Role of alkaline phosphatase in contraception--a review.
High-level influence of alkaline phosphatase (AP) in the endometrium is responsible for conception. Absence or reduction in the level of the same in the endometrium is one of the causes of conception control. The above mechanism is correlated with the observation of Gautray et al. (1969) on "qualitative curve of alkaline phosphatase upon the human endometrium" and the theory of "Rhythm Method"--a role in the fertility control. Conception takes place generally between the 9th and 20th day of the menstrual cycle which is indicated "Baby Days" as the enzymic AP level in the endometrium is helpful for conception and its peak level is between the 16th and 18th day. From the 1st to 8th and 21st to 28th day of the said cycle AP is at low level and almost nil. Implantation becomes unsuitable at this stage and is indicated "No Baby Days". Therefore, it may be concluded that the enzymic influence of AP is responsible both for conception and for contraception. Combined hormonal contraceptive drug also abolishes the AP influence in the endometrium. An attempt at exploration of its essential role is fundamental, because its inadequacy in the endometrium is a factor controlling conception. In view of the documents, it can be concluded that the role of AP uterine enzyme cannot be ruled out with respect to fertility control mechanism which may be considered as a fourth point instead of the three factors for the same, established in medical science.


Anti-tumorigenic Efficacy of Tangeretin in Liver Cancer - An In Silico Approach.
Liver cancer is otherwise known as Hepatic cancer which originated from the liver. Hepatocellular carcinoma (HCC) is the common primary Liver cancer and is one of the emerging problems worldwide. Very few treatments are available to treat HCC because the molecular mechanism and other HCC mechanisms are still unclear. Cyclooxygenase 2 (COX-2), one of the most promising targets for Hepatocellular Carcinoma, is one of the dimeric enzymes which convert Arachidonic acid into Prostaglandin H2 in the step of Prostaglandin biosynthesis. Several natural bioactive compounds are involved in the treatment of various types of cancers. Tangeretin, a natural polymethoxyflavone present in the peel of citrus fruits, acts as an anti-oxidant modulator and anticancerous. The main objective of this study is to find a suitable inhibitor for Hepatocellular Carcinoma. Computational approaches like molecular docking and molecular dynamics were performed to identify the potential inhibitor for Hepatocellular Carcinoma. In this study, COX-2 was considered as a potential target for Hepatocellular Carcinoma which was examined with Tangeretin. Tangeretin was screened against C0X-2 which includes Molecular Docking, DFT analysis, ADMET prediction, and Molecular Dynamics simulation. Tangeretin had good docking scores, fulfilled the pharmacological properties through ADMET prediction, and the Protein-Ligand complex had good stability in Molecular Dynamics simulation.


Changes in histone H3 lysine 36 methylation in porcine oocytes and preimplantation embryos.
Histone H3 lysine 36 (H3K36) methylation is known to be associated with transcriptionally active genes, and is considered a genomic marker of active loci. To investigate the changes in H3K36 methylation in pig, we determined the mono-, di-, and tri-methylations of H3K36 (H3K36me1, H3K36me2 and H3K36me3, respectively) in porcine fetal fibroblasts, oocytes and preimplantation embryos by immunocytochemistry using specific antibodies and confocal microscopy. These analyses revealed that only H3K36me3 in porcine fetal fibroblasts consistently colocalized with transcription sites identified as actively synthesizing RNA based on fluorouridine (FU) incorporation. Treatment of cells with flavopiridol, which blocks transcription elongation, completely abrogated both H3K36me3 signals and RNA synthesis. All three types of H3K36 methylation were present and did not significantly differ during oocyte maturation. In parthenogenetic embryos, H3K36me1 and -me2 were detected in 1-cell through blastocyst-stage embryos. In contrast, H3K36me3 was not detected in most 1-cell stage embryos. H3K36me3 signals became detectable in 2-cell stage embryos, peaked at the 4-cell stage, decreased at the 8-cell stage, and then became undetectable at blastocyst stages in both parthenogenetic and in vitro-fertilized (IVF) embryos. Unlike the case in IVF embryos, H3K36me3 could not be demethylated completely during the 1-cell stage in somatic cell nuclear transfer (SCNT) embryos. These results collectively indicate that H3K36me3, but not H3K36me1 or -me2, is associated with transcription elongation in porcine fetal fibroblasts. H3K36me3 is developmentally regulated and may be a histone mark of embryonic gene activation in pig. Aberrant H3K36 tri-methylation occurred during the nuclear reprogramming of SCNT embryos.


Megestrol acetate-associated adrenal insufficiency.
Megestrol acetate (MA) is commonly used to promote weight gain in malnourished elderly patients. Although adrenal insufficiency has been reported as an adverse effect of MA, this association is not well recognized in clinical practice. An 80-year-old woman with worsening dyspnea was transferred to our university-affiliated community medical center from an inpatient psychiatric facility, where she was being treated for major depressive disorder with psychotic features. She had undergone a general decline in physical function accompanied by some weight loss and anorexia consistent with failure to thrive and, 1 month earlier, had been started on MA 400 mg/d to stimulate her appetite and improve her nutrition. During hospitalization at our center, the patient's dyspnea worsened and she was transferred to the intensive care unit, where she was intubated. While in the intensive care unit, the patient developed hypotension. Infectious, cardiac, and neurologic causes of hypotension having been ruled out, a cosyntropin stimulation test was performed to rule out adrenal insufficiency. Cortisol levels before, 30 minutes after, and 60 minutes after administration of cosyntropin were 1.6, 7.1, and 9.8 microg/dL, respectively, indicating a suboptimal response. The adrenocorticotropic hormone level was 8 pg/mL (normal, 10-60 pg/mL). Based on these findings suggesting adrenal insufficiency, MA was discontinued and steroid replacement was initiated. The patient's blood pressure normalized and she improved slowly. She was weaned from the ventilator several weeks later and was discharged to a skilled nursing facility. At 2-month follow-up, the patient's strength and respiratory function were improved, and the results of a repeat cosyntropin stimulation test were normal (cortisol response before, 30 minutes after, and 60 minutes after cosyntropin administration: 15.4, 22.6, and 25.2 microg/dL, respectively). The Naranjo score for this case was 7, indicating a probable correlation between MA use and adrenal insufficiency. This case of adrenal insufficiency in an elderly woman was probably related to MA use. Clinicians should be alert to the possibility of this adverse effect when considering use of MA therapy.


Measurement of cruelty in children: the Cruelty to Animals Inventory.
Cruelty to animals may be a particularly pernicious aspect of problematic child development. Progress in understanding the development of the problem is limited due to the complex nature of cruelty as a construct, and limitations with current assessment measures. The Children and Animals Inventory (CAI) was developed as a brief self- and parent-report measure of F. R. Ascione's (1993) 9 parameters of cruelty. The CAI emerged as a reliable, stable, and readily utilized measure of cruelty using parent and child reports. Children (especially the older children) reported higher rates of cruelty than their parents and boys reported more cruelty than girls. Self- and parent-reports showed good convergence with independent observations of cruelty versus nurturance during free interactions with domestic animals. The results indicate that cruelty to animals can be reliably measured using brief child and parent report measures.


Experimental model of facial paralysis by nerve compression in primates (Callithrix sp.): a new model of facial paralysis in small nonhuman primates.
We conclude that facial nerve injury induced by compression is associated with a reasonable time window (4 weeks) that allows possible neurotrophic effects to be analyzed. Additionally, there are no hints of cross-innervation by the contralateral facial nerve or parallel innervation by other nerves in the hemiface ipsilateral to the injured nerve. The aim of this work was to develop an experimental model of facial nerve injury in nonhuman primates (Callithrix sp.). In this study, individuals of the non-human primate species Callithrix sp. were subjected to three different types of facial nerve injury, and they were observed for 27 days after surgery by video to record their facial movements. Two types of nerve compression caused severe initial facial paralysis followed by gradual recovery until normal levels were reached at the end of the evaluation period. Injury induced by nerve resection was followed by a complete lack of facial movement recovery.


Analysis of Heart Rate Variability during the Performance of the Wim Hof Method in Healthy Subjects.
Cardiorespiratory interaction is related to the heart rate variability (HRV) synchronized with respiration. These metrics help to comprehend the autonomic nervous system (ANS) functionality in cardiovascular mechanisms. In this work, we aim to study the HRV in healthy subjects aged 18-24 years during the breathing techniques based on deep breaths followed by apnoeas, developed by Wim Hof (WHM). The attributes of all participates have been treated as a group and therefore, separated by gender. A total of 11 intervals have been distinguished: starting of basal respiration (SRI = 1), controlled deep breaths (CDB = 3), long expiratory apnoea (LEA = 3), short inspiratory apnoea (SIA = 3) and ending with basal respiration again (FRI = 1). To strengthen the HRV knowledge extraction from these scenarios, time and frequency analysis is conducted. In general, breathing and apnoea intervals presented significant statistically differences (p < 0.05), heart rate (HR) mean between SRI and FRI (p < 0.001), RR variability of LEA intervals (p < 0.01), root mean square of RR intervals during CDB (p < 0.05), maximum high frequency (HF) peak amplitude between SRI and FRI (p = 0.016), and low frequency (LF) area for LEA intervals (p < 0.001). When performing the frequency analysis, it has been observed that the sympathetic nervous system (SNS) has a higher contribution in the apnoea intervals. In conclusion, the WHM method implementation seems to involve a decrease in the HR. Specific breathing techniques could help to control the body in different conditions.Clinical Relevance- The WHM seems to imply a decrease on HR. Furthermore, after the implementation of the WHM, women presented higher HRV.


