiapoptotic proteins Bcl-2 and Bcl-xL. Increased cell death in SC-treated cells is likely to have resulted from the induction of ferroptosis as suggested by the reduced expression of FPN and the inhibition of the anti-ferroptosis regulator GPX4. In conclusion, the data presented here suggest that SC can reduce lung carcinoma cell growth and metastasis and promote cell death.


Active release of pneumolysin prepores and pores by mammalian cells undergoing a Streptococcus pneumoniae attack.
Streptococcus pneumoniae is a potent human pathogen. Its pore-forming exotoxin pneumolysin is instrumental for breaching the host's epithelial barrier and for the incapacitation of the immune system. Using a combination of life imaging and cryo-electron microscopy we show that pneumolysin, released by cultured bacteria, is capable of permeabilizing the plasmalemma of host cells. However, such permeabilization does not lead to cell lysis since pneumolysin is actively removed by the host cells. The process of pore elimination starts with the formation of pore-bearing plasmalemmal nanotubes and proceeds by the shedding of pores that are embedded in the membrane of released microvesicles. Pneumolysin prepores are likewise removed. The protein composition of the toxin-induced microvesicles, assessed by mass spectrometry, is suggestive of a Ca(2+)-triggered mechanism encompassing the proteins of the annexin family and members of the endosomal sorting complex required for transport (ESCRT) complex. S. pneumoniae releases sufficient amounts of pneumolysin to perforate the plasmalemma of host cells, however, the immediate cell lysis, which is frequently reported as a result of treatment with purified and artificially concentrated toxin, appears to be an unlikely event in vivo since the toxin pores are efficiently eliminated by microvesicle shedding. Therefore the dysregulation of cellular homeostasis occurring as a result of transient pore formation/elimination should be held responsible for the damaging toxin action. We have achieved a comprehensive view of a general plasma membrane repair mechanism after injury by a major bacterial toxin.


Viral etiology of acute respiratory infections in infants and young children.
114 children with acute respiratory infections were investigated to detect the viral etiological agents. The following methods were used: the direct immunofluorescence technique for the rapid diagnosis from tracheobronchial aspirates and the serological reactions--hemaglutinoinhibition and complement fixation reaction--to determine the increase of antibodies titres. Of 55.2% respiratory infections with a viral etiology, 60.3% represent acute infections of the lower respiratory tract. Due to the influenza epidemic reported between October 1996 and February 1997 (with a higher number of cases than in the last 5 years), most viral respiratory infections were caused by influenza viruses (57.14%). The direct immunofluorescence technique proved to be sensitive and specific in detecting the viral etiological agents which caused respiratory infections. Thus, using this technique, a positive diagnosis was made in 68.2% of cases, of which 49.2% were positive by the hemagglutination and complement fixation reactions, too. The test specificity could have been higher if the pathological products had been prelevated within the first three days after the onset of the disease.


Development of tailored nutrition information messages based on the transtheoretical model for smartphone application of an obesity prevention and management program for elementary-school students.
Easy access to intervention and support for certain behaviors is important for obesity prevention and management. The available technology such as smartphone applications can be used for intervention regarding healthy food choices for obesity prevention and management in elementary-school students. The transtheoretical model (TTM) is comprised of stages and processes of change and can be adopted to tailored education for behavioral change. This study aims to develop TTM-based nutrition contents for mobile applications intended to change eating behaviors related to weight gain in young children. A synthesized algorithm for tailored nutrition messages was developed according to the intake status of six food groups (vegetables, fruits, sugar-sweetened beverages, fast food and instant food, snacks, and late-night snacks), decision to make dietary behavioral changes, and self-confidence in dietary behavioral changes. The messages in this study were developed from December 2014 to April 2015. After the validity evaluation of the contents through expert consultation, tailored nutrition information messages and educational contents were developed based on the TTM. Based on the TTM, stages of subjects are determined by their current intake status, decision to make dietary behavioral changes, and self-confidence in dietary behavioral changes. Three versions of tailored nutrition messages at each TTM stage were developed so as to not send the same messages for three weeks at most, and visual materials such as figures and tables were developed to provide additional nutritional information. Finally, 3,276 tailored nutrition messages and 60 nutrition contents for applications were developed. Smartphone applications may be an innovative medium to deliver interventions for eating behavior changes directly to individuals with favorable cost-effectiveness. In addition, using the TTM for tailored nutrition education for healthy eating is an effective approach.


Clinicopathological spectrum of snake bite-induced acute kidney injury from India.
To study the clinico-pathological spectrum of snake bite-induced acute kidney injury (AKI). A retrospective study of patients admitted at Indira Gandhi Medical College Hospital, Shimla with snake bite-induced AKI from July 2003 to June 2016. Medical records were evaluated for patient's information on demographic, clinical characteristics, complications and outcome. Outcomes of duration of hospital stay, requirement for intensive care unit support, treatment with dialysis, survival and mortality were analyzed. The survival and non survival groups were compared to see the difference in the demographic factors, clinical characteristics, laboratory results, and complications. In patients subjected to kidney biopsy, the findings of histopathological examination of the kidney biopsies were also analyzed. One hundred and twenty-one patients were diagnosed with snake bite-induced AKI. Mean age was 42.2 ± 15.1 years and majority (58%) were women. Clinical details were available in 88 patients. The mean duration of arrival at hospital was 3.4 ± 3.7 d with a range of 1 to 30 d. Eighty percent had oliguria and 55% had history of having passed red or brown colored urine. Coagulation defect was seen in 89% patients. The hematological and biochemical laboratory abnormalities were: Anemia (80.7%), leukocytosis (75%), thrombocytopenia (47.7%), hyperkalemia (25%), severe metabolic acidosis (39.8%), hepatic dysfunction (40.9%), hemolysis (85.2%) and rhabdomyolysis (68.2%). Main complications were: Gastrointestinal bleed (12.5%), seizure/encephalopathy (10.2%), hypertension, pneumonia/acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (9.1% each), hypotension and multi organ failure (MOF) (4.5% each). Eighty-two percent patients required renal replacement therapy. One hundred and ten (90.9%) patient survived and 11 (9.1%) patients died. As compared to the survival group, the white blood cell count (P = 0.023) and bilirubin levels (P = 0.006) were significant higher and albumin levels were significantly lower (0.005) in patients who died. The proportion of patients with pneumonia/ARDS (P = 0.001), seizure/encephalopathy (P = 0.005), MOF (P = 0.05) and need for intensive care unit support (0.001) was significantly higher and duration of hospital stay was significantly shorter (P = 0.012) in patients who died. Kidney biopsy was done in total of 22 patients. Predominant lesion on kidney biopsy was acute tubular necrosis (ATN) in 20 (91%) cases. In 11 cases had severe ATN and in other nine (41%) cases kidney biopsy showed features of ATN associated with mild to moderate acute interstitial nephritis (AIN). One patient only had moderate AIN and one had patchy renal cortical necrosis (RCN). AKI due to snake bite is severe and a high proportion requires renal replacement therapy. On renal histology ATN and AIN are common, RCN is rare.


Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis.
Infection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (βHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of βHPVs in actinic keratoses than in cancerous lesions, it is currently discussed that these viruses play a carcinogenic role in cancer initiation. In vitro assays performed to characterize the cell transforming activities of high-risk HPV types of genus alphapapillomavirus have markedly contributed to the present knowledge on their oncogenic functions. However, these assays failed to detect oncogenic functions of βHPV early proteins. They were not suitable for investigations aiming to study the interactive role of βHPV positive epidermis with mesenchymal cells and the extracellular matrix. This review focuses on βHPV gene functions with special focus on oncogenic mechanisms that may be relevant for skin cancer development.


