Use of mechanical and pharmacological restraint over an eight-year period and its relation to clinical factors.
Use of restraint and finding the balance between security and ethics is a continuous dilemma in clinical psychiatry. In daily clinic and in planning health-care service, knowledge on the characteristics of restraint situations is necessary to optimize its use and avoid abuse. We describe characteristics in the use of pharmacological and mechanical restraint in psychiatric acute wards in a hospital in Middle Norway over an eight-year period. Data on all cases of mechanical and pharmacological restraint from 2004 to 2011 were retrospectively collected from hand-written protocols. Complementary information on the patients was obtained from the hospital patient administrative system. Restraint in acute wards was used on 13 persons per 100,000 inhabitants annually. The percentage of admitted patients exposed to restraint was 1.7%, with a mean of 4.5 cases per exposed patient. Frequency per 100 admitted patients varied from 3.7 (in 2007) to 10 (in 2009). The majority of restraint cases concerned male patients under 50 years and with substance-abuse, psychotic, or affective disorders. Significantly more coercive means were used during daytime compared to night and morning. There was a significant increase in pharmacological coercion during spring and mechanical coercion during summer. Restraint was used on 1.7% of admitted patients, representing 13 per 100,000 inhabitants per year. Use of restraint was higher during certain periods of the day and was associated with the patient's diagnosis, age, gender, and legal status of hospitalization. There was a marked variation over the years.


Age and date for early arrival of the Acheulian in Europe (Barranc de la Boella, la Canonja, Spain).
The first arrivals of hominin populations into Eurasia during the Early Pleistocene are currently considered to have occurred as short and poorly dated biological dispersions. Questions as to the tempo and mode of these early prehistoric settlements have given rise to debates concerning the taxonomic significance of the lithic assemblages, as trace fossils, and the geographical distribution of the technological traditions found in the Lower Palaeolithic record. Here, we report on the Barranc de la Boella site which has yielded a lithic assemblage dating to ∼1 million years ago that includes large cutting tools (LCT). We argue that distinct technological traditions coexisted in the Iberian archaeological repertoires of the late Early Pleistocene age in a similar way to the earliest sub-Saharan African artefact assemblages. These differences between stone tool assemblages may be attributed to the different chronologies of hominin dispersal events. The archaeological record of Barranc de la Boella completes the geographical distribution of LCT assemblages across southern Eurasia during the EMPT (Early-Middle Pleistocene Transition, circa 942 to 641 kyr). Up to now, chronology of the earliest European LCT assemblages is based on the abundant Palaeolithic record found in terrace river sequences which have been dated to the end of the EMPT and later. However, the findings at Barranc de la Boella suggest that early LCT lithic assemblages appeared in the SW of Europe during earlier hominin dispersal episodes before the definitive colonization of temperate Eurasia took place.


Specificity versus variability: effects of practice conditions on the use of afferent information for manual aiming.
Although proponents of the motor schema theory hold that a decrease in the reliance on afferent information will occur with practice in consort with the development of motor programs, supporters of the specificity of practice by hypothesis suggest that a performer's reliance on the available sources of afferent information during acquisition increases with the amount of practice. To reconcile these competing positions, four groups of 9 participants aimed to targets under either a constant or a variable practice schedule, with or without vision of the effector. After modest (15 trials) and moderate (150 trials) practice, participants were tested in both their own and in the alternate vision condition. Results indicate that the utilization of online kinesthetic information was enhanced through practice regardless of the availability of vision during acquisition. This was especially true for the groups practicing under a variable practice schedule


High speed silicon microring modulator employing dynamic intracavity energy balance.
High speed coupling-modulation of a microring-based light drop structure is proposed, which removes severe signal distortion due to intracavity energy depletion and separates the modulation speed from the resonator linewidth restriction. Extinction ratio improvement from <1 dB to >20 dB with 40 Gb/s non-return-to-zero (NRZ) signals is obtained with 25 times smaller drive voltage. The tolerance to active ring propagation loss is increased from 5 dB/cm to over 25 dB/cm with less than 5% modulation bandwidth reduction. The possibility of obtaining 160 Gb/s NRZ signal with no more than 4 V drive voltage and less than 5 dB insertion loss is highlighted.


Evidence for a role of oxygen derived free radicals in the pathogenesis of caerulein induced acute pancreatitis in rats.
The effects of a polyethylene glycol linked oxygen free radical scavenger enzyme, superoxide dismutase (PEG:SOD) on caerulein induced acute pancreatitis (AP) in rats were examined. Pancreas weights and serum amylase concentrations in rats given a three hour continuous intravenous infusion of caerulein (7.5 micrograms/kg/h, n = 18) for induction of AP followed by a three hour infusion of normal saline were significantly raised by approximately 25% (p less than 0.005) and 750% (p less than 0.001), respectively, compared with values obtained in control rats (n = 7) infused for six hours with normal saline alone. A single intraperitoneal injection of either 1 X 10(4) U/kg (n = 6), 2 X 10(4) U/kg (n = 5), or 4 X 10(4) U/kg (n = 5) of PEG:SOD immediately before caerulein infusion did not significantly alter pancreas weights, serum amylase content, or pancreatic histopathology compared with rats given caerulein alone. By contrast, a single intravenous bolus injection of 4 X 10(4) U/kg (n = 9) of PEG:SOD before caerulein treatment significantly reduced serum amylase content by approximately 25% (p less than 0.05) and a continuous six hour intravenous infusion of 4 X 10(4) U/kg/h of PEG:SOD (n = 5) produced significant reductions of approximately 25% (p less than 0.001), 35% (p less than 0.05), and 50% (p less than 0.01) in pancreas weights, serum amylase concentrations, and acinar cell vacuolisation (p less than 0.01), respectively, compared with values in rats given caerulein alone. In studies using bovine serum albumin linked to polyethylene glycol and infused for six hours at protein concentrations identical to high dose PEG:SOD (n = 6), no beneficial effects against caerulein induced AP were observed. These data suggest that (a) oxygen derived free radicals are involved in the early pathogenesis of caerulein induced AP in rats, and (b) the greatly extended circulating half life of polyethylene PEG:SOD ( > 35 hours in rats compared with less than six minutes for native superoxide dismutase) may make this compound more suitable than native superoxide dismutase as a potential therapeutic agent in AP.


Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis.
African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children. We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease. A total of 140 AA children in the CKiD study were genotyped. High risk (HR) APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p < 0.001. FSGS was the most common cause of glomerular disease in children with HR APOL1 (89%; 25/28). Of 32 AA children with FSGS, 25 (78%) had HR APOL1. Compared to children with low risk APOL1 and FSGS (comprising 36 non-AA and 7 AA), children with HR APOL1 developed FSGS at a later age, 12.0 (IQR: 9.5, 12.5) vs. 5.5 (2.5, 11.5) years, p = 0.004, had a higher prevalence of uncontrolled hypertension (52 vs. 33%, p = 0.13), left ventricular hypertrophy (LVH) (53 vs. 12%, p < 0.01), C-reactive protein > 3 mg/l (33 vs. 15%, p = 0.12), and obesity (48 vs. 19%, p = 0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of chronic kidney disease and LVH management in this population.


The ALFA-tag is a highly versatile tool for nanobody-based bioscience applications.
Specialized epitope tags are widely used for detecting, manipulating or purifying proteins, but often their versatility is limited. Here, we introduce the ALFA-tag, a rationally designed epitope tag that serves a remarkably broad spectrum of applications in life sciences while outperforming established tags like the HA-, FLAG®- or myc-tag. The ALFA-tag forms a small and stable α-helix that is functional irrespective of its position on the target protein in prokaryotic and eukaryotic hosts. We characterize a nanobody (NbALFA) binding ALFA-tagged proteins from native or fixed specimen with low picomolar affinity. It is ideally suited for super-resolution microscopy, immunoprecipitations and Western blotting, and also allows in vivo detection of proteins. We show the crystal structure of the complex that enabled us to design a nanobody mutant (NbALFAPE) that permits efficient one-step purifications of native ALFA-tagged proteins, complexes and even entire living cells using peptide elution under physiological conditions.