Advanced Corneal Imaging in Keratoconus: A Report by the American Academy of Ophthalmology.
To review the published literature on the diagnostic capabilities of the newest generation of corneal imaging devices for the identification of keratoconus. Corneal imaging devices studied included tomographic platforms (Scheimpflug photography, OCT) and functional biomechanical devices (imaging an air impulse on the cornea). A literature search in the PubMed database for English language studies was last conducted in February 2023. The search yielded 469 citations, which were reviewed in abstract form. Of these, 147 were relevant to the assessment objectives and underwent full-text review. Forty-five articles met the criteria for inclusion and were assigned a level of evidence rating by the panel methodologist. Twenty-six articles were rated level II, and 19 articles were rated level III. There were no level I evidence studies of corneal imaging for the diagnosis of keratoconus found in the literature. To provide a common cross-study outcome measure, diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were extracted. (A perfect diagnostic test that identifies all cases properly has an AUC of 1.0.) RESULTS: For the detection of keratoconus, sensitivities for all devices and parameters (e.g., anterior or posterior corneal curvature, corneal thickness) ranged from 65% to 100%. The majority of studies and parameters had sensitivities greater than 90%. The AUCs ranged from 0.82 to 1.00, with the majority greater than 0.90. Combined indices that integrated multiple parameters had an AUC in the mid-0.90 range. Keratoconus suspect detection performance was lower with AUCs ranging from 0.66 to 0.99, but most devices and parameters had sensitivities less than 90%. Modern corneal imaging devices provide improved characterization of the cornea and are accurate in detecting keratoconus with high AUCs ranging from 0.82 to 1.00. The detection of keratoconus suspects is less accurate with AUCs ranging from 0.66 to 0.99. Parameters based on single anatomic locations had a wide range of AUCs. Studies with combined indices using more data and parameters consistently reported high AUCs. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Human T-cell lymphotropic virus type II-associated myelopathy: clinical and immunologic profiles.
Human T-cell lymphotropic virus type II (HTLV-II) is endemic in several ethnic tribes and among intravenous drug users in metropolitan areas. Despite the presence of HTLV-II in these various populations, the association of HTLV-II with disease is sparse and mainly limited to isolated case reports. This study is an extension of an earlier description of an HTLV-II-infected patient with neurologic disease and presents the clinical and immunologic findings of 4 patients with HTLV-II seropositivity and spastic paraparesis. The patients are of African-American origin with 3 of the patients being of Amerindian descent. All of the patients are seronegative for the human immunodeficiency virus (HIV). The patients progressed to a nonambulatory state in less than 5 years. Magnetic resonance imaging studies obtained from 3 of the patients demonstrated white matter disease in the cerebrum and spinal cord. The cerebrospinal fluid and serum contained antibodies to HTLV-II. The presence of proviral HTLV-II was confirmed by polymerase chain reaction analysis of peripheral blood lymphocytes (PBLs). A spinal cord biopsy from 1 patient demonstrated HTLV RNA within a lesion. Immunologic studies on 2 patients demonstrated that spontaneous lymphoproliferation of PBLs was present but decreased relative to HTLV-I-infected patients. The clinical and immunologic findings from these HTLV-II-infected patient resemble those found in HTLV-I-associated myelopathy/tropical spastic paraparesis.


Effect of short course of 1,25-dihydroxyvitamin D3 on biochemical markers of bone remodelling in postmenopausal women.
This study was designed to test the hypothesis that a short treatment course of 1,25(OH)2D3 elicits a stimulation of osteoblast activity without any action on the osteoclast. To test this, oral daily doses of 0.5 microgram or 1 microgram of 1,25(OH)2D3 were administered for 7 days to two groups (n = 5 and n = 7, respectively) of postmenopausal women with low bone mineral density. Markers of osteoblast activity, i.e. osteocalcin (BGP), total alkaline phosphatase activity (ALP) and bone alkaline phosphatase activity (BALP), and markers of osteoclast activity, i.e. hydroxylysyl-pyridinoline (Pyr), lysyl-pyridinoline (D-Pyr), and galactosyl-hydroxylysine (GHyl) were measured in plasma and in fasting urinary samples, respectively, at sequential times during and after 1,25(OH)2D3 administration. It resulted that short term 1 microgram 1,25(OH)2D3 oral administration induced a significant (P < 0.05) rise of BGP serum level without any associated increase of D-Pyr and GHyl, the latter also expressed as GHyl to GGHyl ratio. Urinary Pyr increased significantly after 1 microgram daily doses of 1,25(OH)2D3. Thus, a short course of 1 microgram daily doses of 1,25(OH)2D3 elicits a stimulation of osteoblast activity without any enhancement of D-Pyr, the most specific marker of osteoclast activity. The enhancement of Pyr after 1 microgram daily doses of 1,25(OH)2D3 might be due to the activation of extraosseous metabolic pathways rather than to the activation of osteoclast.


Assessment of two devices for in vitro preparation of human sperm.
The aim of the study was to assess and compare the efficiency of the ZSC-II versus the Sperm Select techniques in preparing human sperm from normozoospermic patients for use in intrauterine insemination and other assisted reproductive technologies. Twenty-five patients were included in the study. Semen was collected at intercourse and processed via 2 sperm preparation methods. Recovery of motile sperm and other sperm qualitative measurements were evaluated before and after ZSC-II and Sperm Select sperm preparation. Sperm qualitative measurements were not significantly different after the ZSC-II and Sperm Select procedures (p > .05). Differences (p < .05) were noted between the 2 procedures in the number of sperm recovered. A higher survival rate (longevity test, 72 h) was observed after ZSC-II sperm preparation and recovery. The ZSC-II procedure yielded higher total motile sperm than the Sperm Select. The superiority in longevity may suggest possible advantages in obtaining higher fertilization and pregnancy rates.


Impact of the COVID-19 Pandemic on the Future of Nursing Education.
Nursing is the largest health profession, with nearly 4 million providers practicing across acute, primary, and public health care settings. In response to the pandemic, nursing schools halted on-site course delivery and redesigned programs to attenuate risks to students and faculty. Key challenges faced by schools included financial cutbacks, rapid increases in online learning technology, maintaining student academic progression, disruption to clinical learning opportunities, and meeting accreditation standards, while addressing the stress and loss experienced by faculty, staff, and students. Despite challenges, nursing organizations provided guidance for decision making, new learning resources, and faculty development opportunities. Schools of nursing leveraged their resources to redesign nursing curricula, strengthen partnerships for student clinical experiences, and address needs of the community. Nursing education will look different from its prepandemic profile in the future. Lessons learned during the pandemic point to gaps in nursing education, particularly related to disaster and public health preparedness, health equity, and technology. The American Association of Colleges of Nursing's new Essentials-standards for professional nursing education-were finalized during the pandemic and reflect these lessons. The need for nurse scientists to conduct emergency response research was made evident. The importance of strong academic-practice partnerships was highlighted for rapid communication, flexibility, and responses to dynamic environments. For the future, nursing education and practice must collaborate to ensure that students and practicing nurses are prepared to address emergencies and pandemics, as well as the needs of vulnerable populations.


Synthesis, characterization, and crystal structure of aqua-bis-(4,4'-dimeth-oxy-2,2'-bi-pyridine)[μ-(2R,3R)-tartrato(4-)]dicopper(II) octa-hydrate.
Typical electroless copper baths (ECBs), which are used to chemically deposit copper on printed circuit boards, consist of an aqueous alkali hydroxide solution, a copper(II) salt, formaldehyde as reducing agent, an l-(+)-tartrate as complexing agent, and a 2,2'-bi-pyridine derivative as stabilizer. Actual speciation and reactivity are, however, largely unknown. Herein, we report on the synthesis and crystal structure of aqua-1κO-bis-(4,4'-dimeth-oxy-2,2'-bi-pyri-dine)-1κ2 N,N';2κ2 N,N'-[μ-(2R,3R)-2,3-dioxidosuccinato-1κ2 O 1,O 2:2κ2 O 3,O 4]dicopper(II) octa-hydrate, [Cu2(C12H12N2O2)2(C4H2O6)(H2O)]·8H2O, from an ECB mock-up. The title compound crystallizes in the Sohncke group P21 with one chiral dinuclear complex and eight mol-ecules of hydrate water in the asymmetric unit. The expected retention of the tartrato ligand's absolute configuration was confirmed via determination of the absolute structure. The complex mol-ecules exhibit an ansa-like structure with two planar, nearly parallel bi-pyridine ligands, each bound to a copper atom that is connected to the other by a bridging tartrato 'handle'. The complex and water mol-ecules give rise to a layered supra-molecular structure dominated by alternating π stacks and hydrogen bonds. The understanding of structures ex situ is a first step on the way to prolonged stability and improved coating behavior of ECBs.


Estimating Pulsatile Flow Velocity using Four-Dimensional Digital Subtraction Angiography.
Digital subtraction angiography (DSA) is a X-ray based imaging modality for interventional procedures, and remains criterion standard for diagnosing vascular diseases. The imaging protocol of DSA involves administration of a foreign contrast medium into the blood vessel that opacifies the vasculature during the imaging. Using two-dimensional (2D) DSA with high temporal resolution, it was recently demonstrated that the pulsatile velocity can be estimated by evaluating the temporal and spatial variations of the contrast medium distributions in the blood vessel. In this paper, we evaluate the feasibility to estimate the pulsatile flow velocity using the four-dimensional (4D) DSA. To overcome the noise and artefacts of 4D-DSA data, a empirical mode decomposition plus autocorrelation based method is proposed to estimate the pulsatile velocities, and the pulsatile velocities estimated using 2D-DSA are used as reference for comparison.Clinical Relevance-4D-DSA encompasses both structural and temporal information; it theoretically reduces the need of multiple scans, hence reducing the radiation doses. The estimated pulsatile flow velocities open up a new parameter for hemodynamic studies and potential for real-time diagnostic and therapeutic monitoring during interventional procedures.