Association between socioeconomic position and the prevalence of type 2 diabetes in Ghanaians in different geographic locations: the RODAM study.
The prevalence of diabetes has been shown to be socially patterned but the direction of the association in low-income countries and among migrant populations in Europe has varied in the literature. This study examined the association between socioeconomic position (SEP) and diabetes in Ghanaians in Europe and in Ghana. Data were derived from the multicentre Research on Obesity and Diabetes among African Migrants (RODAM) study of Ghanaian adults aged 25-70 years residing in Europe (Amsterdam, Berlin and London) and in urban and rural Ghana. Educational attainment (elementary, secondary or higher) and occupational class (low or high) were used as indicators of SEP. Age-standardised prevalence of diabetes and prevalence ratios were evaluated separately for men and women of different SEP in Ghana and Europe. A total of 5290 participants were included in the analyses. The prevalence of diabetes decreased with increasing level of education in Ghanaian men and women in Europe and in men in urban Ghana, whereas diabetes prevalence increased with increasing level of education in men and women in rural Ghana. The association between occupational class and the prevalence of diabetes followed a less consistent pattern in men and women in the different locations. The association of diabetes and SEP differed in rural Ghana compared with urban settings in Ghana and Europe and comparing men and women, highlighting the complex interaction of SEP and the development of diabetes. These findings have important implications for diabetes prevention strategies in Ghanaians in different locations.


A Multicenter Retrospective Review of Pediatric Leydig Cell Tumor of the Testis.
Leydig cell tumors (LCTs) are rare tumors arising from testosterone-producing Leydig cells. Although LCTs are usually benign, malignancy has been reported in 10% of cases in adults, and local recurrence or metachronous tumors of the contralateral testis have been described. Radical orchiectomy is the current standard of care. We report on 12 children with LCT at 3 institutions between 2000 and 2016. Presenting symptoms included precocious puberty, palpable testicular mass, and scrotal swelling. Radical orchiectomy was performed in 9 patients. Three patients were treated with enucleation. All patients were alive at last follow-up without evidence of local recurrence or metastasis.


Mitogenic stimulation of malignant B cells Waldenstrøm's macroglobulinaemia: secretion of monoclonal IgM by in vitro-induced plasmablasts.
The monoclonal B cells present in the blood of three patients with Waldenstrøm's macroglobulinaemia were analysed according to phenotype and function. As a marker for the monoclonal nature of the detected immunoglobulin (Ig) molecules, the kappa/lambda-ratio (two patients) or the presence of idiotypic (Id) determinants (one patient) were used. With double immunofluorescence it was shown that the neoplastic blood B cells were heterogeneous in respect to maturation stage. In addition to B cells carrying membrane bound IgM and IgD (mIgM+/IgD+), both mIgM+/IgD- and cytoplasmic IgM+ blastoid cells could be detected in the blood of the patients. This heterogeneity was also reflected in the responses of the monoclonal B cells upon stimulation with mitogens and T cell factors. B blastoid cells and IgM secretion could be induced after in vitro culture in the presence of Staphylococcus aureus, Pokeweed mitogen or a combination of both mitogens. It was shown that also T cell factors were effective in inducing monoclonal B cell differentiation.


The Effectiveness of a Parents as Teachers Home Visitation Program on School Readiness: An Application of Complier Average Causal Effect Analysis.
The purpose of this study is to evaluate an encouragement trial of a Parents as Teachers (PAT) home visitation intervention on the school readiness of preschool children using an innovative analysis to address issues of selective enrollment. Families were given the opportunity to enroll in a PAT program through a randomized lottery. The PAT program is assessed using standardized measures of school readiness before and after the two-year program. A comparison of three different analyses is used to evaluate the program - Average Treatment Effect (ATE) analysis, Intent-to-Treat (ITT) analysis, and Complier Average Causal Effect (CACE) analysis. CACE is an innovative analysis developed specifically to diagnose bias arising from selective enrollment in the context of an encouragement trial. All three analyses (ATE, ITT, and CACE) provide statistically significant evidence of an effective PAT program. However, the effect sizes for the CACE analysis are over twice as large as the other two analyses. The Cohen's D for CACE is .934 compared to .424 for ATE and .381 for ITT. This study provides evidence of an effective PAT program. The comparison of ATE, ITT, and CACE analyses reveals the potential for meaningful under-reporting of the program's impact if selective enrollment is ignored. CACE analysis demonstrates how selective enrollment can bias evaluations of home visitation interventions in general.


Cell culture assay for toxigenic Pasteurella multocida from atrophic rhinitis of pigs.
A toxin produced by strains of Pasteurella multocida isolated from pigs with atrophic rhinitis caused a cytopathic effect in cell cultures derived from embryonic bovine lung. The toxin was produced during the late logarithmic phase of bacterial growth and inactivated by heating for 30 minutes at 56 degrees C. The cell culture assay was reproducible and 10(3) to 10(4) times more sensitive than a lethal assay in BALB/c mice. There was complete agreement between results in the two tests with 76 isolates of P multocida. Neutralising activity was demonstrated in both assays with sera from infected gnotobiotic piglets. It was concluded that embryonic bovine lung cell cultures provided a sensitive in vitro test for the differentiation of toxigenic from non toxigenic isolates of P multocida. The assay could be used in diagnostic laboratories and for characterisation of the toxin.


Motivation to Learn.
Learners are more likely to remember what they study if they are motivated to do so. Such motivation can be externally driven by prospective rewards, but also intrinsically driven by curiosity. The present research focused on the role of curiosity during intentional learning. We examined the potential mnemonic benefit of curiosity, whether this benefit is undermined when learners are externally motivated to learn by rewards, and whether it can be attributed to increased study time for information they are more curious about. In two experiments, participants were presented with trivia questions, rated their level of curiosity about each question, and then studied the answers, either with or without a prospect of reward for correct recall on a subsequent test. Study time was either fixed (Experiment 1) or self-paced (Experiment 2). Performance on a memory test 1 week later suggested that curiosity enhanced long-term retention, and that rewards did not undermine the benefit of curiosity. When learning was self-paced, study time increased with curiosity but did not account for the effect of curiosity on memory. The results highlight the important role curiosity plays in learning and suggest that curiosity and rewards can be used together effectively to promote students' learning.


Prevalence of drug resistance in human immunodeficiency virus type 1-infected treatment-naive children in Pune, India.
Abstract We report the presence of drug resistance mutations in 7.4% (2/27) of the treatment-naive, HIV-1-infected children in Pune, India, who had HIV-1 RNA levels >1,000 copies/ml. Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, namely A98G and K103N, were observed in two separate sequences. In addition, three study sequences displayed three separate HIV-1 protease minor resistance mutations-L10I, A71T, and T74S. These preliminary data from Pune, India, reporting the presence of HIVDR in treatment-naive, HIV-1-infected children, reinforces the need to conduct large-scale studies to assess the prevalence of primary HIVDR in the pediatric population, which in turn will aid in planning protocols and policies related to antiretroviral treatment for the pediatric population.