Efficacy of high-frequency repetitive transcranial magnetic stimulation in treatment-resistant depression.
We examined the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) in 419 patients with treatment-resistant depression. The patients received daily sessions of rTMS over the left prefrontal cortex as an adjuvant to pharmacotherapy. The rTMS intensity was set at 100% of the motor threshold and 25 Hz stimulation, with train duration of 2 seconds delivered at 30-second intervals. A full course comprised 1000 magnetic pulses. Depression was rated using the Hamilton Depression Rating Scale (HAMD) before and after treatment. Response was defined as a 50% reduction in the HAMD score. Patients with HAMD scores of less than 8 were considered to be in remission. The mean HAMD score for the study group decreased from 22.59 ± 5.92 to 10.50 ± 5.83 (P < .001). After the treatment period, 268 (64%) out of 419 patients demonstrated significant mood improvements, as indexed by a reduction of more than 50% on the HAMD score. In addition, 140 patients (33.4%) attained remission (HAMD score <8); and 11 patients achieved a partial response. Treatment was generally well tolerated, and no serious adverse effects were reported. In conclusion, high-frequency (25 Hz) rTMS was well tolerated and found to be statistically and clinically effective in patients with treatment-resistant depression. This study contributed to the existing evidence of the antidepressant effect of rTMS in the treatment of depression.


Needle aspiration cytology of a benign and a malignant schwannoma.
The histologic and cytologic features of an uncommon solitary, malignant schwannoma and a benign schwannoma are presented. The benign tumor revealed characteristic interlacing fascicles of spindle-shaped cells on both histology and cytology. The malignant schwannoma produced a variable histologic pattern that was selectively sampled from a recurrence in a scar; only obviously malignant, undifferentiated, spindle-shaped cells not capable of further characterization were seen on cytology. Preliminary experience with immunoperoxidase staining for the neural crest marker S-100 protein has been encouraging and may permit identification of these tumors on aspiration smears.


Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.
Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C. difficile infection (CDI). Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10(4) spores/d for 7 days (n = 43), 10(7) spores/d for 7 days (n = 44), or 10(7) spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 10(7) spores/d and 63% with 10(4) spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 10(7) spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. clinicaltrials.gov Identifier: NCT01259726.


Caring, employment, and quality of life: comparison of employed and nonemployed mothers of adults with intellectual disability.
The effects of caregiving on mothers of adults with intellectual disability was examined by determining whether there are differences in quality of life and related factors between mothers with different employment status. Study participants were 302 working-age mothers who had adult children with intellectual disability based on the 2008 census survey on intellectual disability carried out in Hsinchu, City, Taiwan. Results revealed that nonemployed mothers are more likely to have a lower level of health status, including the WHOQOL Physical Health domain, than are mothers employed fulltime. Multiple regression analysis showed that mothers' quality of life was significantly determined by the availability of a person with whom they could share care work, family income, social support, and employment status.


Can the National Health Service Cancer Plan timeline be applied to colorectal hepatic metastases?
The National Health Service (NHS) Cancer Plan guidelines recommend a maximum 2-week wait from referral to first appointment, and 2 months from referral to treatment for primary cancers. However, there are currently no guidelines available for metastatic disease. In the UK, nearly half of all colorectal cancer patients develop hepatic metastases. Timely, surgical resection offers the potential for cure. The aim of this study was to audit current practice for colorectal liver metastases in a regional hepatobiliary unit, and compare this to the NHS Cancer Plan standards for primary disease. A retrospective review of the unit's database was performed for all hepatic metastases referrals from January 2006 to December 2008. The dates of referral, first appointment, investigations and initiation of treatment, along with patient's age and sex, were recorded on Microsoft Excel and analysed. Time was expressed as mean +/- SD in days. A total of 102 patients with hepatic metastases were identified. Five were excluded due to incomplete data. The average time from referral to first appointment was 10.6 +/- 9.4 days and the average time from referral to treatment was 38.5 +/- 28.6 days. Seventy-five (72.7%) had surgical intervention, of whom 37 also had chemotherapy. The data compare favourably to the NHS Cancer Plan guidelines for primary malignancy, demonstrating that a regional hepatobiliary unit is capable of delivering a service for colorectal liver metastases that adheres to the NHS Cancer Plan. Therefore, the NHS Cancer Plan can be applied to this cohort.


Determinants of gas exchange kinetics during exercise in the dog.
Following exercise onset, CO2 output (VCO2) and O2 uptake (VO2) increase exponentially, but with appreciably different time constants. To determine the sensitivity of the time courses of these variables to altered ventilatory kinetics, rhythmic exercise was induced abruptly in anesthetized dogs by bilateral stimulation of the peripheral ends of the cut sciatic and femoral nerves. This increased the metabolic rate by 83 +/- 25 (SD) %. The dogs were ventilated with a constant-volume pump, the frequency of which was changed exponentially from the start of the exercise up to the ventilation that returned arterial CO2 and O2 pressure (PCO2 and PO2) in the steady state to resting levels. The time constant (tau) of the increase in ventilation (VE) was varied among trials. VCO2, VO2, end-tidal PCO2 and PO2, and arterial PCO2 were measured breath by breath. tauVO2 was constant at approximately 18 s regardless of alterations in tauVE. In contrast, tauVCO2 was strongly dependent on tauVE, apparently due to the larger body stores for CO2; the transitions were isocapnic when tau VE was approximately 40 s. We conclude that ventilatory dynamics can markedly influence the dynamics of CO2 exchange during exercise, but has no appreciable effect on O2 uptake dynamics.


Characterizing Social Media Messages Related to Underage JUUL E-Cigarette Buying and Selling: Cross-Sectional Analysis of Reddit Subreddits.
Stopping the epidemic of e-cigarette use among youth has become the common goal of both regulatory authorities and health departments. JUUL is currently the most popular e-cigarette brand on the market. Young people usually obtain and exchange information about JUUL with the help of social media platforms. Along with the rising prevalence of JUUL, posts about underage JUUL buying and selling have appeared on social media platforms such as Reddit, which sharply increase the risk of minors being exposed to JUUL. This study aims to analyze Reddit messages about JUUL buying and selling among the users of the UnderageJuul subreddit, and to further summarize the characteristics of those messages. The findings and insights can contribute to a better understanding of the patterns of underage JUUL use, and help public health officials provide timely education and guidance to minors who have intentions of accessing JUUL. We used a novel cross-subreddit method to analyze the Reddit messages on 2 subreddits. From July 9, 2017, to January 7, 2018, we collected data from the UnderageJuul subreddit, which was created for underage JUUL use discussion. The data set included 716 threads, 2935 comments, and 844 Reddit users (ie, Redditors). We collected our second data set, comprising 23,840 threads and 162,106 comments posted between July 9, 2017, and January 8, 2019, from the JUUL subreddit. We conducted analyses including the following: (1) annotation of users with buying/selling intention, (2) posting patterns discovery and topic comparison, and (3) posting activeness observation of discovered Redditors. Term frequency-inverse document frequency and regular expression-enhanced keyword search methods were applied during the content analysis to extract the posting patterns. The public posting records of the discovered users on the JUUL subreddit during the year after the UnderageJuul subreddit was shut down were analyzed to determine whether they were still active and interested in obtaining JUUL. Our study revealed the following: (1) Among the 716 threads on the UnderageJuul subreddit, there were 214 threads related to JUUL sale and 168 threads related to JUUL purchase, which accounted for 53.5% (382/714) of threads. (2) Among the 844 Redditors of the UnderageJuul subreddit, 23.82% (201/844) of users were annotated with buying intention, and 21.10% (178/844) of users were annotated with selling intention. There were 34 users with buying/selling intention that self-reported as being <21 years old. (3) The most common key phrases used in selling threads were "WTS," "want to sell," "for sale," and "selling" (154/214, 72.0%). The most common key phrases used in buying threads were "look for/get JUUL/pods" (58/168, 34.5%) and "WTB" (53/168, 31.5%). (4) The most important concern that UnderageJuul Redditors had in obtaining JUULs was the price (311/1306, 23.81%), followed by the delivery service (68/1306, 5.21%). (5) The most popular flavors among the users with buying/selling intention were mango, cucumber, and mint. The flavor preferences remained consistent on both subreddits. Adverse symptoms related to the mango flavor were reported by 3 users on the JUUL subreddit. (6) In total, 24.4% (49/201) of users wanted to buy JUULs and 46.6% (83/178) of users wanted to sell JUULs, including 11 self-reported underage users, who also participated in the discussions on the JUUL subreddit. (7) Within one year of the UnderageJuul subreddit shutting down, there were 40 users who continued to post 186 threads on the JUUL subreddit, including 10 threads indicating buying/selling willingness that were posted shortly after the UnderageJuul subreddit was closed. There were overlapping users active in the JUUL and UnderageJuul subreddits. The buying/selling-related content appeared in multiple venues with certain posting patterns from July 9, 2017, to January 7, 2018. Such content might lead to a high risk of health problems for minors, such as nicotine addiction. Based on these findings, this study provided some insights and suggestions that might contribute to the decision-making processes of regulators and public health officials.