Role of demographic dynamics and conflict in the population-area relationship for human languages.
Many patterns displayed by the distribution of human linguistic groups are similar to the ecological organization described for biological species. It remains a challenge to identify simple and meaningful processes that describe these patterns. The population size distribution of human linguistic groups, for example, is well fitted by a log-normal distribution that may arise from stochastic demographic processes. As we show in this contribution, the distribution of the area size of home ranges of those groups also agrees with a log-normal function. Further, size and area are significantly correlated: the number of speakers p and the area a spanned by linguistic groups follow the allometric relation a proportional to p2, with an exponent z varying accross different world regions. The empirical evidence presented leads to the hypothesis that the distributions of p and a, and their mutual dependence, rely on demographic dynamics and on the result of conflicts over territory due to group growth. To substantiate this point, we introduce a two-variable stochastic multiplicative model whose analytical solution recovers the empirical observations. Applied to different world regions, the model reveals that the retreat in home range is sublinear with respect to the decrease in population size, and that the population-area exponent z grows with the typical strength of conflicts. While the shape of the population size and area distributions, and their allometric relation, seem unavoidable outcomes of demography and inter-group contact, the precise value of z could give insight on the cultural organization of those human groups in the last thousand years.


Immune response of children who develop persistent diarrhea following rotavirus infection.
A prospective study was conducted with Bangladeshi children with rotavirus (RV) diarrhea to assess whether nutritional and clinical parameters, RV serotypes, levels of interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma), and RV-specific antibody titers in plasma and stool were associated with the development of persistent diarrhea. Children with watery diarrhea for 6 to 8 days, selected from the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), were enrolled in the study and monitored until diarrhea improved. Children were classified as having acute diarrhea (AD) if diarrhea resolved within 14 days of onset and as having persistent diarrhea (PD) if diarrhea persisted for more than 14 days after onset. Uninfected, control children (n = 13) from the Nutrition Follow-Up Unit of ICDDR,B were also enrolled. Of the 149 children with diarrhea enrolled, 29 had diarrhea with RV alone, of which 19 had AD and 10 developed PD. Samples of stool and blood were collected from all children on enrollment. Stool samples were collected again from children when they developed PD. Of the 10 children who had an initial RV infection and then developed PD, only one had persistent RV infection. Plasma levels of IL-10 and TNF-alpha were higher in children with diarrhea compared to uninfected controls but were similar in children with AD and PD. Plasma IFN-gamma levels were higher in children who developed PD than in those with AD (P = 0.008) or uninfected controls (P = 0.001). In stools, the levels of TNF-alpha, the only cytokine detected, were similar in the three groups of children. RV-specific immunoglobulin G (IgG) titers in plasma were higher in uninfected children than in those with AD (P < 0.001) or PD (P = 0.024) but titers were similar in children with AD and PD. RV-specific IgA titers in plasma and stool were similar in the three groups of children. From all observed parameters, only elevated plasma IFN-gamma levels were associated with subsequent development of PD. However, a larger sample size is necessary to substantiate this observation.


The Development of Nonthermal Plasma and Tirapazamine as a Novel Combination Therapy to Treat Melanoma In Situ.
Although melanoma accounts for only 5.3% of skin cancer, it results in >75% of skin-cancer-related deaths. To avoid disfiguring surgeries on the head and neck associated with surgical excision, there is a clear unmet need for other strategies to selectively remove cutaneous melanoma lesions. Mohs surgery is the current treatment for cutaneous melanoma lesions and squamous and basal cell carcinoma. While Mohs surgery is an effective way to remove melanomas in situ, normal tissue is also excised to achieve histologically negative margins. This paper describes a novel combination therapy of nonthermal plasma (NTP) which emits a multitude of reactive oxygen species (ROS) and the injection of a pharmaceutical agent. We have shown that the effects of NTP are augmented by the DNA-damaging prodrug, tirapazamine (TPZ), which becomes a free radical only in conditions of hypoxemia, which is often enhanced in the tumor microenvironment. In this study, we demonstrate the efficacy of the combination therapy through experiments with B16-F10 and 1205 Lu metastatic melanoma cells both in vitro and in vivo. We also show the safety parameters of the therapy with no significant effects of the therapy when applied to porcine skin. We show the need for the intratumor delivery of TPZ in combination with the surface treatment of NTP and present a model of a medical device to deliver this combination therapy. The importance of functional gap junctions is indicated as a mechanism to promote the therapeutic effect. Collectively, the data support a novel therapeutic combination to treat melanoma and the development of a medical device to deliver the treatment in situ.


Incidence of Long-Term Esophageal Dilation With Various Treatment Approaches in the Older Head and Neck Cancer Population.
Purpose: Treatments for locoregionally advanced head and neck cancer (LAHNC) negatively impact swallowing function, but the long-term incidence of severe toxicity requiring esophageal dilation is not well-documented in the population. The aim of this study was to compare the incidence of long-term esophageal dilation across varying treatments for LAHNC. Methods and Materials: We identified 5,223 patients with LAHNC diagnosed from 2000 to 2009 in the SEER-Medicare database. We compared the incidence of esophageal dilation for surgery alone vs. surgery plus adjuvant radiotherapy (RT) and chemoradiotherapy (CRT) vs. definitive RT or CRT. Results: The cumulative incidence of esophageal dilation for all sites at 10 years, according to treatment group were as follows: CRT, 14% (95% confidence interval (CI), 12-17%); definitive RT, 13% (95% CI, 10-16%); surgery alone, 5% (95% CI, 3-7%); surgery and CRT, 15% (95% CI, 11-19%); surgery and adjuvant RT: 10% (95% CI, 8-13%). There was no significant difference in the incidence of esophageal dilation between surgery plus adjuvant RT/CRT or definitive RT/CRT (p = 0.37), but the incidence was significantly increased in both groups compared to surgery alone (p = 0.003). On multivariable analysis, chemotherapy was associated with significantly increased incidence of esophageal dilation (HR 2.9, 95% CI 1.5-5.5, p < 0.001) in oropharyngeal cancers. Conclusions: The incidence of esophageal dilation is similar in LAHNC patients undergoing RT with or without surgery. Chemoradiotherapy increases the long-term risk of esophageal dilation events over surgery alone.


Sports Participation, Health Behaviours, and Body Fat during Childhood and Early Adolescence: A Multiple Mediation.
The aim of this study was to simultaneously explore multiple pathways through which sports participation during childhood and adolescence may be associated with adiposity over time. Data were drawn from the Kindergarten cohort of the Longitudinal Study of Australian Children. A total of 4286 children provided sports participation data at age 10 years and were followed up 24 and 48 months later. Time spent in organised sports at age 10 years and time spent in physical activity at age 12 years were measured via parental-reported time-use diary. Dietary behaviours were self-reported at age 12 years. Screen time was parent-reported. Body fat was measured at age 14 using bioelectrical impedance analysis. Two parallel multiple mediation models were tested to examine the longitudinal associations between sport participation at age 10 and body fat at age 14 via the mediating variables of physical activity, screen time, and dietary behaviours. One model was run for all participants, and a second model was run only for those participants who reported participating in organised sports. There were no significant indirect relationships between sports participation and body fat via any of the mediating variables in the total sample, or among sport participants. There is a dearth of evidence to support substantial rhetoric and policy to promote organised sports programs as public health initiatives in their current form during childhood and adolescence. Better quality evidence is needed, however, modifications to sport programs may be necessary to elucidate meaningful benefits for adiposity.


Generation of intense 11-fs ultraviolet pulses using phase modulation by two types of coherent molecular motions.
The use of two types of phase modulations arising from the coherent rotations of ortho-hydrogen and para-hydrogen to generate an intense ultrashort ultraviolet pulse without substantial generation of sub-pulses was demonstrated. This technique allows use of a high-energy long-probe pulse in the pump-probe regime for generating a high-energy compressed pulse. A 100-fs ultraviolet pulse was compressed to 11-fs by the phase modulation followed by dispersion compensation with chirped mirrors.


[Administration of the immunomodulator gepon after tonsillectomy].
The study included 37 patients with chronic tonsillitis. Before and after tonsillectomy all the patients' humoral and cellular immunities were studied. Local thermometry and physiological test "pharynx" were made. For optimization of early postoperative period, all the tonsillectomized patients were given a domestic immunomodulator with local anti-inflammatory activity gepon. The results of gepon therapy allowed conclusion that local use of immunomodulator gepon early after bilateral tonsillectomy is justified and can be recommended for wide clinical practice.


Mixed metal double salt ionic liquids comprised of [HN222]2[ZnCl4] and AlCl3 provide tunable Lewis acid catalysts related to the ionic environment.
Two solids of differing Lewis acidities, triethylammonium tetrachlorozincate ([HN222]2[ZnCl4]) and AlCl3, have been combined across 0.1 to 0.9 mole fractions (with respect to [HN222]2[ZnCl4]), and homogeneous solid double salts or mixed metal [HN222]2x[(1 - x)AlCl3 + xZnCl4] double salt ionic liquids (DSILs) were obtained at x = 0.33, 0.4, and 0.5 with varying Lewis acidities. The characterization of the prepared DSILs (melting point, color, homogeneity, 1H, 13C, and 27Al nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), single crystal X-ray diffraction (SCXRD), and matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry) suggests that [HN222]2[ZnCl4] transfers Cl- from [ZnCl4]2- to the stronger Lewis acid AlCl3, forming intermediate acidic DSILs with [AlCl4]- and [Al2Cl7]- anions and mixed anionic Zn species. Qualitative Lewis acidity measurements using acetonitrile as an IR-active probe showed that the acidity of the DSILs decreased as the amount of [ZnCl4]2- increased. In a Beckman rearrangement reaction of acetophenone oxime, significant catalytic activity was observed for the DSIL at x = 0.33, where the activity of the DSIL was found to be even higher than [HN222][Al2Cl7], AlCl3, [HN222]2[ZnCl4], or ZnCl2 despite its lower Lewis acidity, apparently due to the synergistic effect of AlCl3 and [ZnCl4]2- as Cl- donors for the formation of catalytically active species. The findings illustrate a DSIL-based approach for modifying the catalytic activity of a known complex without changing its inner coordination sphere.