Surgical outcomes of parathyroidectomy for secondary hyperparathyroidism resistant to calcimimetic treatment: A retrospective single-center cohort study.
To evaluate the surgical outcomes of parathyroidectomy (PTx) for secondary hyperparathyroidism (SHPT) resistant to calcimimetic treatment, we retrospectively studied 187 patients with SHPT who had no history of calcimimetic treatment (NCMT) (NCMT group) and 186 patients with SHPT who were resistant to calcimimetic treatment (RCMT) (RCMT group). Success rate and operative time of PTx were compared among the two groups. Operative time was significantly longer in the RCMT group than in the NCMT group (180 vs 158 minutes, P < .001), but the difference was attenuated after multivariate adjustment including the weight of the largest parathyroid gland. No significant differences were observed in success rate of PTx (90.9% vs 91.4%, P = 1.000) between the two groups. In patients with SHPT who are resistant to calcimimetic treatment, operative time could be elongated but success rate of PTx remains unchanged.


Pitfalls in non-therapeutic research in children.
Research has brought significant medical advances in modern times benefiting virtually all people. Children as a class should not be excluded from research studies. However, non-therapeutic research is potentially problematic in children because they must be afforded special protection from harm and exploitation by care-givers, researchers, and institutional review boards. An article in this month's journal provides an opportunity for a systematic analysis using the methodology provided by the United States Code of Federal Regulations. The research design of this particular study does not appear to stand up to the requirements of the Code.


Noninvasive Assessment of Internal and External Player Load: Implications for Optimizing Athletic Performance.
Heishman, AD, Curtis, MA, Saliba, E, Hornett, RJ, Malin, SK, and Weltman, AL. Noninvasive assessment of internal and external player load: implications for optimizing athletic performance. J Strength Cond Res 32(5): 1280-1287, 2018-Few data exist that assess athlete tracking and monitoring for the development of strategies to optimize performance and reduce fatigue in elite athletes. The purpose of the present study was to assess the efficacy of external load and internal stress monitoring as assessment tools for examining a performance index of fatigue. A retrospective analysis was performed on data collected over the course of the preseason in 10 elite male NCAA Division 1 basketball players. Internal stress was assessed using Omegawave Technology readiness scores and compared with the performance index of countermovement jump (CMJ). The external load that accumulated during the previous practice, quantified by PlayerLoad (PL; Catapult), was compared with CMJ values and Omegawave scores. The results indicated that high, compared to low CNS Omegawave Readiness Scores (6.7 ± 05.1, 4.5 ± 1.2 AU; p < 0.001), were associated with increased CMJ (62.1 ± 6.5 vs. 59.4 ± 6.6 cm; p = 0.05), Power (6,590 ± 526.7 vs. 6,383.5 ± 606.8 W; p = 0.05), Omegawave Overall Readiness (5.8 ± 1.1 vs. 5.0 ± 0.7 AU; p = 0.05), and Omega Potential (Omega) (21.3 ± 6.3 vs. 9.9 ± 20.8 mV; p = 0.07). An increased PL during the previous exposure was associated with decreased CMJ (58.7 ± 4.7 cm vs. 60.4 ± 5.1 cm; p < 0.001) and increased TRIMP (135.1 ± 35.9 vs. 65.6 ± 20.0 AU; p < 0.001), and duration (115.4 ± 27.1 vs. 65.56 ± 20.0 minutes; p = < 0.001) despite no differences in Omegawave CNS Readiness scores. We conclude that Omegawave and Catapult technologies provide independent information related to performance and may be effective tools for monitoring athlete performance.


Mixed valence Mn(II)/Mn(III) [3 x 3] grid complexes: structural, electrochemical, spectroscopic, and magnetic properties.
Mn(II)9 grid complexes with a [Mn9(mu-O)12] core, obtained by self-assembly of a series of tritopic picolinic dihydrazone ligands with Mn(II) salts, have been oxidized by both chemical and electrochemical methods to produce mixed oxidation state systems. Examples involving [Mn(III)3Mn(II)6] and [Mn(III)4Mn(II)5] combinations have been produced. Structures are reported for [Mn9(2poap-2H)6](NO3)6.14H2O (1), [Mn9(2poap-2H)6](ClO4)10.10H2O (3), and [Mn9(Cl2poap-2H)6](ClO4)9.14H2O.3CH3CN (10). Structural studies show distinct contraction of the corner grid sites on oxidation, with overall magnetic properties consistent with the resulting changes in electron distribution. Antiferromagnetic exchange in the outer ring of eight metal centers creates a ferrimagnetic subunit, which undergoes antiferromagnetic coupling to the central metal, leading to S=1/2 (3) and S2/2 (10) ground states. Two moderately intense absorptions are observed on oxidation of the Mn(II) grids in the visible and near-infrared (1000 nm, 700 nm), associated with charge transfer transitions (LMCT, IVCT respectively). Compound 1 crystallized in the monoclinic system, space group P2 1/n, with a=21.308(2) A, b=23.611(2) A, c=32.178(3) A, beta=93.820(2) degrees . Compound 3 crystallized in the tetragonal system, space group I, with a=b=18.44410(10) A, c = 24.9935(3) A. Compound 10 crystallized in the triclinic system, space group P, with a=19.1150(10) A, b=19.7221(10) A, c=26.8334(14) A, alpha=74.7190(10) degrees, beta=77.6970(10) degrees, gamma=64.7770(10) degrees. The facile oxidation of the Mn(II)9 grids is highlighted in terms of their potential use as molecular based platforms for switching and data storage.


Pd(II)/Bipyridine-Catalyzed Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Carboxylic Acids. Synthesis of β-Quaternary Carbons Substituted Carboxylic Acids.
Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carboxylic acids (including β,β-disubstituted acrylic acids) was developed and optimized, which provided a mild and convenient method for the highly challenging synthesis of β-quaternary carbons substituted carboxylic acids.


Depletion of skeletal muscle mass adversely affects long-term outcomes for men undergoing gastrectomy for gastric cancer.
Although low skeletal muscle mass has an adverse impact on the treatment outcomes of cancer patients, whether the relationship between preoperative skeletal muscle mass and gastrectomy outcomes in gastric cancer (GC) differs between men and women is unclear. The study aimed to clarify this relationship based on gender. Between January 2007 and December 2015, 1054 patients who underwent gastrectomy for GC at Osaka City General Hospital were enrolled in this study. We evaluated sarcopenia by the skeletal muscle index (SMI), which was measured by computed tomography (CT) using areas of muscle in the third lumbar vertebral body (L3). Male and female patients were each divided into two groups (low skeletal muscle and high skeletal muscle). The SMI emerged as an independent predictor of 5-year overall survival (OS) in male GC patients (Hazard ratio 2.51; 95% confidence interval (CI) 1.73-3.63, p < 0.001) based on multivariate analysis. However, this index was not an independent predictive determinant of 5-year cancer-specific survival (CSS). The SMI was not an independent predictor of either OS or CSS in female GC patients. The incidence of leakage and major complication (Clavien Dindo grade ≧ 3) did not differ significantly across groups. Preoperative skeletal muscle mass is a valuable prognostic predictor of OS in male GC patients.


(How) can we reduce violence against women by 50% over the next 30 years?
In this month's editorial, PLOS Medicine Editorial Board member Rachel Jewkes identifies challenges that the violence prevention research community faces in substantially reducing violence against women and girls over the next 30 years. Please see later in the article for the Editors' Summary.