Gender affects naming latencies for living and nonliving things: implications for familiarity.
Recent studies indicate the presence of a gender-by-category interaction in the naming abilities of both Alzheimer's patients and normal subjects (Laiacona, Barbarotto and Capitani, 1998; McKenna and Parry, 1994). In particular, males appear to be better than females at naming nonliving things and females better at naming living things. Similarly, in a recent study of semantic fluency, males retrieved more names of tools than females and females more names of fruit than males (Capitani, Laiacona and Barbarotto, 1999). Such findings have important implications for our understanding of category-specific disorders. The current study examined the naming latencies of normal subjects to pictures of living and nonliving things. We confirm a gender-by category interaction across both subject and item, with females being slower than males to name nonliving things and males slower to name living things. This finding could not be explained by differential difficulty of items or differences in gender-based familiarity ratings.


[Localised swelling of a child's leg is not always harmless].
Soft tissue swelling of the leg is a relatively uncommon occurrence in children, and is often benign. In adults, 1% of malignancies originate in soft tissue, whereas for children the figure is 8%. Based on medical history and physical examination alone, it is difficult to differentiate between benign and malignant soft tissue tumours. A 15-year-old girl presented to her GP with a swelling in the left thigh, without alarming symptoms. The GP suspected the lesion to be benign and she was asked to return if the swelling increased in size. Five months later, when the lesion was excised, it proved to be a granular cell tumour. The second case concerns a 12-year-old boy who presented to his GP with a swelling of the lateral malleolus, which had developed after impact against a door five years ago. The boy was referred to the surgical department where after excision it was shown to be a dermatofibrosarcoma protuberans. In paediatric cases when diagnosis is inconclusive, including cases involving possible growth of the swelling, suspicions raised during physical examination, or unusually lengthy recovery after trauma, awareness is important. Imaging diagnostics or even tissue excision with histopathology may be indicated to allow the correct diagnosis to be made.


The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries.
The contribution of psychological disorders to the burden of skin disease has been poorly explored, and this is a large-scale study to ascertain the association between depression, anxiety, and suicidal ideation with various dermatological diagnoses. This international multicenter observational cross-sectional study was conducted in 13 European countries. In each dermatology clinic, 250 consecutive adult out-patients were recruited to complete a questionnaire, reporting socio-demographic information, negative life events, and suicidal ideation; depression and anxiety were assessed with the Hospital Anxiety and Depression Scale. A clinical examination was performed. A control group was recruited among hospital employees. There were 4,994 participants--3,635 patients and 1,359 controls. Clinical depression was present in 10.1% patients (controls 4.3%, odds ratio (OR) 2.40 (1.67-3.47)). Clinical anxiety was present in 17.2% (controls 11.1%, OR 2.18 (1.68-2.82)). Suicidal ideation was reported by 12.7% of all patients (controls 8.3%, OR 1.94 (1.33-2.82)). For individual diagnoses, only patients with psoriasis had significant association with suicidal ideation. The association with depression and anxiety was highest for patients with psoriasis, atopic dermatitis, hand eczema, and leg ulcers. These results identify a major additional burden of skin disease and have important clinical implications.


Orofacial Manifestations and Temporomandibular Disorders of Sjögren Syndrome: An Observational Study.
AIMS: Sjӧgren Syndrome is a disorder involving oral tissues, with xerostomia, dysgeusia, dysphagia, tooth decay, gingivitis, angular cheilitis and glossitis. Temporomandibular disorders are a generic term referred to clinical conditions involving the jaw muscles and temporomandibular joint. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in Sjӧgren Syndrome (SS) patients compared with healthy people. METHODS: The study group included 72 SS patients (2 men, 70 women) diagnosed according to the American-European Consensus Group (AECG) Criteria. A randomly selected group of 72 patients, matched by sex and age, served as control group. The examination for TMD signs and symptoms was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a questionnaire and clinical examination. RESULTS: SS patients complained more frequently (95.8%) of oral symptoms (xerostomia, dysgeusia, dysphagia) than controls (22.2%) (χ2= 80.66 p< 0.001). TMD symptoms (muscle pain on chewing, difficulty in mouth opening, arthralgia, headaches, tinnitus) were complained by 91.7% of SS patients and by 84.7% of controls (χ2= 1,667 p= 0,196). At the clinical examination, 91,7% of SS had at least one oral sign respect to 75 % of controls. The salivary flow measurements showed high statistical significance between the two groups (Unpaired test, p< 0,0001). Myofascial pain (caused by muscular contracture) was significantly higher in the study group than in the control one (p≤ 0,05). Furthermore 18,05% of SS patients showed deflection versus 5,5% of controls (χ2=5,402 p=0,020). CONCLUSIONS: Sjӧgren's Syndrome seems to play a role in temporomandibular joint disorders.


Purification and characterization of the bacteriophage T4 dda protein. A DNA helicase that associates with the viral helix-destabilizing protein.
A DNA-dependent ATPase found in crude preparations of the phage T4 gene 32 protein, shown to be the product of the nonessential T4 dda gene, has been purified to apparent homogeneity and free of nucleases. The dda protein hydrolyzes ATP or dATP to the respective nucleoside diphosphates, in a reaction that is completely dependent on the presence of DNA. DNA in a single-stranded form is strongly preferred and there is little effect of differences in strand length or base composition. We show that the dda protein is the DNA helicase previously studied by Krell et al. (Krell, H., Durwald, H., and Hoffmann-Berling, H. (1979) Eur. J. Biochem. 94, 387-395); it can unwind extensive stretches of double-stranded DNA very rapidly, appearing to move with a 5'-3' polarity relative to the single DNA strand to which it initially binds. The reaction is highly distributive, indicating that the dda protein is continuously dissociating and reassociating with the DNA being unwound. The T4 gene 32 protein, a single-strand-binding, helix-destabilizing protein, competes with the dda protein for binding to single-stranded DNA. Consequently, it seems to inhibit rather than to promote the helicase reaction. The other known T4-encoded DNA helicase, the gene 41 protein, has little effect on the helicase activity of the dda protein. These results are relevant to the suspected role of the dda protein in phage T4 DNA replication, as well as to its possible role in phage genetic recombination.