Identification of a structural element in phospholipase C beta2 that interacts with G protein betagamma subunits.
To delineate the specific regions of phospholipase C beta2 (PLC beta2) involved in binding and activation by G protein betagamma subunits, we synthesized peptides corresponding to segments of PLC beta2. Two overlapping peptides corresponding to Asn-564-Lys-583 (N20K) and Glu-574-Lys-593 (E20K) inhibited the activation of PLC beta2 by betagamma subunits (IC50 50 and 150 microM, respectively), whereas two control peptides did not. N20K and E20K, but not the control peptides, inhibited betagamma-dependent ADP-ribosylation of Galphai1 by pertussis toxin and betagamma-dependent activation of phosphoinositide 3-kinase. To demonstrate direct binding of the peptides to betagamma subunits, the peptides were chemically cross-linked to purified beta1gamma2. N20K and E20K cross-linked to both beta1 and gamma2 subunits, whereas the control peptides did not. Cross-linking to beta and gamma was inhibited by incubation with excess PLC beta2 or PLC beta3, whereas cross-linking to gamma but not beta was inhibited by r-myr-alphai1. These data together demonstrate specificity of N20K and E20K for G betagamma binding and inhibition of effector activation by betagamma subunits. The results suggest that an overlapping region of the two active peptides, Glu-574-Lys-583, mimics a region of PLC beta2 that is involved in binding to betagamma subunits. Changing a tyrosine to a glutamine in this overlapping region of the peptides inhibited binding of the peptide to betagamma subunits. Alignment of these peptides with the three-dimensional structure from PLC delta1 identifies a putative alpha helical region on the surface of the catalytic domain of PLC beta2 that could interact with betagamma subunits.


Value of turbinoplasty in rhinosurgery - a controlled randomized study.
Turbinoplasty is a common procedure in patients with nasal obstruction and hypertrophy of the nasal turbinates. A general recommendation regarding the necessity of turbinoplasty in functional rhinosurgery is still missing. For the first time, the value of turbinoplasty in septo- and septorhinoplasty regarding patient satisfaction as well as objective data in rhinomanometry and acoustic rhinometry was analyzed in a prospective randomized controlled trial. 73 patients with nasal obstruction due to septal deviation and / or a deviated nose were included in the study. After randomization, anterior turbinoplasty was or was not performed during septo- or septorhinoplasty. Pre- and postoperative rhinomanometry and acoustic rhinometry were accomplished. NOSE© and SNOT 20 questionnaires were completed by the patients before and 9 months after surgery. Additionally, the patients were asked about their subjective satisfaction. 81% of the patients were subjectively satisfied with the postoperative improvement of nasal breathing. There was a significant improvement in the values of NOSE© and SNOT 20 questionnaires with no relevant difference between the two study groups. Acoustic rhinometry and rhinomanometry showed values in MCA1 and 2, Vol 1 and Vol 2 as well as higher nasal flows with no statistically significant difference between the two study groups. Patient satisfaction after functional septo- and septorhinoplasty is high and does not seem to be affected by turbinate surgery. There was no statistically significant difference in the postoperative results regarding objective rhinological measurements with or without turbinoplasty. As extensive resections of the turbinates can have a negative impact on nasal physiology, the indication for turbinoplasty must be considered carefully.


Laser heterodyne interferometric signal processing method based on rising edge locking with high frequency clock signal.
A novel phase measurement method composed of the rising-edge locked signal processing and the digital frequency mixing is proposed for laser heterodyne interferometer. The rising-edge locked signal processing, which employs a high frequency clock signal to lock the rising-edges of the reference and measurement signals, not only can improve the steepness of the rising-edge, but also can eliminate the error counting caused by multi-rising-edge phenomenon in fringe counting. The digital frequency mixing is realized by mixing the digital interference signal with a digital base signal that is different from conventional frequency mixing with analogue signals. These signal processing can improve the measurement accuracy and enhance anti-interference and measurement stability. The principle and implementation of the method are described in detail. An experimental setup was constructed and a series of experiments verified the feasibility of the method in large displacement measurement with high speed and nanometer resolution.


Adipose tissue hormones and appetite and body weight regulators in insulin resistance.
Impaired sensitivity to insulin (the so called insulin resistance, IR) occurs in a number of genetic and acquired conditions, including obesity, non-insulin dependent diabetes mellitus, polycystic ovary syndrome (PCOS) and metabolic syndrome (MS). In this review we discuss the correlation between IR, the adipose tissue hormones and appetite and body weight regulators. Leptin acts as a major adipostat: it suppresses food intake and activates catabolic pathways associated with increased energy production. It improves the peripheral insulin sensitivity and affects beta-cell function. Adiponectin is the only adipocytokine discovered so far that has anti-atherogenic properties. There is a reverse correlation between the serum adiponectin levels and the degree of obesity, IR, impaired glucose tolerance, dyslipidemia and atherosclerosis. Ghrelin stimulates food intake; of all circulating orexigenic hormones ghrelin is the most thoroughly studied. Ghrelin levels are decreased in MS and PCOS patients as this hormone is negatively correlated with body mass. Resistin is a hormone secreted by adipose tissues; a growing body of evidence suggests that it might be implicated in the link between obesity and diabetes. It has been found that the hormone's levels are significantly higher in obese people than those in normal body mass people. The recently discovered adipose tissue hormones, vaspin, visfatin, omentin-1 and their effect on IR development, have been increasingly researched.


The performance of cathodically pretreated boron-doped diamond electrode in cationic surfactant media for enhancing the adsorptive stripping voltammetric determination of catechol-containing flavonoid quercetin in apple juice.
In the present paper, an electroanalytical methodology was developed for the determination of an important catechol-containing flavonoid derivative, quercetin using adsorptive stripping voltammetry at a cathodically pretreated boron-doped diamond electrode. In cyclic voltammetry, the compound showed a couple of oxidation/reduction peak at low positive potentials, and additional two oxidation peaks at more positive potentials. The sensitivity of the stripping voltammetric measurements was significantly improved when the cationic surfactant, cetyltrimethylammonium bromide (CTAB) was present in the electrolyte solution. Using square-wave stripping mode, a highly linear analytical curve was obtained for quercetin determination in 0.1 M acetate buffer solution (pH 4.7) containing 3 × 10-4 M CTAB at + 0.37 V (vs. Ag/AgCl) (after 30 s accumulation at open-circuit condition) in the range of 0.5-200 ng mL-1 (1.7 × 10-9-3.3 × 10-7 M), with a detection limit of 0.132 ng mL-1 (4.4 × 10-10 M). As an example, the practical applicability of proposed method was successfully tested with the measurement of quercetin concentration in commercial apple juice samples.


Methodology for Estimation of Annual Risk of Rupture for Abdominal Aortic Aneurysm.
Estimating patient specific annual risk of rupture of abdominal aortic aneurysm (AAA) is currently based only on population. More accurate knowledge based on patient specific data would allow surgical treatment of only those AAAs with significant risk of rupture. This would be beneficial for both patients and health care system. A methodology for estimating annual risk of rupture (EARR) of abdominal aortic aneurysms (AAA) that utilizes Bayesian statistics, mechanics and patient-specific blood pressure monitoring data is proposed. EARR estimation takes into consideration, peak wall stress in AAA computed by patient-specific finite element modeling, the probability distributions of wall thickness, wall strength, systolic blood pressure and the period of time that the patient is known to have already survived with the intact AAA. Initial testing of proposed approach was performed on fifteen patients with intact AAA (mean maximal diameter 51mm±8mm). They were equipped with a pressure holter and their blood pressure was recorded over 24 hours. Then, we calculated EARR values for four possible scenarios - without considering any days of survival prior identification of AAA at computed tomography scans (EARR_0), considering past survival of 30 (EARR_30), 90 (EARR_90) and 180 days (EARR_180). Finally, effect of patient-specific blood pressure variability was analyzed. Consideration of past survival does indeed significantly improve predictions of future risk: EARR_30 (1.04%± 0.87%), EARR_90 (0.67%± 0.56%) and EARR_180 (0.47%± 0.39%) which are unrealistically high otherwise (EARR_0 5.02%± 5.24%). Finally, EARR values were observed to vary by an order as a consequence of blood pressure variability and by factor of two as a consequence of neglected growth. Methodology for computing annual risk of rupture of AAA was developed for the first time. Sensitivity analyses showed respecting patient specific blood pressure is important factor and should be included in the AAA rupture risk assessment. Obtained EARR values were generally low and in good agreement with confirmed survival time of investigated patients so proposed method should be further clinically validated.


Dynamic mutation-selection balance as an evolutionary attractor.
The vast majority of mutations are deleterious and are eliminated by purifying selection. Yet in finite asexual populations, purifying selection cannot completely prevent the accumulation of deleterious mutations due to Muller's ratchet: once lost by stochastic drift, the most-fit class of genotypes is lost forever. If deleterious mutations are weakly selected, Muller's ratchet can lead to a rapid degradation of population fitness. Evidently, the long-term stability of an asexual population requires an influx of beneficial mutations that continuously compensate for the accumulation of the weakly deleterious ones. Hence any stable evolutionary state of a population in a static environment must involve a dynamic mutation-selection balance, where accumulation of deleterious mutations is on average offset by the influx of beneficial mutations. We argue that such a state can exist for any population size N and mutation rate U and calculate the fraction of beneficial mutations, ε, that maintains the balanced state. We find that a surprisingly low ε suffices to achieve stability, even in small populations in the face of high mutation rates and weak selection, maintaining a well-adapted population in spite of Muller's ratchet. This may explain the maintenance of mitochondria and other asexual genomes.