Changing the obesogenic environment of severe mentally ill residential patients: ELIPS, a cluster randomised study design.
Severe mentally ill (SMI) patients have a reduced life expectancy of 13-30 years compared to the general population, largely due to an increased risk of cardiovascular mortality. Unhealthy lifestyle behaviours in SMI patients contribute to this increased risk. The obesogenic living environment of patients in residential facilities may even pose an extra risk. Although several studies have shown positive effects of lifestyle interventions on SMI patients' weight status, studies including residential patients and their obesogenic environment are scarce. This paper describes the Effectiveness of Lifestyle Interventions in PSychiatry trial (ELIPS). The goal of this trial is to improve cardiometabolic health in severe mentally ill residential patients by addressing the obesogenic environment. The ELIPS study is a multi-site cluster randomised controlled trial (RCT) based on the principles of a pragmatic RCT. All residential and long-term clinical care teams of two large mental health care organisations in the North of the Netherlands serving SMI patients are invited to participate. The intervention is aimed at team level. Lifestyle coaches first develop a team specific lifestyle plan that tailors the ELIPS goals and protocol and then train teams on how to create a healthy environment and stimulate healthy behaviours in patients. After three months, teams take over the intervention after they have set out goals to achieve in the following nine months. In this phase, adherence to the lifestyle plan and pre-set goals is monitored. Patients in the control arm receive care as usual. Primary outcome measure is waist circumference at three and 12 months after baseline. ELIPS is different from previously published lifestyle intervention studies in three ways. First, it follows the principles of a pragmatic design, which enables the examination of effects in everyday practice. Second, by implementing the intervention at team level, we expect lifestyle activities to be maintained when interventionists leave. Last, by targeting the obesogenic environment we create a prerequisite for any sustainable health improvement, as patients can only make healthy choices in a healthy living environment. Nederlands Trialregister NTR2720 (Dutch Trial Register, www.trialregister.nl). Registered 27 January 2011.


Critical examination of the characterization techniques, and the evidence, for the existence of extra-long amylopectin chains.
It has been suggested that amylopectin can contain small but significant amounts of extra-long chains (ELCs), which could affect functional properties, and also would have implications for the mechanism of starch biosynthesis. However, current evidence for the existence of ELCs is ambiguous. The amylose/amylopectin separation and the characterization techniques used for the investigation of ELCs are reviewed, problems in those techniques are examined, and studies of ELCs of amylopectin are discussed. A model for the biosynthesis of amylopectin chains in terms of conventional biosynthesis enzymes, which provides an excellent fit to a large amount of experimental data, is used to provide a rigorous definition of ELCs. In addition, current investigations of ELCs, involving separation, is hindered by the lack of a method to quantitatively separate all the amylopectin from starch without any traces of residual amylose (which would have long chains). Unambiguous evidence for the existence of ELCs can be obtained using two-dimensional (2D) characterization, these dimensions being the degree of polymerization of a chain and the size of the whole molecule. Available 2D data indicate that there are no ELCs present in currently detectable quantities in native rice starches. However, concluding this more rigorously requires improvements in the resolution of current 2D methods.


Bone Allograft Segment Covered with a Vascularized Fibular Periosteal Flap: A New Technique for Pediatric Mandibular Reconstruction.
The free vascularized fibular graft is nowadays the preferred technique for pediatric mandibular reconstruction. Despite the versatility and proven efficacy for restoring the facial appearance and maxillomandibular function, those mandibular reconstructions with free vascularized fibula associate difficulties for a simultaneous restoration of the alveolar height and facial contour, which are derived from the height discrepancy between the fibula and the native mandible. In addition, the donor-site growth and morbidity are of special concern in the pediatric patient. We report a novel technique for pediatric mandibular reconstruction, in an 11-year-old girl, using a combination of a bone allograft segment with a vascularized fibular periosteal flap (VFPF), after resection of an Ewing sarcoma located at the right body of the mandible. The patient has showed optimal cosmetic, functional, and radiological outcomes, which have been maintained for 2.5 years, without detecting donor-site complications. Through this original technique, and based on the powerful osteogenic and vasculogenic properties of the pediatric VFPFs, we could effectively reconstruct a large mandibular defect providing a functional and aesthetic reconstruction, while avoiding the potential morbidity associated with the fibula resection.


Dispersion cancellation in a quantum interferometer with independent single photons.
A key technique to perform proper quantum information processing is to get a high visibility quantum interference between independent single photons. One of the crucial elements that affects the quantum interference is a group velocity dispersion that occurs when single photons pass through a dispersive medium. We theoretically and experimentally demonstrate that an effect of group velocity dispersion on the two-photon interference can be cancelled if two independent single photons experience the same amount of pulse broadening. This dispersion cancellation effect can be applied to a multi-path linear interferometer with multiple independent single photons. As multi-path quantum interferometers are at the heart of quantum communication, photonic quantum computing, and boson sampling applications, our work should find wide applicability in quantum information science.


Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register.
To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.


Multiple dentoalveolar traumatic lesions: report of a case and proposition of dental polytrauma as a new term.
Traumatic injuries to permanent teeth are common, and dramatic episodes can occur during childhood. The aim of this paper is to present a report of severe trauma to the orofacial complex of an 8-year old girl that resulted in multiple injuries. The use of the term "dental polytrauma" (concomitant different dental traumatic injuries) is advocated in this case presentation.


Estimation of the incubation period of invasive aspergillosis by survival models in acute myeloid leukemia patients.
The duration of the incubation of invasive aspergillosis (IA) remains unknown. The objective of this investigation was to estimate the time interval between aplasia onset and that of IA symptoms in acute myeloid leukemia (AML) patients. A single-centre prospective survey (2004-2009) included all patients with AML and probable/proven IA. Parametric survival models were fitted to the distribution of the time intervals between aplasia onset and IA. Overall, 53 patients had IA after aplasia, with the median observed time interval between the two being 15 days. Based on log-normal distribution, the median estimated IA incubation period was 14.6 days (95% CI; 12.8-16.5 days).


Vaccination against the nematode Trichinella spiralis in high- and low-responder mice. Effects of different adjuvants upon protective immunity and immune responsiveness.
Groups of NIH and C57BL/10 (B10) mice were vaccinated subcutaneously with excretory/secretory material from the nematode parasite Trichinella spiralis using a variety of different adjuvants, i.e. complete Freund's adjuvant (CFA), 'TiterMax', alum and ISCOMs. ISCOMs were also given orally. NIH mice, known to be rapid responders to T. spiralis, expelled their worms earlier than usual with vaccination. The slow-responder B10 mice did not expel worms any earlier, no matter which adjuvant was used. The antibody isotype response profiles following vaccination with the four adjuvants did not differ significantly; however NIH mice generally produced higher levels of antibody than B10 and CFA induced the highest overall response. NIH cells yielded stimulation indices far in excess of the B10 following in vitro stimulation with T. spiralis antigen. Secretion of interleukin-5 (IL-5) and interferon-gamma (IFN-gamma) by these cells followed similar trends, i.e. higher levels from NIH than B10. A high IL-5 level in the NIH strain was accompanied by low-level IFN-gamma production following infection, whereas the IFN-gamma response was not observed in B10 supernatants. This study shows that vaccination using these adjuvants did not appear to modify the immune response qualitatively, but the magnitude of the response was affected greatly.