Germination and early growth of Brassica juncea in copper mine tailings amended with technosol and compost.
Mine tailings represent a serious threat to the environment and human health; thus their restoration has become a major concern. In this study, the interactions between Brassica juncea and different mine soil treatments were evaluated in order to understand their effect on germination and early growth. Three soil treatments containing 25% and 50% of technosol and 30% of compost were prepared. Germination and early growth were assessed in soil and pore water extracts from the treatments. Unlike the untreated mine soil, the three treatments allowed germination and growth, achieving levels comparable to those of seedlings from the same species developed in normal conditions. The seedlings grown in 50% of technosol and 30% of compost exhibited greater germination percentages, higher growth, and more efficient mechanisms against oxidative stress, ascribed to the organic matter and nutrients content of these treatments. Considering the unequivocal ability of B. juncea for phytoremediation, the results suggest that technosol and compost may be an auspicious solution to allow the germination and early growth of this species in mine tailings.


De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease.
Arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an autosomal-dominantly inherited disease caused by mutations in genes encoding desmosomal proteins and is characterised by fibrofatty replacement occurring predominantly in the right ventricle and can result in sudden cardiac death. Naxos and Carvajal syndrome, autosomal recessive forms of ARVC/D, are characterised by involvement of the right and/or left ventricle in association with palmoplantar keratoderma and woolly hair. The aim of the present study has been to screen for mutations in the desmosomal protein genes of two unrelated patients with Naxos-Carvajal syndrome. Desmosomal protein genes were screened for mutations by polymerase chain reaction as well as direct sequencing approach. In each patient we identified a single heterozygous de novo mutation in the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile, leading to severe combined cardiac/dermatological and cardiac/dermatological/dental phenotypes. The DSP missense mutations are localised in the N terminal domain of desmoplakin. The identified variations in DSP involve highly conserved residues. Moreover, the variations are de novo mutations and they are localised in critical protein domains that appear to be mutation hot spots. We assume that these heterozygous variations are causal for the mixed Naxos-Carvajal syndrome phenotype in the screened patients.


Case report: Rectal adminstration of ivermectin to a patient with Strongyloides hyperinfection syndrome.
Strongyloides hyperinfection syndrome may be complicated by paralytic ileus that interferes with the absorption of oral anti-helminthics. We report on the administration of ivermectin as a rectal enema preparation to a renal transplant recipient with Strongyloides hyperinfection syndrome and progressive ileus. Attempts at treatment using nasogastric albendazole and ivermectin were unsuccessful despite clamping the nasogastric tube after drug administration. Ivermectin tablets were ground to a powder, resuspended in a commercially available suspending agent, and administered per rectum. The suspending agent was chosen for its near-physiologic osmolality to allow longer retention, in contrast to many enema preparations that have a laxative effect. The patient improved markedly within 72 hours of initiation of the therapy per rectum and recovered fully. Ivermectin administered as an enema may be beneficial in patients with severe strongyloidiasis who are unable to absorb or tolerate oral therapy.


Economic evaluation of a cluster randomized trial of interventions to improve health workers' practice in diagnosing and treating uncomplicated malaria in Cameroon.
Malaria rapid diagnostic tests (RDTs) are a valid alternative to malaria testing with microscopy and are recommended for the testing of febrile patients before prescribing an antimalarial. There is a need for interventions to support the uptake of RDTs by health workers. To evaluate the cost-effectiveness of introducing RDTs with basic or enhanced training in health facilities in which microscopy was available, compared with current practice. A three-arm cluster randomized trial was conducted in 46 facilities in central and northwest Cameroon. Basic training had a practical session on RDTs and lectures on malaria treatment guidelines. Enhanced training included small-group activities designed to change health workers' practice and reduce the consumption of antimalarials among test-negative patients. The primary outcome was the proportion of febrile patients correctly treated: febrile patients should be tested for malaria, artemisinin combination therapy should be prescribed for confirmed cases, and no antimalarial should be prescribed for patients who are test-negative. Individual patient data were obtained from facility records and an exit survey. Costs were estimated from a societal perspective using project reports and patient exit data. The analysis used bivariate multilevel modeling and adjusted for imbalance in baseline covariates. Incremental cost per febrile patient correctly treated was $8.40 for the basic arm and $3.71 for the enhanced arm. On scale-up, it was estimated that RDTs with enhanced training would save $0.75 per additional febrile patient correctly treated. Introducing RDTs with enhanced training was more cost-effective than RDTs with basic training when each was compared with current practice.


Gas Sensor Based on 3-D WO₃ Inverse Opal: Design and Applications.
A three-dimensional inverse opal (3DIO) WO₃ architecture has been synthesized via a simple sacrificial template method. Morphology features of the 3DIO were characterized by scanning electron microscope (SEM) and its structure was characterized by X-ray diffraction (XRD). The shrinking ratio of the PMMA spheres was ~28.2% through measuring the distribution of the PMMA spheres and 3DIO WO₃ center-to-center distance between the spheres and macropores, respectively. Beyond that, the 3DIO gas sensing properties were investigated systematically and the sensing mechanism of 3DIO WO₃ was proposed. The results indicated that the response of the 3DIO sensor possessed excellent sensitivity to acetone gas, especially at trace levels. The 3DIO gas sensor response was ~7 to 5 ppm of acetone and could detect acetone low to 0.2 ppm effectively, which was in close proximity to the theoretical low detection limit of 0.14 ppm when Ra/Rg ≥ 1.2 was used as the criterion for reliable gas sensing. All in all, the obvious satisfaction of the gas-sensing properties was ascribed to the structure of the 3DIO, and the sensor could be a promising novel device in the future.


Chemokine Receptors CXCR4 and CXCR7 are Associated with Tumor Aggressiveness and Prognosis in Extramammary Paget Disease.
Chemokines are involved in many aspects of oncogenesis, including regulation of cancer cell growth, dissemination and host-tumor response. However, the potential of the chemokine receptors, CXCR4 and CXCR7, in serving as biomarkers in extramammary Paget's disease (EMPD) has been rarely examined. Expressions of CXCR4 and CXCR7 were evaluated in 92 EMPD specimens by immunohistochemistry. High expression of CXCR4 and CXCR7 were both correlated with regional lymph node metastasis and presence of lymphovascular invasion. High expression of CXCR7 also correlated with the depth of invasion. The prognostic value of these two chemokines were also investigated in progression-free survival (PFS) and cancer-specific survival (CSS). Both high expression of CXCR4 and CXCR7 were indicative of shorter PFS and CSS. In the combined prognostic model, concomitant high expression of CXCR4 and CXCR7 were suggestive of poor prognosis compared with the other two groups. In the multivariate analysis, depth of invasion, combined prognostic model and regional lymph node metastasis at diagnosis were the independent prognostic factors for EMPD patients for PFS, and the former two factors independently impacted CSS. Our results demonstrated that CXCR4 and CXCR7 can be used as prognostic biomarkers and prediction of aggressiveness of EMPD. Therapy targeting CXCR4 and CXCR7 may helpful to prevent EMPD progression and improve the prognosis of EMPD.


[Treatment of inflammatory bowel disease with infliximab: experience in 25 patients].
Biological therapy has an important role in the treatment of Inflammatory Bowel Disease (IBD). However, the use of these drugs is resisted due to fears about their side effects. To report the experience with the use of Infliximab in patients with IBD. Descriptive study of a historical cohort of patients with IBD treated between 2007 and 2012 with Infliximab. A favorable clinical response was considered when general, intestinal and extra-intestinal symptoms subsided after the second or third dose of the drug. Endoscopic or imaging response was evaluated between three and six months of treatment. Twenty five patients aged 18 to 61 years (12 women) were included. Sixteen had Cohn's Disease and 9 had Ulcerative Colitis. Treatment was indicated due to refractory disease in 13 patients, perianal involvement in nine, stenosis in two and pyoderma gangrenosum in one. Ten patients initiated Infliximab within less than two years of diagnosis. Twenty-two patients received combined treatment with immunosuppressive medications and the other three patients were treated exclusively with Infliximab. A favorable clinical response was observed in 88% after the second dose and 64% had endoscopic or imaging remission after 3-6 months. Twelve patients discontinued Infliximab, due to bad response to treatment in three patients, economic cost in three patients, and patient/doctor decision in six. Only three patients had side effects (herpes zoster and sinusitis). None of these motivated the discontinuation of treatment. In this cohort of patients with IBD, the use of Infliximab was associated with endoscopic or imaging remission in 64% of cases after 3-6 months of treatment with no major side effects.