Chasing bacterial chassis for metabolic engineering: a perspective review from classical to non-traditional microorganisms.
The last few years have witnessed an unprecedented increase in the number of novel bacterial species that hold potential to be used for metabolic engineering. Historically, however, only a handful of bacteria have attained the acceptance and widespread use that are needed to fulfil the needs of industrial bioproduction - and only for the synthesis of very few, structurally simple compounds. One of the reasons for this unfortunate circumstance has been the dearth of tools for targeted genome engineering of bacterial chassis, and, nowadays, synthetic biology is significantly helping to bridge such knowledge gap. Against this background, in this review, we discuss the state of the art in the rational design and construction of robust bacterial chassis for metabolic engineering, presenting key examples of bacterial species that have secured a place in industrial bioproduction. The emergence of novel bacterial chassis is also considered at the light of the unique properties of their physiology and metabolism, and the practical applications in which they are expected to outperform other microbial platforms. Emerging opportunities, essential strategies to enable successful development of industrial phenotypes, and major challenges in the field of bacterial chassis development are also discussed, outlining the solutions that contemporary synthetic biology-guided metabolic engineering offers to tackle these issues.


The utility of lactate dehydrogenase in the follow up of patients with diffuse large B-cell lymphoma.
Serum lactate dehydrogenase is a non-specific marker for lymphoma whose prognostic significance is well established for both indolent and aggressive lymphomas at the time of diagnosis. The performance characteristics of this enzyme in predicting relapse in patients with diffuse large B-cell lymphoma has not been well studied. This study compared serum lactate dehydrogenase levels in 27 patients with diffuse large B-cell lymphoma who relapsed after sustaining a complete response versus 87 patients who did not relapse. For relapsed patients, the serum lactate dehydrogenase level at relapse was compared with the level three months before (considered baseline). For non-relapsed patients, the last two levels during follow-up were compared. For statistical analysis the T-test was used to compare differences in mean values between groups. The sensitivity, specificity, positive and negative predictive values for serum lactate dehydrogenase in detecting relapse compared to confirmatory imaging were calculated. At relapse, only 33% patients had increases in serum lactate dehydrogenase above the upper limit of normal. The mean increase was 1.2-fold above the upper limit of normal for relapsed vs. 0.83 for those who did not relapse (p-value = 0.59). The mean increase in serum lactate dehydrogenase, from baseline, was 1.1-fold in non-relapsed vs. 1.3 in relapsed patients (p-value = 0.3). The likelihood ratio of relapse was 4.65 for patients who had 1.5-fold increases in serum lactate dehydrogenase above baseline (p-value = 0.03). The sensitivity, specificity, positive and negative predictive values of 1.5-fold increases for detecting relapse, compared to clinical and imaging findings were 0.18, 0.95, 0.55, and 0.79, respectively. A 1.5-fold increase in serum lactate dehydrogenase, over a period of 3 months, is associated with increased likelihood of relapse from diffuse large B-cell lymphoma.


Geographutoxin II, a novel peptide inhibitor of Na channels of skeletal muscles and autonomic nerves.
Geographutoxin II (GTX II, 3 X 10(-9) to 10(-7) M) from a cone shell Conus geographus inhibited twitch responses of the isolated mouse diaphragm to direct stimulation in a dose-dependent manner. The contraction of the diaphragm induced by grayanotoxin I or veratridine was abolished by GTX II (3 X 10(-7) M), whereas the contractile response to KCI or caffeine was not affected. GTX II induced similar effects on isolated bullfrog sartorius muscles, but required higher concentrations (6 X 10(-7) to 3 X 10(-6) M). GTX II (greater than 10(-6) M) inhibited or abolished the action potential evoked in sartorius muscles markedly. In the isolated guinea pig vas deferens and ileum, GTX II caused a dose-dependent inhibition of the twitch responses to indirect nerve stimulation at concentrations of 3 X 10(-8) to 10(-6) M and 10(-7) to 10(-6) M, respectively. But the toxin had no effect on the dose contractile-response curves for norepinephrine, carbamylcholine or KCI in the vas deferens and for carbamylcholine or histamine in the ileum. GTX II (5 X 10(-8) to 10(-6) M) decreased norepinephrine release induced by veratridine from the vas deferens in a dose-dependent manner. These results suggest that GTX II blocks the voltage-sensitive Na channels in the cell membrane of skeletal muscles and autonomic nerves and these may play an important role in the mechanism of inhibitory effects of GTX II on contractile responses of these tissues to electrical stimulation.


Resuscitation from Cardiac Arrest with Tension Gastrothorax Due to Acquired Diaphragmatic Hernia.
Tension gastrothorax is a rare cause of obstructive shock induced by a distended stomach herniating into the thorax through a diaphragmatic defect. We report the process of diagnosis and emergency treatment for tension gastrothorax during cardiopulmonary resuscitation (CPR). A 71-year-old woman with multiple surgical histories had nausea and vomiting for two days. She was transferred to our hospital with circulatory failure and loss of consciousness. She presented pulseless electric activity and received CPR immediately after arrival. The right atrium and right ventricle were collapsed in the echocardiography. A chest X-ray demonstrated a dilated intestine extending from the peritoneal cavity to the mediastinum. The nasogastric tube (NGT) drained 1000 mL of stomach content and alleviated the abdominal distension, and spontaneous circulation returned immediately after the drainage. Thoracoabdominal CT showed the stomach and the transverse colon had escaped from the peritoneal cavity to the mediastinum. We diagnosed the situation as tension gastrothorax due to an acquired diaphragmatic hernia. History of multiple surgery and multiple operative scars was the first step of the diagnostic process, and the chest X-ray during CPR was the key to the diagnosis. Tension gastrothorax can be misdiagnosed as other conditions. A chest X-ray should be preceded in non-trauma settings, unlike the setting of a tension pneumothorax in trauma patients. Gastrointestinal decompression with NGT placement could be attempted quickly to improve the hemodynamic condition.


[Long-range electron transfer in globular proteins by polaron excitation].
Considering polaron model, we have calculated an electron state localized in the protein heme. Using these calculations: the electron density and electron energy, we estimated the self-exchange rate constant for cyt c (horse heart), its reorganization energy, matrix element, and dependence of this rate on the distance between hemes. The results are compared with the experimental data and other theoretical estimations. We discuss the role of polaron excitations in the long-range electron transfer in globular proteins.


C5orf51 is a component of the MON1-CCZ1 complex and controls RAB7A localization and stability during mitophagy.
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy.Abbreviations: ATG9A: autophagy related 9A; Baf A1: bafilomycin A1; BioID: proximity-dependent biotin identification; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CCZ1: CCZ1 homolog, vacuolar protein trafficking and biogenesis associated; DQ-BSA: dye quenched-bovine serum albumin; FYCO1: FYVE and coiled-coil domain autophagy adaptor 1; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; KO: knockout; LRPPRC: leucine rich pentatricopeptide repeat containing; MG132: carbobenzoxy-Leu-Leu-leucinal; MON1: MON1 homolog, secretory trafficking associated; mtDNA: mitochondrial DNA; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; RMC1: regulator of MON1-CCZ1; TBC1D15: TBC1 domain family member 15; TBC1D17: TBC1 domain family member 17; TOMM20: translocase of outer mitochondrial membrane 20; WDR91: WD repeat domain 91; WT: wild type.


Association between rhythmic masticatory muscle activity during sleep and masticatory myofascial pain: a polysomnographic study.
To test for an association between rhythmic masticatory muscle activity during sleep, as assessed according to polysomnographic criteria for sleep bruxism (RMMA-SB), and myofascial pain (MFP), as well as the chance of occurrence of MFP in patients with RMMA-SB. Thirty MFP patients (diagnosed according to the Research Diagnostic Criteria for Temporomandibular Disorders) and 30 age- and gender-matched asymptomatic controls underwent a polysomnographic examination. Also, any self-reporting of daytime clenching (DC) was registered in 58 of these subjects. Most MFP patients reported mild or moderate pain (46.67% and 43.33%, respectively), and only 3 (10%) reported severe pain. Pain duration ranged from 2 to 120 months (mean 34.67 +/- 36.96 months). Significant associations were observed between RMMA-SB and MFP as well as between DC and MFP. (1) RMMA-SB is significantly associated with MFP; (2) although RMMA-SB represents a risk factor for MFP, this risk is low; and (3) DC probably constitutes a stronger risk factor for MFP than RMMA-SB.


A Qualitative Study of Hospitalists' Perceptions of Patient Satisfaction Metrics on Pain Management.
Hospital initiatives to promote pain management may unintentionally contribute to excessive opioid prescribing. To better understand hospitalists' perceptions of satisfaction metrics on pain management, the authors conducted 25 interviews with hospitalists. Transcribed interviews were systematically analyzed to identify emergent themes. Hospitalists felt institutional pressure to earn high satisfaction scores for pain, which they perceived influenced practices toward opioid prescribing. They felt tying compensation to satisfaction scores commoditized pain. Hospitalists believed satisfaction would improve with increased time spent at the bedside. Focusing on methods to improve patient-physician communication, while maintaining efficiency in clinical practice, may promote both patient-centered pain management and satisfaction.


Dispersive photon blockade in a superconducting circuit.
Mediated photon-photon interactions are realized in a superconducting coplanar waveguide cavity coupled to a superconducting charge qubit. These nonresonant interactions blockade the transmission of photons through the cavity. This so-called dispersive photon blockade is characterized by measuring the total transmitted power while varying the energy spectrum of the photons incident on the cavity. A staircase with four distinct steps is observed and can be understood in an analogy with electron transport and the Coulomb blockade in quantum dots. This work differs from previous efforts in that the cavity-qubit excitations retain a photonic nature rather than a hybridization of qubit and photon and provides the needed tolerance to disorder for future condensed matter experiments.


Fathers of Children With Type 1 Diabetes: Perceptions of a Father's Involvement From a Health Promotion Perspective.
This study describes how fathers of children diagnosed with type 1 diabetes understand their involvement in their child's daily life from a health promotion perspective. Sixteen Swedish fathers of children living with type 1 diabetes were interviewed. Manifest and latent content analysis was used to identify two themes: the inner core of the father's general parental involvement and the additional involvement based on the child's diabetes. The former was underpinned by the fathers' prioritization of family life and the fathers being consciously involved in raising the child, and the latter by the fathers promoting and controlling the child's health and promoting and enabling the child's autonomy. The results highlight that the quality of the fathers' involvement is essential in the management of a child's chronic illness. It is important for pediatric diabetes health care professionals to assess the quality of fathers' involvement to promote the child's health.