DLFF-ACP: prediction of ACPs based on deep learning and multi-view features fusion.
An emerging type of therapeutic agent, anticancer peptides (ACPs), has attracted attention because of its lower risk of toxic side effects. However process of identifying ACPs using experimental methods is both time-consuming and laborious. In this study, we developed a new and efficient algorithm that predicts ACPs by fusing multi-view features based on dual-channel deep neural network ensemble model. In the model, one channel used the convolutional neural network CNN to automatically extract the potential spatial features of a sequence. Another channel was used to process and extract more effective features from handcrafted features. Additionally, an effective feature fusion method was explored for the mutual fusion of different features. Finally, we adopted the neural network to predict ACPs based on the fusion features. The performance comparisons across the single and fusion features showed that the fusion of multi-view features could effectively improve the model's predictive ability. Among these, the fusion of the features extracted by the CNN and composition of k-spaced amino acid group pairs achieved the best performance. To further validate the performance of our model, we compared it with other existing methods using two independent test sets. The results showed that our model's area under curve was 0.90, which was higher than that of the other existing methods on the first test set and higher than most of the other existing methods on the second test set. The source code and datasets are available at https://github.com/wame-ng/DLFF-ACP.


Improved Survival of a Patient with Gastric and Other Multiple Metastases from Ovarian Cancer by Multimodal Treatment: A Case Report.
Gastric metastasis from ovarian carcinoma is extremely rare and the prognosis for patients is poor. We report a case of multimodal treatment improving the survival time of a patient with gastric metastasis from ovarian cancer. A 73-year-old woman with known serous ovarian cancer was admitted to the hospital due to epigastric pain and dyspepsia. On esophagogastroduodenoscopy, a protruding mass was noted at the gastric antrum. She underwent distal gastrectomy with Billroth I anastomosis and lymph node dissection, including the para-aortic lymph nodes. The final pathology revealed gastric metastasis from ovarian serous adenocarcinoma. In this case, after cytoreductive surgery, chemotherapy was performed each time a recurrence was diagnosed, and remission was accomplished. She survived for 108 months after the first diagnosis of the metastatic tumor in the stomach. Multimodal treatment of metastatic lesions since the first diagnosis allowed the patient to survive longer than those in previous reports.


Decision-to-delivery interval in emergency cesarean delivery in tertiary care hospital in Thailand.
To determine the decision-to-delivery interval (DDI) in emergency cesarean delivery and associated factors. A total of 431 pregnant women who were indicated for emergency cesarean delivery were included. Clinical information and timing of process after decision until delivery and pregnancy outcomes were evaluated. Mean age was 30 years, and 59.4% were nulliparous. Mean gestational age at delivery was 37.9 weeks. The decision was made during normal office hour in 33.2%. Median decision-to-operating room interval, decision-to-incision interval, and DDIs were 45, 70, and 82 minutes, respectively. Only 3.5% of patients had DDI ≤30 minutes, while 52.0% had DDI >75 minutes. During after office hours, every time interval was significantly shorter and 4.9% had DDI ≤30 minutes compared to 0.7% in normal office hours (P=0.001). Compared to other indications, time intervals were significantly shorter in those with non-reassuring fetal heart rate (FHR), and DDI ≤30 minutes was achieved in 18.8% vs. 0.8% (P<0.001). Shortest DDI was observed among those with non-reassuring FHR during after office hours. Neonatal outcomes were comparable between different DDIs. Only 3.5% of emergency cesarean delivery had a DDI ≤30 minutes (median 82 minutes). Significant shorter time intervals were observed in those with non-reassuring FHR during after office hours.


The risk of cancer progression in women with gynecological malignancies and thrombophilic polymorphisms: a pilot case-control study.
Cancer produces a hypercoagulable state, which might lead to thrombosis, and on contrary, unprovoked venous thromboembolism might be the manifestation of an occult cancer. In this pilot case-control study, we assessed the risk of gynecological malignant diseases related to the presence of the factor V Leiden and prothrombin G20210A polymorphisms. Fifty-two women underwent an operation for gynecological malignancy and were enrolled in the study. Women who underwent an operation for gynecological nonmalignant disease in the same days of cases were considered as controls. The presence of factor V Leiden and prothrombin G20210A was assessed in case and control groups. In all, 7 out of 52 cases were carriers of the 2 polymorphisms compared with 20 out of 198 controls (odds ratio = 1.3; 95% confidence interval, 0.6-3.0). The results were also similar when the risk was considered separately for the site of cancer. As for advanced and metastatic malignancies, the odds ratios were 2.3 (95% confidence interval, 0.9-6.0) and 3.3 (95% confidence interval, 1.0-11), respectively, compared to noncancer patients. When these 2 groups were compared to nonadvanced cancer group, the odds ratios for carriers of polymorphisms were 2.7 (95%confidence interval, 0.7-11.0) and 3.9 (95%confidence interval, 0.8-18.6) for advanced cancer and metastatic malignancies, respectively. Women with factor V Leiden or prothrombin G20210A polymorphisms who developed gynecological malignancy might present with a higher stage of cancer at the time of surgery. Larger case-control studies in similar cohort of patients are needed to confirm these findings.


A carcinoma in situ arising in an endocervical polyp--a case report.
A rare case of a carcinoma in situ arising from an endocervical polyp is described. The covering epithelium of the polyp transformed gradually into a carcinoma in situ via squamous metaplasia and dysplasia, spreading horizontally with glandular involvement, and colliding with the surface columnar cells. The lack of tumor tissue in the pedicle and adjacent cervical region confirms the case was a carcinoma in situ originating from the surface epithelium of the endocervical polyp.


Writing interventions in older adults and former children of the World War II: impact on quality of life and depression.
The aim of the current study was to analyze whether biographical writing interventions have an impact on depression and QoL compared to daily diary writing. We also wanted to investigate differential effects between structured and unstructured interventions. In two Northern regions of Germany, 119 older adults aged 64-90 were randomly assigned to three different types of narrative writing interventions: written structured and unstructured biographical disclosure as well as daily diary writing. Depression (PHQ-9), QoL (SF-12, EUROHIS) and trauma-related symptoms (PCL-C) were obtained pre- and post-interventions as well as at three-month follow-up. Follow-up measures were obtained from 85 participants (29% loss to follow-up; mean age = 73.88; 68.2% female). Results of repeated measurement analysis demonstrated a significant effect on depression with the daily diary writing group showing lower depressive symptoms than structured biographical writing. We did not find a significant impact on QoL. Post-hoc analyses showed that posttraumatic symptoms lead to increases in depressive symptoms. In a non-clinical sample of community-dwelling older adults, biographical writing interventions were not favorable to daily diary writing concerning the outcomes of the study. This might be related to the association of traumtic reminiscences of former children of World War II and outcome measures.


Update on use of instrumentation in lumbar spine disorders.
The past 20 years have witnessed significant changes in the indications for and use of instrumentation in lumbar spine surgery. Absolute indications for surgical instrumentation include cases of clearly defined instability that commonly occur in the setting of trauma, tumour and infection. Relative indications for instrumentation must consider the clinical context and individual patient characteristics but may include cases of spondylolisthesis, junctional stenosis and pseudarthrosis. The use of instrumentation in the surgical treatment of degenerative disc disease is prevalent but remains highly controversial. Pedicle screws and interbody cages represent alternative forms of instrumentation with substantial clinical evidence supporting their safety and efficacy when applied in the correct clinical settings. Minimally invasive and computer-assisted surgical techniques have shown promising early results but must be subject to longer-term scrutiny. The development of prosthetic disc replacements is an exciting area of research, but clinical results have not approached the success currently enjoyed by hip and knee prostheses, and these devices should be considered experimental. One of the goals of instrumentation is to enhance the rate of spinal fusion. However, achievement of solid radiographic fusion does not guarantee a clinically successful outcome and, conversely, excellent results can be obtained in the setting of radiographic pseudarthrosis. The most important determinant of favourable surgical outcome is appropriate patient selection through a sound understanding of surgical indications.