Consensus statement on antimicrobial treatment of odontogenic bacterial infections.
The infection of the oral cavity is a common public health problem and constant cause for antibiotic prescription, with 10% of antibiotics used to treat this problem. However, few studies have so far aimed to determine its incidence. Added to this, its relationship with certain sytemic diseases (cardiac, endocrine, etc) confers this pathology vital importance. In spite of the frequency and importance of odontogenic infection, the current dispersion in criteria regarding key aspects in classification, terminology and therapeutic recommendations is noticeable. The main objective of this document, compiled as a consensus statement by specialists in microbiology and odontology, is to establish useful recommendations for all of those involved in the clinical management of this pathology. Special attention has been placed on the rise in bacterial resistance observed over the last years, specifically the proliferation of betalactamase producing strains. Another important factor causing the resistance to appear is lack of therapeutic compliance, specially what regards dosage and treatment duration. Therefore, this pathology constitutes a complex problem which requires the instauration of broad spectrum antimicrobials, well tolerated and a convenient posology so that patients receive the adequate dose over the necessary period. High doses of amoxicillin/clavulanate (2000 mg/125 mg) have showed good results and power to overcome resistance. Other agents such as metronidazole and clindamycin, followed by de claritromycin and azithromycin have also proved to be active against most of microorganisms responsible for odontogenic infection.


Packed domain Rayleigh-Sommerfeld wavefield propagation for large targets.
For applications in the domain of digital holographic microscopy, we present a fast algorithm to propagate scalar wave fields from a small source area to an extended, parallel target area of coarser sampling pitch, using the first Rayleigh-Sommerfeld diffraction formula. Our algorithm can take full advantage of the fast Fourier transform by decomposing the convolution kernel of the propagation into several convolution kernel patches. Using partial overlapping of the patches together with a soft blending function, the Fourier spectrum of these patches can be reduced to a low number of significant components, which can be stored in a compact sparse array structure. This allows for rapid evaluation of the partial convolution results by skipping over negligible components through the Fourier domain pointwise multiplication and direct mapping of the remaining multiplication results into a Fourier domain representation of the coarsly sampled target patch. The algorithm has been verified experimentally at a numerical aperture of 0.62, not showing any significant resolution limitations.


Genome-wide association study of smoking behaviours in patients with COPD.
Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.


Simulator-Based Angiography and Endovascular Neurosurgery Curriculum: A Longitudinal Evaluation of Performance Following Simulator-Based Angiography Training.
This study establishes performance metrics for angiography and neuroendovascular surgery procedures based on longitudinal improvement in individual trainees with differing levels of training and experience. Over the course of 30 days, five trainees performed 10 diagnostic angiograms, coiled 10 carotid terminus aneurysms in the setting of subarachnoid hemorrhage, and performed 10 left middle cerebral artery embolectomies on a Simbionix Angio Mentor™ simulator. All procedures were nonconsecutive. Total procedure time, fluoroscopy time, contrast dose, heart rate, blood pressures, medications administered, packing densities, the number of coils used, and the number of stent-retriever passes were recorded. Image quality was rated, and the absolute value of technically unsafe events was recorded. The trainees' device selection, macrovascular access, microvascular access, clinical management, and the overall performance of the trainee was rated during each procedure based on a traditional Likert scale score of 1=fail, 2=poor, 3=satisfactory, 4=good, and 5=excellent. These ordinal values correspond with published assessment scales on surgical technique. After performing five diagnostic angiograms and five embolectomies, all participants demonstrated marked decreases in procedure time, fluoroscopy doses, contrast doses, and adverse technical events; marked improvements in image quality, device selection, access scores, and overall technical performance were additionally observed (p < 0.05). Similarly, trainees demonstrated marked improvement in technical performance and clinical management after five coiling procedures (p < 0.05). However, trainees with less prior experience deploying coils continued to experience intra-procedural ruptures up to the eighth embolization procedure; this observation likely corresponded with less tactile procedural experience to an exertion of greater force than appropriate for coil placement. Trainees across all levels of training and prior experience demonstrated a significant performance improvement after completion of our simulator curriculum consisting of five diagnostic angiograms, five embolectomy cases, and 10 aneurysm coil embolizations.


The effect of acute intermittent hypoxia on human limb motoneurone output.
What is the central question of this study? Does a single session of repeated bouts of acute intermittent hypoxic breathing enhance the motoneuronal output of the limb muscles of healthy able-bodied participants? What is the main finding and its importance? Compared to breathing room air, there were some increases in motoneuronal output following acute intermittent hypoxia, but the increases were variable across participants and in time after the intervention and depended on which neurophysiological measure was checked. Acute intermittent hypoxia (AIH) induces persistent increases in output from rat phrenic motoneurones. Studies in people with spinal cord injury (SCI) suggest that AIH improves limb performance, perhaps via postsynaptic changes at cortico-motoneuronal synapses. We assessed whether limb motoneurone output in response to reflex and descending synaptic activation is facilitated after one session of AIH in healthy able-bodied volunteers. Fourteen participants completed two experimental days, with either AIH or a sham intervention (randomised crossover design). We measured H-reflex recruitment curves and homosynaptic post-activation depression (HPAD) of the H-reflex in soleus, and motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) and their recruitment curves in first dorsal interosseous. All measurements were performed at rest and occurred at baseline, 0, 20, 40 and 60 min post-intervention. The intervention was 30 min of either normoxia (sham, F i O 2 ${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$ ≈ 0.21) or AIH (alternate 1-min hypoxia [ F i O 2 ${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$ ≈ 0.09], 1-min normoxia). After AIH, the H-reflex recruitment curve shifted leftward. Lower stimulation intensities were needed to evoke 5%, 50% and 99% of the maximal H-reflex at 40 and 60 min after AIH (P < 0.04). The maximal H-reflex, recruitment slope and HPAD were unchanged after AIH. MEPs evoked by constant intensity TMS were larger 40 min after AIH (P = 0.027). There was no change in MEP recruitment or the maximal MEP. In conclusion, some measures of the evoked responses from limb motoneurones increased after a single AIH session, but only at discrete time points. It is unclear to what extent these changes alter functional performance.


Impact of thermal stress on evolutionary trajectories of pathogen resistance in three-spined stickleback (Gasterosteus aculeatus).
Pathogens are a major regulatory force for host populations, especially under stressful conditions. Elevated temperatures may enhance the development of pathogens, increase the number of transmission stages, and can negatively influence host susceptibility depending on host thermal tolerance. As a net result, this can lead to a higher prevalence of epidemics during summer months. These conditions also apply to marine ecosystems, where possible ecological impacts and the population-specific potential for evolutionary responses to changing environments and increasing disease prevalence are, however, less known. Therefore, we investigated the influence of thermal stress on the evolutionary trajectories of disease resistance in three marine populations of three-spined sticklebacks Gasterosteus aculeatus by combining the effects of elevated temperature and infection with a bacterial strain of Vibrio sp. using a common garden experiment. We found that thermal stress had an impact on fish weight and especially on survival after infection after only short periods of thermal acclimation. Environmental stress reduced genetic differentiation (QST) between populations by releasing cryptic within-population variation. While life history traits displayed positive genetic correlations across environments with relatively weak genotype by environment interactions (GxE), environmental stress led to negative genetic correlations across environments in pathogen resistance. This reversal of genetic effects governing resistance is probably attributable to changing environment-dependent virulence mechanisms of the pathogen interacting differently with host genotypes, i.e. GPathogenxGHostxE or (GPathogenxE)x(GHostxE) interactions, rather than to pure host genetic effects, i.e. GHostxE interactions. To cope with climatic changes and the associated increase in pathogen virulence, host species require wide thermal tolerances and pathogen-resistant genotypes. The higher resistance we found for some families at elevated temperatures showed that there is evolutionary potential for resistance to Vibrio sp. in both thermal environments. The negative genetic correlation of pathogen resistance between thermal environments, on the other hand, indicates that adaptation to current conditions can be a weak predictor for performance in changing environments. The observed feedback on selective gradients exerted on life history traits may exacerbate this effect, as it can also modify the response to selection for other vital components of fitness.