Ultrasonic locating devices for central venous cannulation: meta-analysis.
To assess the evidence for the clinical effectiveness of ultrasound guided central venous cannulation. 15 electronic bibliographic databases, covering biomedical, science, social science, health economics, and grey literature. Systematic review and meta-analysis of randomised controlled trials. Populations Patients scheduled for central venous access. INTERVENTION REVIEWED: Guidance using real time two dimensional ultrasonography or Doppler needles and probes compared with the anatomical landmark method of cannulation. Risk of failed catheter placement (primary outcome), risk of complications from placement, risk of failure on first attempt at placement, number of attempts to successful catheterisation, and time (seconds) to successful catheterisation. 18 trials (1646 participants) were identified. Compared with the landmark method, real time two dimensional ultrasound guidance for cannulating the internal jugular vein in adults was associated with a significantly lower failure rate both overall (relative risk 0.14, 95% confidence interval 0.06 to 0.33) and on the first attempt (0.59, 0.39 to 0.88). Limited evidence favoured two dimensional ultrasound guidance for subclavian vein and femoral vein procedures in adults (0.14, 0.04 to 0.57 and 0.29, 0.07 to 1.21, respectively). Three studies in infants confirmed a higher success rate with two dimensional ultrasonography for internal jugular procedures (0.15, 0.03 to 0.64). Doppler guided cannulation of the internal jugular vein in adults was more successful than the landmark method (0.39, 0.17 to 0.92), but the landmark method was more successful for subclavian vein procedures (1.48, 1.03 to 2.14). No significant difference was found between these techniques for cannulation of the internal jugular vein in infants. An indirect comparison of relative risks suggested that two dimensional ultrasonography would be more successful than Doppler guidance for subclavian vein procedures in adults (0.09, 0.02 to 0.38). Evidence supports the use of two dimensional ultrasonography for central venous cannulation.


International trends in nutritionally-related health and their implication for health policy.
To establish health policy which will be relevant and effectual for a decade or more, let alone the much longer term, is a challenging task for any period of human or planetary history. Presently it is more so than ever because of major demographic, economic, technological and scientific, climatic and territorial changes and uncertainties. There are various scenarios which might be envisaged for food-health relationships before global population size is expected to stabilize by about 2050, dependent on planetary health. These will reflect achieved food intakes which for many will not be optimal but realizable and food systems with varying degrees of safety, security and sustainability. Health patterns themselves are bound to continue to change from those associated with different levels of economic development to those which have more to do with locality, climate, education and equity. Every aspect of health is in some way intertwined with food and this will become more explicit. Decisions about food-health relationships will take into account the United Nations MDGs (Millennium Development Goals), but be strongly influenced by technology, affordability, sustainability and ethics.


Blunt liver injury in children and adults: is there really a difference?
Hepatic injuries are increasingly managed nonoperatively with the availability of adjunctive procedures such as angiography, ERCP, and percutaneous drainage. Although extensively discussed in the adult population, little has been reported on outcomes and management of pediatric liver injury. Retrospective review of all patients with blunt liver injuries admitted to an adult Level I trauma center and pediatric trauma center within the same community was performed from 2004 to 2006. The necessity for operation, adjuncts to nonoperative management, and outcome were collected and compared for the pediatric (PED) (<18 years of age) versus the adult (> or = 18 years of age) injured patients. There were 389 liver injuries identified (PED = 90, adult = 299); 25 per cent of adult injuries were greater than or equal to grade III, while 23 per cent of PED injuries were high-grade injuries. Each group of patients had similar rates of primary operative intervention: adult patients (18%) versus PED patients (16%). Adjunctive therapies were rarely used in the PED patients with only one patient requiring a percutaneous drain and one patient undergoing ERCP twice. Conversely, the adult patient group required eight percutaneous drains, 15 angiograms, 6 ERCPs and 14 laparoscopic abdominal washout procedures. ICU and hospital LOS were 25 per cent and 33 per cent lower in the adult population for high-grade injuries. The overall mortality rates were similar at 7 per cent (PED) and 9 per cent (adult). Liver-related mortality was 50 per cent (3/6 deaths) in the PED group with no liver-related deaths in the adult group (27 deaths). Adult patients with blunt liver injury were no more likely to sustain high grade liver injuries than PED patients. Furthermore, adult and PED patients underwent similar rates of operative intervention and primary liver procedures. Adult patients used adjunctive measures as part of their nonoperative management more frequently, but both subsets had similar length of hospital stays and low overall mortality. A higher rate of liver-related mortality was seen in the PED population. Overall, PED patients seemed to sustain fewer liver related complications necessitating invasive procedures despite similar injury patterns.


Cell surface expression of the multidrug resistance P-glycoprotein (P-170) as detected by monoclonal antibody MRK-16 in pediatric acute myeloid leukemia fails to define a poor prognostic group: a report from the Childrens Cancer Group.
Expression of the multidrug resistance (MDR-1) gene product, P-glycoprotein (P-170), and the stem cell antigen, CD34, at diagnosis were determined using monoclonal antibodies (MoAbs) MRK-16 and 12.8 respectively, in 130 pediatric acute myeloid leukemia (AML) patients entered onto Childrens Cancer Group (CCG) study CCG-2891. Fluorescein isothiocyanate (FITC) as a second step reagent was employed for the measurement of P-170 expression since it is commonly used in clinical laboratories. Nine of 30 (30%) infant ( < 1 year of age) de novo specimens expressed P-170 at levels > or = 20% of control cells. In contrast, eight of 100 (8%) AML samples from older children ( > or = 1 year of age) expressed the multidrug resistance surface protein at diagnosis. With the exception of one infant, all de novo samples that expressed P-170 also expressed CD34. Pediatric patients of any age with positive P-170 expression using MoAb MRK-16 with a FITC-conjugated second step reagent fared no worse than remaining patients treated on the same treatment with regard to induction failure, incidence of relapse, event-free survival, or overall survival. Further investigation is necessary to determine whether P-170 assay systems with greater sensitivity will distinguish pediatric AML patients with poor prognosis.


Feed-forward mechanism of converting biochemical cooperativity to mitotic processes at the kinetochore plate.
The feed-forward mechanism is observed in some of the intracellular events, such as metabolic and transcriptional regulatory networks, but not in dynamic mitotic processes. Mammalian polo-like kinase 1 (Plk1) rapidly accumulates at centrosomes and kinetochores as cells enter mitosis. Plk1 function is spatially regulated through the targeting activity of the polo-box domain (PBD) that binds to a phosphoepitope generated by either cyclin dependent kinase 1 (Cdk1) (non-self-priming) or Plk1 itself (self-priming). "Non-self-priming and binding" is thought to ensure the orderly execution of cell cycle events. The physiological significance of the "self-priming and binding" is unknown. Using a pair of ELISA, here we demonstrated that mutations of the self-priming site of a kinetochore component, PBIP1/MLF1IP/KLIP1/CENP-50/CENP-U (PBIP1), to a Cdk1-dependent non-self-priming site abolished product-activated cooperativity in the formation of the Plk1-PBIP1 complex. Both PBD-dependent "two-dimensional" interaction with surface-restricted PBIP1 and subsequent phosphorylation of PBIP1 by anchored Plk1 were crucial to cooperatively generate the Plk1-PBIP1 complex. Highlighting the importance of this mechanism, failure in this process resulted in improper Plk1 recruitment to kinetochores, mitotic arrest, chromosome missegregation, and apoptosis. Thus, Plk1 PBD-dependent biochemical cooperativity is tightly coupled to mitotic events at the kinetochore plate through a product-activated, feed-forward mechanism. Given the critical role of self-priming and binding in the recruitment of Plk1 to surface-confined structures, such as centrosomes, kinetochores, and midbody, we propose that the observed feed-forward mechanism serves as a fundamental biochemical process that ensures dynamic nature of Plk1 localization to and delocalization from these subcellular locations.


[Rehabilitation of schizophrenic patients with a protracted course under usual industrial conditions].
The authors studied the effectively of rehabilitation in 220 patients with a protracted course of the schizophrenic process in individually created conditions, at a usual industrial plant and in conditions of state farms. The clinical observations and dispersed analysis detected that there are multifold correlations between different clinical factors and the effectiveness of rehabilitation. The authors have their opinion concerning the necessity of elaborating differentiated clinical indications to the rehabilitation of schizophrenic patients with a prologned continuous stay in a hospital. According to 2-year following up the general outcome of rehabilitation was evaluated as favourable in 69%. These data permit to expand the present concept of the clinical and social prognosis in protracted forms of schizophrenia.


Isolation and Characterization of Two Postsynaptic Neurotoxins From Indian Cobra (Naja Naja) Venom.
The Indian Cobra (Naja naja) is among the "Big Four" responsible for most of the snakebite envenoming cases in India. Although recent proteomic studies suggest the presence of postsynaptic neurotoxins in N. naja venom, little is known about the pharmacology of these toxins. We isolated and characterized α-Elapitoxin-Nn2a (α-EPTX-Nn2a; 7020 Da) and α-Elapitoxin-Nn3a (α-EPTX-Nn3a; 7807 Da), a short-chain and long-chain postsynaptic neurotoxin, respectively, which constitute 1 and 3% of N. naja venom. α-EPTX-Nn2a (100-300 nM) and α-EPTX-Nn3a (100-300 nM) both induced concentration-dependent inhibition of indirect twitches and abolished contractile responses of tissues to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The prior incubation of tissues with Indian polyvalent antivenom (1 ml/0.6 mg) prevented the in vitro neurotoxic effects of α-EPTX-Nn2a (100 nM) and α-EPTX-Nn3a (100 nM). The addition of Indian polyvalent antivenom (1 ml/0.6 mg), at the t90 time point, could not reverse the in vitro neurotoxicity of α-EPTX-Nn2a (100 nM). The in vitro neurotoxicity of α-EPTX-Nn3a (100 nM) was partially reversed by the addition of Indian polyvalent antivenom (1 ml/0.6 mg), as well as repeated washing of the tissue. α-EPTX-Nn2a displayed non-competitive antagonism of concentration-response curves to carbachol, with a pA2 of 8.01. In contrast, α-EPTX-Nn3a showed reversible antagonism of concentration-response curves to carbachol, with a pA2 of 8.17. De novo sequencing of α-EPTX-Nn2a and α-EPTX-Nn3a showed a short-chain and long-chain postsynaptic neurotoxin, respectively, with 62 and 71 amino acids. The important observation made in this study is that antivenom can reverse the neurotoxicity of the clinically important long-chain neurotoxin, but not the short-chain neurotoxin, from N. naja venom.