Immunogenic cell death as driver of autoimmunity in granulomatosis with polyangiitis.
Cell death and dysregulated clearance of dead cells play essential roles in the induction of chronic inflammatory processes and autoimmune diseases. Granulomatosis with polyangiitis (GPA), a neutrophil-driven autoimmune disorder, is characterized by necrotizing inflammation predominantly of the respiratory tract and an anti-neutrophil cytoplasmic autoantibody (ANCA)-associated systemic necrotizing vasculitis. Defective regulation of neutrophil homeostasis and cell death mechanisms have been demonstrated in GPA. Disturbed efferocytosis (i.e., phagocytosis of apoptotic neutrophils by macrophages) as well as cell death-related release of damage-associated molecular patterns (DAMP) such as high mobility group box 1 (HMGB1) contribute to chronic non-resolving inflammation in GPA. DAMP have been shown to induce innate as well as adaptive cellular responses thereby creating a prerequisite for the development of pathogenic autoimmunity. In this review, we discuss factors contributing to as well as the impact of regulated cell death (RCD) accompanied by DAMP-release as early drivers of the granulomatous tissue inflammation and autoimmune responses in GPA.


Comparison of the cell surface properties and growth characteristics of Listeria monocytogenes and Listeria innocua.
Growth kinetics and physicochemical surface properties were compared for three Listeria strains with differing degrees of virulence: L. monocytogenes LO28; its isogenic, nonhemolytic mutant L. monocytogenes Bof415; and a nonvirulent species, L. innocua (strain Lin9). The influences of growth stage (mid-exponential phase, early stationary phase, and mid-stationary phase) and culture temperature (20 and 37 degrees C) were assessed by determining the electrical properties and the hydrophobic-hydrophilic and Lewis acid-base characteristics of the three strains. L. innocua, although taxonomically very similar to L. monocytogenes, exhibited physicochemical surface properties that differed significantly from those of L. monocytogenes LO28 and L. monocytogenes Bof415. Indeed, under our experimental conditions, L. innocua cells presented a more marked electronegative character (particularly when cultured at 20 degrees C), as well as greater variability in their Lewis acid-base characteristics as a function of temperature and growth stage. Furthermore, the growth kinetics of the three strains revealed the onset of a decay phase after 16 h of culture at 37 degrees C for the L monocytogenes Bof415 mutant. All of these results demonstrate that under our experimental conditions, the growth and/or physicochemical characteristics of the slightly pathogenic or nonpathogenic Listeria strains (Bof415 and Lin9) differed from those of the virulent strain (L. monocytogenes LO28). Consequently, the use of Listeria strains recognized as nonvirulent appeared to provide a model that was not fully suitable for simulating the bioadhesive behavior of the pathogenic strains involved in foodborne diseases.


Physiologic responses of grizzly bears to different methods of capture.
The physiologic effects of two methods of capture, chemical immobilization of free-ranging (FR) bears by remote injection from a helicopter and physical restraint (PR) by leg-hold snare prior to chemical immobilization, were compared in 46 grizzly bears (Ursus arctos) handled during 90 captures between 1999 and 2001. Induction dosages and times were greater for FR bears than PR bears, a finding consistent with depletion of, or decreased sensitivity to, catecholamines. Free-ranging bears also had higher rectal temperatures 15 min following immobilization and temperatures throughout handling that correlated positively with induction time. Physically restrained bears had higher white blood cell counts, with more neutrophils and fewer lymphocytes and eosinophils, than did FR bears. This white blood cell profile was consistent with a stress leukogram, possibly affected by elevated levels of serum cortisol. Serum concentrations of alanine aminotransferase, aspartate aminotransferase, and creatine kinase were higher in PR bears that suggested muscle injury. Serum concentrations of sodium and chloride also were higher in PR bears and attributed to reduced body water volume through water deprivation and increased insensible water loss. Overall, different methods of capture resulted in different patterns of physiologic disturbance. Reducing pursuit and drug induction times should help to minimize increase in body temperature and alteration of acid-base balance in bears immobilized by remote injection. Minimizing restraint time and ensuring snare-anchoring cables are short should help to minimize loss of body water and prevent serious muscle injury in bears captured by leg-hold snare.


Contact allergies to potential allergens in patients with oral lichen lesions.
The aim of the present controlled study was to investigate a possible relationship between contact allergies to potential allergens and oral lichen lesions. Eighty-three patients with oral lichen lesions (OLL) and control groups of age- and gender-matched dermatitis patients (DP, n = 83) and patch-tested dermatitis patients randomly selected from files (PSFF, n = 319) were included in the study. OLL and DP groups were patch-tested epicutaneously and examined intraorally. The frequencies of contact allergy to mercury and carvone were statistically higher in the OLL group than in the DP group. Surfaces of amalgam and composite restorations were statistically more frequent in the OLL group compared to the DP group. Contact allergy to nickel and colophony, the latter with a statistically significant difference, was more common in the DP group. The numerical difference found for nickel allergy was, however, not significant comparing the OLL and PSFF groups. Contact allergy to mercury was overrepresented in patients with OLL and has been reported in previous studies, but the present finding of an overrepresentation of contact allergy to carvone in patients with oral lichen lesions has not been reported previously. Carvone, in addition to mercury and gold, as previously suggested, can be one of the causative or maintenant factors for oral lichen lesions. Carvone-hypersensitive patients with oral lichen lesions should therefore avoid carvone-containing products for oral use.


An analysis of spatiotemporal localized solutions in the variable coefficients (3 + 1)-dimensional nonlinear Schrödinger equation with six different forms of dispersion parameters.
We construct spatiotemporal localized envelope solutions of a (3 + 1)-dimensional nonlinear Schrödinger equation with varying coefficients such as dispersion, nonlinearity and gain parameters through similarity transformation technique. The obtained localized rational solutions can serve as prototypes of rogue waves in different branches of science. We investigate the characteristics of constructed localized solutions in detail when it propagates through six different dispersion profiles, namely, constant, linear, Gaussian, hyperbolic, logarithm, and exponential. We also obtain expressions for the hump and valleys of rogue wave intensity profiles for these six dispersion profiles and study the trajectory of it in each case. Further, we analyze how the intensity of another localized solution, namely, breather, changes when it propagates through the aforementioned six dispersion profiles. Our studies reveal that these localized solutions co-exist with the collapsing solutions which are already found in the (3 + 1)-dimensional nonlinear Schrödinger equation. The obtained results will help to understand the corresponding localized wave phenomena in related fields.


Costly Nutritious Diets do not Necessarily Translate into Better Performance of Artificially Reared Fruit Flies (Diptera: Tephritidae).
Protein, lipid, carbohydrate, and energy contents of three artificial diets (Xal2, Met1, and Met2) used for laboratory-rearing and mass-rearing the Mexican fruit fly, Anastrepha ludens (Loew), for a sterile insect technique program were measured. The larval survival, pupation, pupal weight, adult emergence, sex ratio, and flight capacity of the flies reared on each of these diets were also quantified. The diet with the highest nutrient and energy content was Xal2 followed by Met2 and Met1, but larval recovery and percent pupation was significantly higher in flies reared on either the Met1 or Met2 diets. A. ludens reared on Xal2 exhibited the highest proportion of adults capable of flight. No other response variable differed significantly among the three diets tested. This suggests that a high content of nutrients and multiple sources of protein (dried yeast and wheat germ in the case of the Xal2 diet) do not necessarily improve overall performance or fly quality. We conclude that nutritious diets for A. ludens can be modified to reduce their cost without compromising the performance of artificially reared flies.