An explorative study of factors contributing to the job satisfaction of primary care midwives.
the main objectives of our study was to gain an understanding of how primary care midwives in the Netherlands feel about their work and to identify factors associated with primary care midwives׳ job satisfaction and areas for improvement. a qualitative analysis was used, based on the constructivist/interpretative paradigm. Three open-ended questions in written or online questionnaire, analysed to identify factors that are linked with job satisfaction, were as follows: 'What are you very satisfied with, in your work as a midwife?', 'What would you most like to change about your work as a midwife?' and 'What could be improved in your work?'. 20 of the 519 primary care practices in the Netherlands in May 2010 were included. at these participating practices 99 of 108 midwives returned a written or online questionnaire. in general, most of the participating primary care midwives were satisfied with their job. The factors positively associated with their job satisfaction were their direct contact with clients, the supportive co-operation and teamwork with immediate colleagues, the organisation of and innovation within their practice group and the independence, autonomy, freedom, variety and opportunities that they experienced in their work. Regarding improvements, the midwives desired a reduction in non-client-related activities, such as paperwork and meetings. They wanted a lower level of work pressure, and a reduced case-load in order to have more time to devote to individual clients׳ needs. Participants identified that co-operation with other partners in the health care system could also be improved. our knowledge, our study is the first explorative study on factors associated with job satisfaction of primary care midwives. While there are several studies on job satisfaction in health care; little is known about the working conditions of midwives in primary care settings. Although the participating primary care midwives in the Netherlands were satisfied with their job, areas for improvement were identified. The results of our study can be relevant for countries that have a comparable obstetric system as in the Netherlands, or are implementing or scaling up midwifery-led care.


The pure rotational spectrum of the T-shaped AlC2 radical (X[combining tilde]2A1).
The pure rotational spectrum of the AlC2 radical (X[combining tilde]2A1) has been measured using Fourier transform microwave/millimeter-wave (FTMmmW) techniques in the frequency range 21-65 GHz. This study is the first high-resolution spectroscopic investigation of this molecule. AlC2 was created in a supersonic jet from the reaction of aluminum, generated by laser ablation, with a mixture of CH4 or HCCH, diluted in argon, in the presence of a DC discharge. Three transitions (NKa,Kc = 101 → 000, 202 → 101, and 303 → 202) were measured, each consisting of multiple fine/hyperfine components, resulting from the unpaired electron in the species and the aluminum-27 nuclear spin (I = 5/2). The data were analyzed using an asymmetric top Hamiltonian and rotational, fine structure, and hyperfine constants determined. These parameters agree well with those derived from previous theoretical calculations and optical spectra. An r0 structure of AlC2 was determined with r(Al-C) = 1.924 Å, r(C-C) = 1.260 Å, and θ(C-Al-C) = 38.2°. The Al-C bond was found to be significantly shorter than in other small, Al-bearing species. The Fermi contact term established in this work indicates that the unpaired electron in the valence orbital has considerable 3pza1 character, suggesting polarization towards the C2 moiety. A high degree of ionic character in the molecule is also evident from the quadrupole coupling constant. These results are consistent with a T-shaped geometry and an Al+C2- bonding scheme. AlC2 is a possible interstellar molecule that may be present in the circumstellar envelopes of carbon-rich AGB stars.


Strategies to decrease costs of prescribing selective serotonin reuptake inhibitors at a VA Medical Center.
The authors examined the efficacy of a multifaceted intervention designed to contain the cost of prescribing selective serotonin reuptake inhibitors (SSRIs) to inpatients and outpatients served by a Veterans Affairs (VA) medical center. Elements of the intervention included identification of a preferred agent, tablet splitting, education and feedback for prescribers, and an electronic record and ordering system to facilitate changes in prescriber behaviors. VA databases were searched for information on use and costs of antidepressants. Over 35 months the number of patients treated with SSRIs and the amount spent on SSRIs increased. However, the mean monthly cost per patient decreased from $57.12 to $42.19. The projected cost savings over the 35 months was approximately $700,000; one-fourth of the savings was due to tablet splitting and three-fourths to changes in the proportions of the various SSRIs prescribed. A survey of the top 75 antidepressant prescribers showed that after the educational interventions, 91 percent were aware that citalopram was the medical center's preferred antidepressant, and 59 percent identified it as their own preferred first-line treatment. The results suggest that multifaceted interventions can influence antidepressant costs through provider education and changes in pharmacy and computerized information processes, resulting in substantial cost savings for institutions.


Sociodemographic Profile, Semiology, and Etiology of Patients with Status Epilepticus: A Study from a Tertiary Care Hospital in North India.
Despite advance in treatment of status epilepticus (SE), a major neurological emergency, it is still associated with mortality and morbidity. The objective of our study was to estimate sociodemographic profile, semiology, and etiology in the children with SE admitted in pediatric intensive care. Children between 1 month and 18 years with continuous seizure activity of >5 min or two or more sequential seizures without full recovery of consciousness between seizures, admitted in the Pediatric Intensive Care Unit of the Department of Pediatrics, Government Medical College, Srinagar, were included in the study. A semi-structured tool was designed to record the sociodemographic details. Detailed history, clinical examination, and investigations (including neuroimaging as and when needed) were used to determine the type of seizure and etiology. A total of 51 patients were included in our study. Most of the patients were <5 years with 47.10% in 1-5 years' age group and 43.10% in >1-year age group. Males (60.80%) outnumbered females. Thirty-nine patients (76.47%) belonged to "known" or "symptomatic" group with 35 (68.60%) of them presenting with SE as their fresh seizure. Thirty-nine (76.47%) of our patients had generalized tonic-clonic seizure (GTCS) type of SE. Most of the children (90%) were below the age of 5 years with male predominance. Most of the patients had SE as their first seizure without prior history of seizures with GTCSs was the most frequent seizure type.


Problems and trends in radiotherapeutic treatment of deep-seated tumors.
The heterogeneous structure of tumors is described and the importance of oxygen is explained and analyzed. Three ways of solving the clinical problems of anoxic tumor cells are today being tried. Hyperbaric oxygen breathing before and during irradiation; using fast neutrons and thirdly the use of improved treatment schemes with low LET (i.e. low alpha-value) radiation. The various methods are described and critically evaluated. Calculations are made with the two-component model of radiation. The improved treatment schemes seem in most cases to work well and to solve the problem. If necessary, for certain radio-resistant tumors the normal treatment might also be supplemented by other methods.


Software for the frontiers of quantum chemistry: An overview of developments in the Q-Chem 5 package.
This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange-correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an "open teamware" model and an increasingly modular design.