Needle-shaped deposits on retinal surface in a case of ocular amyloidosis.
To report a case in which optical coherence tomography (OCT) showed needle-shaped deposits on the retinal surface oriented toward the vitreous cavity and immunohistochemical findings suggested light chain-related amyloidosis. A 59-year-old man with no systemic complications had bilateral neovascular glaucoma and vitreous opacities in the right eye. Vitrectomy was conducted on the right eye and the excised vitreous was examined histopathologically. Glass wool-like opacities were observed during vitrectomy. Postoperative fundus examination of the right eye showed retinal hemorrhage and white deposits around blood vessels and on retinal surface. Fluorescein angiography revealed hyperfluorescence of the optic disc, non-perfusion areas, and vascular focal staining. OCT depicted needle-shaped deposits perpendicular to the retinal surface oriented toward the vitreous. Histologic examination of deposits revealed positive reaction for Congo red stain, and immunohistochemical examination demonstrated positive reactivities for anti-lambda and anti-kappa light chains (precursors of amyloid protein), suggesting a diagnosis of light chain-related amyloidosis. In this case, OCT showed needle-shaped deposits perpendicular to the retinal surface. Special staining with Congo red revealed the deposit to be amyloid deposition. Immunohistochemical staining suggested light chain-related amyloidosis. Vascular obstructive lesions and neovascular glaucoma secondary to retinal vascular damage in amyloidosis warrant particular attention.


Entanglement Area Laws for Long-Range Interacting Systems.
We prove that the entanglement entropy of any state evolved under an arbitrary 1/r^{α} long-range-interacting D-dimensional lattice spin Hamiltonian cannot change faster than a rate proportional to the boundary area for any α>D+1. We also prove that for any α>2D+2, the ground state of such a Hamiltonian satisfies the entanglement area law if it can be transformed along a gapped adiabatic path into a ground state known to satisfy the area law. These results significantly generalize their existing counterparts for short-range interacting systems, and are useful for identifying dynamical phase transitions and quantum phase transitions in the presence of long-range interactions.


Identification and antibiotic susceptibility of Nocardia farcinica and N. nova in the UK.
Nocardia asteroides has long been recognised as a heterogeneous group of organisms. The description and identification of two new subgroups, N. farcinica and N. nova, in other countries encouraged us to re-examine a collection of N. asteroides isolates from the UK. Of 73 clinical isolates identified as N. asteroides from different parts of England and Wales during 1991-1993, and now subjected to further differentiation tests by the Mycobacterial/Nocardial Reference Laboratory, 15 (20.5%) were identified as N. farcinica based on three out of four characteristics: growth property, acetamide production, rhamnose assimilation and a distinct antibiogram. No isolates were identified as N. nova. A revised identification and susceptibility system has significant clinical and taxonomic implications. Its introduction will improve speciation, identify antibiotic resistance and influence the choice of safer alternative therapy for patients infected with Nocardia spp. in the UK.


Identification of CCAAT/enhancer-binding protein alpha as a transactivator of the mouse amelogenin gene.
Amelogenin expression is ameloblast-specific and developmentally regulated at the temporal and spatial levels. In a previous transgenic mouse analysis, the expression pattern of the endogenous amelogenin gene was recapitulated by a reporter gene driven by a 2. 2-kilobase mouse amelogenin proximal promoter. To understand the molecular mechanisms underlying the spatiotemporal expression of the amelogenin gene during odontogenesis, the mouse amelogenin promoter was systematically analyzed in mouse ameloblast-like LS8 cells. Deletion analysis identified a minimal promoter (-70/+52) containing a CCAAT/enhancer-binding protein (C/EBP)-binding site upstream of the TATA box. In transient transfection assays, C/EBPalpha up-regulated the promoter activity in a dose-dependent manner. The C/EBP-binding site was necessary for both C/EBPalpha-mediated transactivation and basal promoter activity. Electrophoresis mobility shift assays demonstrated that C/EBPalpha bound to its cognate site in the amelogenin promoter and that the binding was specific. Endogenous C/EBPalpha was detected in LS8 cells, and overexpression of exogenous C/EBPalpha in LS8 cells was able to increase the expression level of the endogenous amelogenin protein. The activity of the amelogenin promoter in rat parotid Pa-4 cells and Madin-Darby canine kidney cells was minimal, ranging from 20 to 30% of the activity in ameloblast-like cells. Transient transfection experiments showed that C/EBPalpha transactivated the mouse amelogenin reporter gene in Pa-4 cells, but not in Madin-Darby canine kidney cells. Taken together, these data indicate that C/EBPalpha is a bona fide transcriptional activator of the mouse amelogenin gene in a cell type-specific manner.


Detergent effects on the phosphatidylinositol-specific phospholipase C in rat brain synaptosomes.
In the presence of Ca2+ (2.5 mM) and using [14C]arachidonoyl phosphatidylinositol (PI) membrane as substrate, phosphatidylinositol-specific phospholipase C (PI-PLC) (EC 188.8.131.52) in rat brain synaptosomes was activated by deoxycholate but not taurocholate. Calcium stimulated enzymic hydrolysis by both detergents, but the stimulatory effect of taurocholate was less than that of deoxycholate. Peak stimulation for deoxycholate was observed at 1 mg/ml, whereas that for taurocholate was 4 mg/ml. When 1 mM EDTA was added to the taurocholate (4 mg/ml) and Ca2+ (3.5 mM) system, synaptosomal PI-PLC activity was greatly stimulated, to almost the same level as the deoxycholate + Ca2+ system. This system required the presence of all three factors, and EGTA could not effectively replace EDTA in the stimulatory action. The detergent-induced hydrolysis of synaptosomal PI by the deoxycholate + Ca2+ and the taurocholate + Ca2+ + EDTA systems was strongly inhibited by divalent metal ions such as Zn2+, Cu2+, Pb2+, and Fe2+, whereas Mg2+ and Ca2+ were ineffective. Nevertheless, only the deoxycholate + Ca2+ system was responsive to enzyme inhibition by membrane-perturbing agents such as lysophospholipids and free fatty acids. The specific requirement for EDTA in the taurocholate system may be due to the release of a pool of inhibitory divalent metal ions from the membranes.


Predicting defaunation: accurately mapping bushmeat hunting pressure over large areas.
Unsustainable hunting is emptying forests of large animals around the world, but current understanding of how human foraging spreads across landscapes has been stymied by data deficiencies and cryptic hunter behaviour. Unlike other global threats to biodiversity like deforestation, climate change and overfishing, maps of wild meat hunters' movements-often based on forest accessibility-typically cover small scales and are rarely validated with real-world observations. Using camera trapping data from rainforests across Malaysian Borneo, we show that while hunter movements are strongly correlated with the accessibility of different parts of the landscape, accessibility measures are most informative when they integrate fine-scale habitat features like topography and land cover. Measures of accessibility naive to fine-scale habitat complexity, like distance to the nearest road or settlement, generate poor approximations of hunters' movements. In comparison, accessibility as measured by high-resolution movement models based on circuit theory provides vastly better reflections of real-world foraging movements. Our results highlight that simple models incorporating fine-scale landscape heterogeneity can be powerful tools for understanding and predicting widespread threats to biodiversity.


Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals.
To perform a detailed clinical and psychophysical assessment of the members of three British families affected with blue cone monochromatism (BCM), and to determine the molecular basis of disease in these families. Affected and unaffected members of three families with BCM were examined clinically and underwent electrophysiological and detailed psychophysical testing. Blood samples were taken for DNA extraction. The strategy for molecular analysis was to amplify the coding regions of the long wavelength-sensitive (L) and middle wavelength-sensitive (M) cone opsin genes and the upstream locus control region by polymerase chain reaction, and to examine these fragments for mutations by direct sequencing. We have confirmed the reported finding of protan-like D-15 arrangements of patients with BCM. In addition, we have demonstrated that the Mollon-Reffin (MR) Minimal test is a useful colour-discrimination test to aid in the diagnosis of BCM. Affected males were shown to fail the protan and deutan axes, but retained good discrimination on the tritan axis of the MR test, a compelling evidence for residual colour vision in BCM. This residual tritan discrimination was also readily detected with HRR plates. In two families, psychophysical testing demonstrated evidence for progression of disease. In two pedigrees, BCM could be linked to unequal crossovers within the opsin gene array that resulted in a single 5'-L/M-3' hybrid gene, with an inactivating Cys203Arg mutation. The causative mutations were not identified in the third family. The MR test is a useful method of detecting BCM across a wide range of age groups; residual tritan colour discrimination is clearly demonstrated and allows BCM to be distinguished from rod monochromatism. BCM is usually classified as a stationary cone dysfunction syndrome; however, two of our families show evidence of progression. This is the first report of progression associated with a genotype consisting of a single 5'-L/M-3' hybrid gene carrying an inactivating mutation. We have confirmed that the Cys203Arg inactivating mutation is a common sequence change in blue cone monochromats.