The degree of substitution affects the enantioselectivity of sulfobutylether-β-cyclodextrin chiral stationary phases.
Three chiral stationary phases were prepared by dynamic coating of sulfobutylether-β-cyclodextrin (SBE-β-CD) with different degrees of substitution, onto strong anion-exchange stationary phases. The enantioselective potential and stability of newly prepared chiral stationary phases were examined using a set of structurally different chiral analytes. Measurements were performed in RP-HPLC. Mobile phases consisted of methanol/formic acid, pH 2.10, and methanol/10 mM ammonium acetate buffer, pH 4.00, in various volume ratios. SBE-β-CDs with degrees of substitution (DS) 4, 6.3, and 10 proved suitable for the enantioseparation of 14, 11, and 8 analytes, respectively. The SBE-β-CD DS 4 based chiral stationary phase enabled the enantioseparation of the nearly all basic and neutral compounds. Chiral stationary phases with higher sulfobutylether-β-cyclodextrin substitution (especially DS 10) yielded higher enantioresolution values for acidic compounds.


The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation.
The yeast Ca2+ adenosine triphosphatase Pmr1, located in medial-Golgi, has been implicated in intracellular transport of Ca2+ and Mn2+ ions. We show here that addition of Mn2+ greatly alleviates defects of pmr1 mutants in N-linked and O-linked protein glycosylation. In contrast, accurate sorting of carboxypeptidase Y (CpY) to the vacuole requires a sufficient supply of intralumenal Ca2+. Most remarkably, pmr1 mutants are also unable to degrade CpY*, a misfolded soluble endoplasmic reticulum protein, and display phenotypes similar to mutants defective in the stress response to malfolded endoplasmic reticulum proteins. Growth inhibition of pmr1 mutants on Ca2+-deficient media is overcome by expression of other Ca2+ pumps, including a SERCA-type Ca2+ adenosine triphosphatase from rabbit, or by Vps10, a sorting receptor guiding non-native luminal proteins to the vacuole. Our analysis corroborates the dual function of Pmr1 in Ca2+ and Mn2+ transport and establishes a novel role of this secretory pathway pump in endoplasmic reticulum-associated processes.


Progression to AIDS in SIV-Infected Rhesus Macaques is Associated with Distinct KIR and MHC class I Polymorphisms and NK Cell Dysfunction.
Killer cell immunoglobulin-like receptors (KIR) regulate the activity of natural killer (NK) cells and have been shown to be associated with susceptibility to a number of human infectious diseases. Here, we analyzed NK cell function and genetic associations in a cohort of 52 rhesus macaques experimentally infected with SIVmac and subsequently stratified into high viral load (HVL) and low viral load (LVL) plasma viral loads at set point. This stratification coincided with fast (HVL) and slow (LVL) disease progression indicated by the disease course and critical clinical parameters including CD4+ T cell counts. HVL animals revealed sustained proliferation of NK cells but distinct loss of peripheral blood NK cell numbers and lytic function. Genetic analyses revealed that KIR genes 3DL05, 3DS05, and 3DL10 as well as 3DSW08, 3DLW03, and 3DSW09 are correlated, most likely due to underlying haplotypes. SIV-infection outcome associated with presence of transcripts for two inhibitory KIR genes (KIR3DL02, KIR3DL10) and three activating KIR genes (KIR3DSW08, KIR3DS02, KIR3DS05). Presence of KIR3DL02 and KIR3DSW08 was associated with LVL outcome, whereas presence of KIR3DS02 was associated with HVL outcome. Furthermore, we identified epistasis between KIR and MHC class I alleles as the transcript presence of the correlated genes KIR3DL05, KIR3DS05, and KIR3DL10 increased HVL risk when Mamu-B*012 transcripts were also present or when Mamu-A1*001 transcripts were absent. These genetic associations were mirrored by changes in the numbers, the level of proliferation, and lytic capabilities of NK cells as well as overall survival time and gastro-intestinal tissue viral load.


Long-term lithium treatment and renal functions. A prospective study.
Renal functions were examined in 53 patients before the start of long-term lithium treatment (I) and then after 4 months (II) and 12 months (III) on lithium treatment. The tubular function was studied by means of the DDAVP (Minirin) test and the glomerular filtration rate was measured by creatinine clearance. The mean maximum urine osmolality (+/- SE) on the first occasion (I) was 800 +/- 20 mosm/kg H2O, 702 +/- 20 on the second (II), and on the third (III) 723 +/- 17 mosm/kg H2O. The mean creatinine clearance before the start of lithium treatment (I) was 128 +/- 5 ml/min, after 4 months (II) 106 +/- 4 and after 12 months (III) 114 +/- 5 ml/min. The results of the present study suggest that lithium treatment with serum levels of approximately 0.6 mmol/l causes a decrease in renal concentrating ability and the glomerular filtration rate in the early stages after the start of therapy. This decrease in the renal functions does not seem to progress during the first year of lithium treatment.


In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver.
CD4+ T cells recruited to the liver play a key role in the pathogenesis of ischemia/reperfusion (I/R) injury. The mechanism of their activation during alloantigen-independent I/R is not completely understood. We hypothesized that liver-resident dendritic cells (DCs) interact with CD4+ T cells in the postischemic liver and that modulation of DCs or T-cell-DC interactions attenuates liver inflammation. In mice, warm hepatic I/R (90/120-240 min) was induced. Tolerogenic DCs were generated in situ by pretreatment of animals with the vitamin D analog paricalcitol. A mAb-CD44 was used for blockade of CD4+ T-cell-DC interactions. As shown by 2-photon in vivo microscopy as well as confocal microscopy, CD4+ T cells were closely colocalized with DCs in the postischemic liver. Pretreatment with paricalcitol attenuated I/R-induced maturation of DCs (flow cytometry), CD4+ T-cell recruitment into the liver (intravital microscopy), and hepatocellular/microvascular damage (intravital microscopy, alanine aminotransferase/aspartate aminotransferase, histology). However, interruption of T-cell-DC interaction increased proinflammatory DC maturation and even enhanced tissue damage. Simultaneous treatment with an anti-CD44mAb completely abolished the beneficial effect of paricalcitol on T-cell migration and tissue injury. Our study demonstrates for the first time that hepatic DCs interact with CD4+ T cells in the postischemic liver in vivo; modulation of DCs and/or generation of tolerogenic DCs attenuates intrahepatic CD4+ T-cell recruitment and reduces I/R injury; and interruption of CD44-dependent CD4+ T-cell-DC interactions enhances tissue injury by preventing the modulatory effect of hepatic DCs on T cells, especially type 1 T helper effector cells. Thus, hepatic DCs are strongly involved in the promotion of CD4+ T-cell-dependent postischemic liver inflammation.-Funken, D., Ishikawa-Ankerhold, H., Uhl, B., Lerchenberger, M., Rentsch, M., Mayr, D., Massberg, S., Werner, J., Khandoga, A. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver.


A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in beta-cells.
Low levels of somatic mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these mutations is unknown. In contrast, mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic beta-cells may be extremely sensitive to the accumulation of mtDNA mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO(2). Type 2 diabetes arises when beta-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of beta-cell function or beta-cell death. This loss of beta-cell function/beta-cell death has been attributed to the toxic effects of elevated levels of lipids and glucose resulting in the enhanced production of free radicals in beta-cells. mtDNA, localized in close proximity to one of the major cellular sites of free radical production, comprises more than 95% coding sequences such that mutations result in changes in the coding sequence. It has long been known that mtDNA mutations accumulate with age; however, only recently have studies examined the influence of somatic mtDNA mutation accumulation on disease pathogenesis. This article will focus on the effects of low-level somatic mtDNA mutation accumulation on ageing, cardiovascular disease and diabetes.