Focus on the actual clinical target volume irradiated with intraoperative radiotherapy for breast cancer.
Intraoperative radiotherapy (IORT) has been investigated as an exclusive adjuvant treatment option for early-stage breast cancer (BC). We analysed our experience on the technical aspects of this innovative approach in terms of identification of breast volume actually to be treated during IORT. A total of 315 patients at low risk of breast cancer recurrence underwent IORT as exclusive treatment after breast-conservative surgery. To evaluate the breast volume actually irradiated with IORT, we considered a sample of eight patients, chosen retrospectively as having enough clips to identify the tumour bed and IORT site in computed-tomography (CT). The clinical target volume (CTV) was assessed for each patient with two different methods: the first, cc-IORT, was considered during surgery according to the chosen collimator diameter and glandular thickness, while the second, cc-CT, was evaluated through computed-tomography performed after surgery. The cc-CT CTV was obtained by contouring the cc-IORT on the CT section on the basis of the clips placed by the surgeon on the resection margins. In our experience, the 5-cm (50%) and the 6-cm (36%) diameter collimators have been the ones, used the most. The diameter of the collimator used did not appear to adversely affect the satisfactory aesthetic result. The comparison between CTVs showed that glandular breast volume contoured with CT (cc-CT) appeared to be three fold larger than the target identified at surgery and included in the area of chosen collimator (cc-IORT). The actual volume of breast gland irradiated with the IORT procedure appears to be larger than expected. This may be due to the area being prepared for IORT by placing tissue compactly.


Patellar and Achilles tendinopathies are predominantly peripheral pain states: a blinded case control study of somatosensory and psychological profiles.
Case-control design. Tendinopathy is characterised by pain on tendon loading. In persistent cases of upper limb tendinopathy, it is frequently associated with central nervous system sensitisation, whereas less commonly linked in the case of persistent lower limb tendinopathies. Compare somatosensory and psychological profiles of participants with persistent patellar (PT) and Achilles tendinopathies (AT) with pain-free controls. A comprehensive battery of Quantitative Sensory Testing (QST) was assessed at standardised sites of the affected tendon and remotely (lateral elbow) by a blinded assessor. Participants completed the Victorian Institute of Sports Assessment, a health-related quality of life questionnaire, the Hospital Anxiety and Depression Scale and the Active Australia Questionnaire. Independent t-test and analysis of covariance (sex-adjusted and age-adjusted) were performed to compare groups. Participants with PT and AT did not exhibit differences from controls for the QST at the remote site, but there were differences at the affected tendon site. Compared with controls, participants with PT displayed significantly lower pressure pain threshold locally at the tendon (p=0.012) and fewer single limb decline squats before pain onset, whereas participants with AT only displayed fewer single heel raises before pain onset, but this pain was of a higher intensity. PT and AT appear to be predominantly local not widespread pain states related to loading of tendons without significant features of central sensitisation. Level 4.


Distress tolerance and pain experience among young adults.
Pain and pain related problems affect a significant proportion of the United States population. Past research suggests that emotional distress is associated with more severe and disabling pain experience. Yet, it is less clear how individual reactions to distress are related to pain experience. Distress tolerance, defined as the perceived ability to withstand cognitive, affective, or physical distress, is an individual difference factor that may be particularly important to understanding the experience of pain. The current study examined the association of distress tolerance with pain severity, pain disability, and frequency of pain disability in a sample of young adults (N = 1577, M age = 22.17) with mild to severe pain. Results indicated that, after controlling for gender, past 30-day opiate use, and perceived health status, lower distress tolerance was significantly associated with more severe and disabling pain. These novel empirical findings suggest distress tolerance may be a useful construct in need of further study among young adults with pain complaints.


Systematic review of the literature on postpartum care: methodology and literature search results.
The postpartum period is a time for multiple clinical interventions. To date, no critical review of these interventions exists. This systematic review examined evidence for the effectiveness of postpartum interventions that have been reported in the literature. MEDLINE, Cinahl, PsycINFO, and the Cochrane Library were searched for randomized controlled trials of interventions initiated from immediately after birth to 1 year in postnatal women that were conducted in North America, Europe, Australia, or New Zealand. The initial literature search was done in 1999, using postpartum content search terms, and was enhanced in 2003. In both years, bibliographic databases were searched from their inception. Studies were categorized into key topic areas. Data extraction forms were developed and completed for each study, and the quality of each study was systematically reviewed. Groups of studies in a topic area were reviewed together, and clinically relevant questions emanating from the studies were identified to determine whether the studies, alone or together, provided evidence to support the clinical intervention. In the 1999 search, of 671 studies identified, 140 studies were randomized controlled trials that met the selection criteria: 41 studies related to breastfeeding, 33 to postpartum perineal pain management, and 63 to 11 other key topic areas (Papanicolaou test, rubella immunization, contraception, postpartum support, early discharge, postpartum depression and anxiety, postpartum medical disorders, smoking cessation, nutrition supplements other than breastfeeding, effects of pelvic floor exercise, and effects of early newborn contact). The results of the systematic review of each topic will be summarized in separate papers as they are completed. This systematic search has identified key topic areas in postpartum care for which randomized controlled trials have been conducted. Our ultimate goal is to provide evidence-based guidelines on the use of routine postpartum interventions.


The plastic human brain.
In this review I summarize and discuss reported findings of structural and functional plasticity in the intact human brain. The main focus is placed on research that uses musicians as a model to study brain plasticity. I summarize therefore mostly studies dealing with musicians or with the effect of music practice. In the first section, structural plasticity is described on the basis of modern neuroanatomical studies using magnetic resonance imaging (MRI) techniques. In the second part, emphasis is given to studies reporting functional plasticity on the basis of changed neurophysiological activation patterns. These studies are discussed in the context of two approaches employed to study plasticity in the human brain: the cross-sectional and longitudinal approaches. The reviewed studies altogether indicate that experience can shape brain anatomy and brain physiology. Brain plasticity as demonstrated here is related to changed grey and white mater densities (and volumes) but also to changed activation patterns in the brain areas involved in controlling the expertise task. Taken together, all studies support the view that the human brain is much more plastic than had been anticipated 20 years ago.


Deficiency in homologous recombination renders Mammalian cells more sensitive to proton versus photon irradiation.
To investigate the impact of the 2 major DNA repair machineries on cellular survival in response to irradiation with the 2 types of ionizing radiation. The DNA repair and cell survival endpoints in wild-type, homologous recombination (HR)-deficient, and nonhomologous end-joining-deficient cells were analyzed after irradiation with clinically relevant, low-linear energy transfer (LET) protons and 200-keV photons. All cell lines were more sensitive to proton irradiation compared with photon irradiation, despite no differences in the induction of DNA breaks. Interestingly, HR-deficient cells and wild-type cells with small interfering RNA-down-regulated Rad51 were markedly hypersensitive to proton irradiation, resulting in an increased relative biological effectiveness in comparison with the relative biological effectiveness determined in wild-type cells. In contrast, lack of nonhomologous end-joining did not result in hypersensitivity toward proton irradiation. Repair kinetics of DNA damage in wild-type cells were equal after both types of irradiation, although proton irradiation resulted in more lethal chromosomal aberrations. Finally, repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual γH2AX foci after irradiation. Our data indicate a differential quality of DNA damage by proton versus photon irradiation, with a specific requirement for homologous recombination for DNA repair and enhanced cell survival. This has potential relevance for clinical stratification of patients carrying mutations in the DNA damage response pathways.


Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN.
Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha. European Société Internationale d'Oncologie Pédiatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth). Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years. Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted.


Fluoride-induced oxidative stress is involved in the morphological damage and dysfunction of liver in female mice.
Fluoride (F), one of the most toxic environmental and industrial pollutants, is known to exert hepatotoxicity. The contribution of oxidative stress to the F tolerance of liver remains largely unknown. In this study, the morphological and ultrastructural characteristics of liver were observed using hematoxylin and eosin staining and transmission electron microscopy (TEM), respectively. Oxidative-stress participations was analysed and the mRNA expression levels of catalase (Cat), glutathione peroxidase 1 (GSH-Px1), nitric oxide synthase 2 (NOS2), and superoxide dismutase 1 (SOD1) were investigated by real-time PCR. Changes in liver-function parameters were also detected. Results showed that the reactive content of reactive oxygen species increased significantly, whereas SOD and GSH-Px activities, as well as total anti-oxidising capability (T-AOC), decreased significantly, with increased nitric oxide (NO) and malondialdehyde (MDA) contents in liver and serum after 70days of F treatment. The mRNA expression levels of Cat, GSH-Px1, and SOD were significantly downregulated, whereas NOS2 mRNA expression level was up upregulated, after F treatment for 70days. Light microscopy also revealed that hepatocytes were fused into pieces; cell boundaries were unclear, and nuclei were lightly stained. TEM further showed that hepatocytes were characterised by vague nuclear and mitochondrial membranes, dilated endoplasmic reticulum, and aggravated vacuolar degeneration. Activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase, as well as the level of total bilirubin in serum increased. Overall, these results indicated that F interfered with the balance of antioxidase activity and morphological changes in liver, which were involved in mouse liver dysfunction.