Coherent branched flow in a two-dimensional electron gas.
Semiconductor nanostructures based on two-dimensional electron gases (2DEGs) could form the basis of future devices for sensing, information processing and quantum computation. Although electron transport in 2DEG nanostructures has been well studied, and many remarkable phenomena have already been discovered (for example, weak localization, quantum chaos, universal conductance fluctuations), fundamental aspects of the electron flow through these structures have so far not been clarified. However, it has recently become possible to image current directly through 2DEG devices using scanning probe microscope techniques. Here, we use such a technique to observe electron flow through a narrow constriction in a 2DEG-a quantum point contact. The images show that the electron flow from the point contact forms narrow, branching strands instead of smoothly spreading fans. Our theoretical study of this flow indicates that this branching of current flux is due to focusing of the electron paths by ripples in the background potential. The strands are decorated by interference fringes separated by half the Fermi wavelength, indicating the persistence of quantum mechanical phase coherence in the electron flow. These findings may have important implications for a better understanding of electron transport in 2DEGs and for the design of future nanostructure devices.


Mesenchymal stem cells seldomly fuse with hepatocellular carcinoma cells and are mainly distributed in the tumor stroma in mouse models.
Mesenchymal stem cells (MSCs) can have an effect on the growth and metastasis of human malignancies, including hepatocellular carcinoma (HCC); however, their mechanisms of action are not yet fully understood. The cell fusion of stem cell derived from bone marrow with other cells has been increasingly emphasized. The purpose of this study was to investigate the distribution of MSCs in mouse models of HCC, as well as the cell fusion between MSCs and HCC cells. We labeled HCC cells and MSCs with green fluorescence protein (GFP), red fluorescence protein (RFP), 4',6-diamidino-2-phenylindole (DAPI) and 5-bromo-2'-deoxyuridine (BrdU). We found that MSCs fused with HCC cells at a low frequency in vitro. MSCs were found to be merged into HCC tissues after intravenous injection, and compared with the mice not injected with MSCs, the MSCs were mainly distributed in the tumor stroma; Following the injection of the MSCs, the tumor stroma was found to have expanded in size, and the rate of pulmonary metastasis in the MSC-injected group was significantly lower (20%) compared to that in the group not injected with MSCs (100%, P=0.01). These data suggest that cell fusion between MSCs and HCC after engraftment is not one of the main mechanisms of action of the MSCs, while stromal differentiation is a major mechanism of action of the MSCs, leading to the inhibition of the pulmonary metastasis of HCC.


Iatrogenic Ankle Charcot Neuropathic Arthropathy after Spinal Surgery: A Case Report and Literature Review.
Charcot neuropathic arthropathy is a relatively rare, chronic disease that leads to joint destruction and reduced quality of life of patients. Early diagnosis of Charcot arthropathy is essential for a good outcome. However, the diagnosis is often based on the clinical course and longitudinal follow-up of patients is required. Charcot arthropathy is suspected in patients with suggestive symptoms and an underlying etiology. Failed spinal surgery is not a known cause of Charcot arthropathy. Herein we report a patient with ankle Charcot neuropathic arthropathy that developed after failed spinal surgery. A 58-year-old man presented to the emergency room due to painful swelling of the left ankle for 2 weeks that developed spontaneously. He underwent spinal surgery 8 years ago that was associated with nerve damage, which led to weakness of great toe extension and ankle dorsiflexion, and sensory loss below the knee. CT and T2-weighted sagittal MRI showed a fine erosive lesion, subluxation, sclerosis, fragmentation, and large bone defects. Based on the patient's history and radiological findings, Charcot arthropathy was diagnosed. However, the abnormal blood parameters, positive blood cultures, and severe pain despite the decreased sensation suggested a diagnosis of septic arthritis. Therefore, diagnostic arthroscopy was performed. The ankle joint exhibited continued destruction after the initial surgery. Consequently, several repeat surgeries were performed over the next 2 years. Despite the early diagnosis and treatment of Charcot arthropathy, the destruction of the ankle joint continued. Given the chronic disease course and poor prognosis of Charcot arthropathy, it is essential to consider this diagnosis in patients with neuropathy.


Adolescents' experiences of a school-based health promotion intervention in socioeconomically advantaged and disadvantaged areas in Sweden: a qualitative process evaluation study.
Adolescence is a transition period in which positive experiences of physical activity have the potential to last into later adulthood. These experiences are influenced by socioeconomic determinants, leading to health inequalities. This study aims to explore adolescents' experiences and participation in a multi-component school-based intervention in schools located in socioeconomically advantaged and disadvantaged areas in Sweden. A qualitative design was used to evaluate how participants experienced the intervention. The intervention was a multi-component school-based intervention. It was conducted in six schools (four control and two intervention schools) with a total of 193 students and lasted one school year. It was teacher-led and consisted of three 60-minute group sessions per week: varied physical activities, homework support with activity breaks, and walks while listening to audiobooks. In total, 23 participant observations were conducted over eight months and 27 students participated in focus groups. A content analysis was conducted. The results describe a main category 'Engaging in activities depending on socioeconomic status' and three generic categories: 1. Variations in participation in PA together with classmates and teachers; 2. Variations in engagement in PA after school; and 3. Differences in time and place allocated to do homework and listen to audiobooks. These categories illustrate how participants looked forward to the physical activities but used the time spent during the walks and homework support differently depending on how busy they were after school. Frequently, those who were busiest after school were also those from the advantaged area, and those who had little to do after school were from the disadvantaged area. Socioeconomic factors influence participants' possibilities to engage in the intervention activities as well as how they use their time in the activities. This study showed that it is crucial to support adolescents' participation in physical activities by providing structure and engaging well-known teachers in the activities, especially in schools located in disadvantaged areas.


KRAS Pathway-based Therapeutic Approaches in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the highly aggressive malignancies and the leading cause of cancer-related deaths. Despite recent advancements, the overall therapeutic responses in PDAC patients remained relatively low or short-lived. While KRAS is the most frequently mutated proto-oncogene and represents a critical driver, it remains challenging to target all mutant variants. Thus, strategies to target the downstream signaling cascades (RAS-RAF-MEK-ERK) in PDAC were associated with improved response rates. Nevertheless, the activation of other oncogenic cascades, such as PI3K/AKT/mTOR, has also been documented within the same context and implicated in the development of acquired tumor resistance mechanisms and/or reduced efficacy of therapeutic agents. Therefore, an in-depth understanding of overlapping and intersecting pathways is required to overcome the tumor resistance mechanisms to devise novel approaches to enhance the effectiveness of ongoing treatment options. The current review highlights the mechanistic insights from cellular and preclinical studies with particular emphasis on KRAS (i.e., MEK and ERK)-based approaches for PDAC treatment.


Focus on international research strategy and teaching: the FIRST programme.
Research, education and patient care are important missions of academic health centres and their respective teaching programmes. Yet, teaching hospitals struggle with ways to effectively support quality research initiatives. These issues are even more pronounced in countries with developing medical education systems where inconsistencies in training programme structure and quality, along with the lack of uniformity in the backgrounds and experience of the faculty, can hinder meaningful research activities. Hospital leaders recognized the need to inculcate both the desire and the ability to conduct quality research into every postgraduate training programme. Given the lack of global benchmarks, the institution developed and implemented the FIRST Programme (Focus on International Research Strategy and Teaching), a hospital-wide approach to research strategy training and support in 2010-2012. Over a 3-year period, the number of resident and faculty research activities has more than doubled. The types of research studies have also changed over the past few years, with an increase in basic science and randomized clinical trials. Our experience with implementing an institution-wide research initiative has been quite encouraging. Through leadership commitment, the institution has witnessed substantial increases in both trainee and faculty scholarship over a 3-year period.


Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis.
To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable. NCT01352858.


The impact of a universal intervention targeting perfectionism in children: An exploratory controlled trial.
Perfectionism is considered to be an underlying mechanism of relevance to a broad array of indicators of psychological distress. The current research examined the impact of a three-session intervention targeting perfectionism in children on perfectionism, self-criticism, and well-being. The design of the current study can be considered quasi-experimental as the intervention and control classes were not randomly allocated but decided by convenience factors at the school level. Students (aged 10.08-12.79 years) were allocated to the intervention (N = 107, 41 boys) or control condition (N = 105, 33 boys), completing self-report assessments on perfectionism, self-criticism, and well-being at baseline, post-intervention, and 3-month follow-up. At post-intervention, children in the intervention group had significantly lower perfectionism than the control group (d = 0.35, 95% confidence intervals [CI]: 0.07-0.62) and at 3-month follow-up had significantly higher levels of well-being (d = 0.33, 95% CI: 0.06-0.60). As predicted by theory, decreases in perfectionism mediated the relationship between condition and improved well-being. This exploratory study provides evidence for the usefulness of a brief universal prevention programme targeting perfectionism. Future research should use more robust designs, explore longer-term effects, and the impact on a wider range of variables, including scholastic achievement. Clinical implications Perfectionism linked with negative outcomes in children can be decreased in a classroom setting. Decreasing perfectionism leads to improved well-being in children. Limitations More rigorous designs along with better assessment of perfectionism are required in further evaluations. The impact of perfectionism on scholastic achievement in children requires further investigation.


Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.
The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting. All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment. A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m2, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x103/mm3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks. A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.


Pain, immunity, opiate and opioid compounds and health.
We surmise that opioid peptides, i.e., methionine enkephalin, first arose during evolution as modulators of cellular immune function given their immune actions and the presence of enkelytin, a potent antibacterial peptide, and its precursor proenkephalin in animals 500 million years divergent in evolution. Pain probably emerged from this perspective because of its association with proinflammatory events. Endogenous morphine appears to exert positive effects on homeostasis by limiting the degree of excitation. Supporting this view is the fact that the mu3 opiate receptor subtype, which is opioid peptide insensitive and morphine selective, is coupled to constitutive nitric oxide release, which also has this down regulating action in neural, immune, vascular and gastrointestinal tissues. Thus, morphine down regulates immune processes in addiction, an action/function that it appears to normally perform when the situation calls for this action and by so doing in this natural setting, sustains life.