The peroxyl radical-induced oxidation of Escherichia coli FtsZ and its single tryptophan mutant (Y222W) modifies specific side-chains, generates protein cross-links and affects biological function.
FtsZ (filamenting temperature-sensitive mutant Z) is a key protein in bacteria cell division. The wild-type Escherichia coli FtsZ sequence (FtsZwt) contains three tyrosine (Tyr, Y) and sixteen methionine (Met, M) residues. The Tyr at position 222 is a key residue for FtsZ polymerization. Mutation of this residue to tryptophan (Trp, W; mutant Y222W) inhibits GTPase activity resulting in an extended time in the polymerized state compared to FtsZwt. Protein oxidation has been highlighted as a determinant process for bacteria resistance and consequently oxidation of FtsZwt and the Y222W mutant, by peroxyl radicals (ROO•) generated from AAPH (2,2'-azobis(2-methylpropionamidine) dihydrochloride) was studied. The non-oxidized proteins showed differences in their polymerization behavior, with this favored by the presence of Trp at position 222. AAPH-treatment of the proteins inhibited polymerization. Protein integrity studies using SDS-PAGE revealed the presence of both monomers and oligomers (dimers, trimers and high mass material) on oxidation. Western blotting indicated the presence of significant levels of protein carbonyls. Amino acid analysis showed that Tyr, Trp (in the Y222W mutant), and Met were consumed by ROO•. Quantification of the number of moles of amino acid consumed per mole of ROO• shows that most of the initial oxidant can be accounted for at low radical fluxes, with Met being a major target. Western blotting provided evidence for di-tyrosine cross-links in the dimeric and trimeric proteins, confirming that oxidation of Tyr residues, at positions 339 and/or 371, are critical to ROO•-mediated crosslinking of both the FtsZwt and Y222W mutant protein. These findings are in agreement with di-tyrosine, N-formyl kynurenine, and kynurenine quantification assessed by UPLC, and with LC-MS data obtained for AAPH-treated protein samples.


Hey2 enhancer activity defines unipotent progenitors for left ventricular cardiomyocytes in juxta-cardiac field of early mouse embryo.
The cardiac crescent is the first structure of the heart and contains progenitor cells of the first heart field, which primarily differentiate into left ventricular cardiomyocytes. The interface between the forming cardiac crescent and extraembryonic tissue is known as the juxta-cardiac field (JCF), and progenitor cells in this heart field contribute to the myocardium of the left ventricle and atrioventricular canal as well as the epicardium. However, it is unclear whether there are progenitor cells that differentiate specifically into left ventricular cardiomyocytes. We have previously demonstrated that an enhancer of the gene encoding the Hey2 bHLH transcriptional repressor is activated in the ventricular myocardium during mouse embryonic development. In this study, we aimed to investigate the characteristics of cardiomyocyte progenitor cells and their cell lineages by analyzing Hey2 enhancer activity at the earliest stages of heart formation. We found that the Hey2 enhancer initiated its activity prior to cardiomyocyte differentiation within the JCF. Hey2 enhancer-active cells were present rostrally to the Tbx5-expressing region at the early phase of cardiac crescent formation and differentiated exclusively into left ventricular cardiomyocytes in a lineage distinct from the Tbx5-positive lineage. By the late phase of cardiac crescent formation, Hey2 enhancer activity became significantly overlapped with Tbx5 expression in cells that contribute to the left ventricular myocardium. Our study reveals that a population of unipotent progenitor cells for left ventricular cardiomyocytes emerge in the JCF, providing further insight into the mode of cell type diversification during early cardiac development.


Hypothyroidism In Hepatitis C Patients On Pegylated Interferon Therapy.
Chronic hepatitis has become a major health problem all over the world especially in the third world countries. The most common cause of chronic hepatitis in Pakistan is hepatitis C which can lead Toliver cirrhosis and hepatocellular carcinoma. In Pakistan Pegylated Interferon Alpha is still corner stone of therapy for chronic hepatitis C. One of the major side effects of this therapy is the development of thyroid dysfunction, i.e., hypothyroidism and hyperthyroidism. This study was done to assess the frequency of hypothyroidism in hepatitis C patients after three months of pegylated interferon therapy. This study was conducted from 1st October 2013 to 31st march 2014 at outpatients department (OPD) of Gastroenterology and Hepatology, Lahore General Hospital Lahore. Descriptive case series study design was used. The sample of 200 patients was taken from the patients who visited OPD and fulfil the inclusion criteria of the study. Serum thyroid stimulating hormone level (TSH) was done before and after completion of three months therapy at centre for Nuclear Medicine (CENUM) laboratory, Mayo Hospital, Lahore by immune-radiometric assay (IRMA) and patients having TSH>4.0 mIU/L (normal range: 0.2-4.0 mIU/L) were considered hypothyroid. The mean age of the patients was 36.29±8.5 years. One hundred and twenty-three (61.5%) were male and 77 (38.5%) were female. After 3 months of interferon therapy, 163 (81.5%) patients were euthyroid and 37(18.5%) patients were having thyroid dysfunction. There were total 29 (14.5%) hypothyroid patients; 8 (27.6%) were male and 21 (72.4%) female. It is concluded from this study that frequency of hypothyroidism in patients with chronic hepatitis C was 14.5% after treatment with pegylated interferon therapy for 3 months. Female patients were more prone to develop hypothyroidism as compared to male patients.


Automatic telomere length measurements in interphase nuclei by IQ-FISH.
To benefit from the fluorescence-based automatic microscope (FLAME), we have adapted a PNA FISH technique to automatically determine telomere length in interphase nuclei. The method relies on the simultaneous acquisition of pan-telomeric signals and reference probe signals. We compared the quantitative figures to those for existing methods, i.e. Southern blot analysis and quantitative FISH (Q-FISH). Quantitative-FISH on interphase nuclei (IQ-FISH) allows the exact quantification of telomere length in interphase nuclei. Thus, this enables us to obtain not only exact information on the telomere length, but also morphological and topological details. The automatic measurement of large cell numbers allows the measurement of statistically relevant cell populations.


An Educational Intervention to Decrease Drug Costs Related to Terminal Secretions in a Hospice Organization.
Terminal secretions is a common symptom seen in hospice patients. Antimuscarinic drugs are commonly used to treat this symptom despite a lack of supporting data. Wide variability in cost exists among these treatments. Hospice program data were assessed to identify high-use and high-cost medications. An educational intervention (EI) was developed to target one such medication, transdermal scopolamine. The EI focused on efficacy, safety, and actual cost (by unit and total expenditure) for each possible treatment of terminal secretions. Following the EI, drug utilization data was re-evaluated. Prior to the deployment of the EI, total monthly hospice drug costs averaged $91,405 (SD 1,444) with an average drug cost per patient per day of $11.42 (SD 0.54). Monthly costs of drugs frequently employed to treat terminal secretions averaged $7,187.67 (SD 2,253) pre-intervention. Following the EI, monthly drug costs decreased 22.5%, average daily patient drug costs decreased 11.1%, and total anti-secretion costs decreased 28.5% after adjusting for difference in census. Education regarding the use and cost of medications to treat symptoms at end-of-life in hospice patients can be an intervention used to lead to significant cost savings to hospice organizations while maintaining appropriate symptom management for patients. Future interventions to target additional high-cost medications are warranted.