Trends in Nonlipid Cardiovascular Disease Risk Factor Management in the Women's Interagency HIV Study and Association with Adherence to Antiretroviral Therapy.
Cardiovascular disease (CVD) is increasingly common among women with HIV, but literature on nonlipid CVD risk factor management is lacking. We examined semiannual trends from 2006 to 2014 in hypertension treatment and control (blood pressure <140/90 mmHg), diabetes treatment and control (fasting glucose <130 mg/dL), and smoking quit rates in the Women's Interagency HIV Study. Unadjusted and adjusted Poisson regression models tested time trends and differences between HIV+ and HIV- women. Among antiretroviral therapy (ART) users, we examined the association of ART adherence and virologic suppression with each outcome. We evaluated 1636 HIV+ and 683 HIV- women, with a hypertension prevalence of 40% and 38%, respectively; diabetes prevalence of 21% and 22%; and smoking prevalence of 37% and 48%. Hypertension treatment was higher among HIV+ than HIV- women (77% vs. 67%, p < 0.001) and increased over time with no difference in trend by HIV status. Hypertension control was greater among HIV+ women (56% vs. 43%, p < 0.001) and increased over time among HIV+ but not HIV- women. Diabetes treatment was similar among HIV+ and HIV- women (48% vs. 49%) and increased over time in both groups. Diabetes control was greater among HIV+ women (73% vs. 64%, p = 0.03) and did not change over time. The percent of recent smokers who reported no longer smoking was similar between HIV+ and HIV- women (10% vs. 9%), with no differences over time. Virologic suppression was significantly associated with increased hypertension treatment and greater control. HIV+ women have better control of hypertension and diabetes than HIV- women, but many are still not at target levels.


Tissue response to poly(L-lactic acid)-based blend with phospholipid polymer for biodegradable cardiovascular stents.
A temporary cardiovascular stent device by bioabsorbable materials might reduce late stent thrombosis. A water-soluble amphiphilic phospholipid polymer bearing phosphorylcholine groups (PMB30W) was blended with a high-molecular-weight poly(l-lactic acid) (PLLA) to reduce unfavorable tissue responses at the surface. The PLLA implants and the polymer blend (PLLA/PMB30W) implants were inserted into subcutaneous tissues of rats, the infrarenal aorta of rats, and the internal carotid arteries of rabbits. After 6 months subcutaneous implantation, the PLLA/PMB30W maintained high density of phosphorylcholine groups on the surface without a significant bioabsorption. After intravascular implantation, the cross-sectional areas of polymer tubing with diameters less than 1.6 mm were histomorphometrically measured. Compared to the PLLA tubing, the PLLA/PMB30W tubing significantly reduced the thrombus formation during 30 d of implantation. Human peripheral blood mononuclear cells were cultured on the PLLA and the PLLA/PMB30W to compare inflammatory reactions. Enzyme-linked immunosorbent assay quantified substantially decreased proinflammatory cytokines in the case of the PLLA/PMB30W. They were almost the same level as the negative controls. Thus, we conclude that the phosphorylcholine groups could reduce tissue responses significantly both in vivo and in vitro, and the PLLA/PMB30W is a promising material for preparing temporary cardiovascular stent devices.


A Simplified Lateral Hinge Approach to the Proximal Interphalangeal Joint.
Proximal interphalangeal joint replacement is an effective treatment for painful arthritis affecting the joint. However, the complication rate is relatively high, with many of these complications related to soft-tissue imbalance or instability. Volar, dorsal, and lateral approaches have all been described with varying results. We describe a new simplified lateral hinge approach that splits the collateral ligament to provide adequate exposure of the joint. Following insertion of the prosthesis the collateral ligament is simply repaired, side-to-side, which stabilizes the joint. As the central slip, opposite collateral ligament, flexor and extensor tendons have not been violated, early active mobilization without splinting is possible, and the risk of instability, swan-neck, and boutonniere deformity are reduced. The indications, contraindications, surgical technique, and rehabilitation protocol are described.


Anal fissure (chronic).
Anal fissures are a common cause of anal pain during, and for 1 to 2 hours after, defecation. The cause is not fully understood, but low intake of dietary fibre may be a risk factor. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-surgical treatments for chronic anal fissure? What are the effects of surgical treatments for chronic anal fissure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: anal advancement flap, anal stretch/dilation, botulinum A toxin-haemagglutinin complex alone or with nitrates, calcium channel blockers, internal anal sphincterotomy, and nitric oxide donors.


Characterising 'near miss' events in complex laparoscopic surgery through video analysis.
Root cause analyses of surgical complications are of high importance to ensure surgical quality, but specific details on technical causes often remain unclear. Identifying subclinical intraoperative incidents attributable to technical errors is essential for developing rescue mechanisms to prevent adverse outcomes. Descriptive study to characterise intraoperative technical error-event patterns in successful laparoscopic procedures. Events (injuries) identified during prior blinded analyses of 54 unedited recordings of bariatric laparoscopic procedures were subjected to a secondary review to determine the presumed underlying error mechanism. The recordings were obtained from one university-based bariatric collaborative programme, and represented consultant, fellow and shared trainee cases. Sixty-six events were identified in 38 recordings, while 16 videos showed no events. In 25 (66%) of the videos that showed events, additional measures such as haemostasis or suture repair were required. Common identified events were minor bleeding (n=39, 59%), thermal injury to non-target tissue (n=7, 11%), serosal tears (n=6, 9%). Common error mechanisms were 'inadequate use of force/distance (too much)' (n=20, 30%) and 'inadequate visualisation' during grasping/dissecting (n=6, 9%), 'inadequate use of force/distance (too much)' using an energy device (n=6, 9%), or during suturing (n=6, 9%). All events were recognised intraoperatively. Analysis of successful operations allowed the identification of numerous error-event sequences. Reviewing injury mechanisms can enhance surgeons' understanding of relevant errors. This error awareness may aid surgeons in preparing for cases, help avoid errors and mitigate their consequences. Thus, this approach may impact future surgical education and quality initiatives aimed at reducing surgical risks.


Hiding in plain sight: New virus genomes discovered via a systematic analysis of fungal public transcriptomes.
The distribution and diversity of RNA viruses in fungi is incompletely understood due to the often cryptic nature of mycoviral infections and the focused study of primarily pathogenic and/or economically important fungi. As most viruses that are known to infect fungi possess either single-stranded or double-stranded RNA genomes, transcriptomic data provides the opportunity to query for viruses in diverse fungal samples without any a priori knowledge of virus infection. Here we describe a systematic survey of all transcriptomic datasets from fungi belonging to the subphylum Pezizomycotina. Using a simple but effective computational pipeline that uses reads discarded during normal RNA-seq analyses, followed by identification of a viral RNA-dependent RNA polymerase (RdRP) motif in de novo assembled contigs, 59 viruses from 44 different fungi were identified. Among the viruses identified, 88% were determined to be new species and 68% are, to our knowledge, the first virus described from the fungal species. Comprehensive analyses of both nucleotide and inferred protein sequences characterize the phylogenetic relationships between these viruses and the known set of mycoviral sequences and support the classification of up to four new families and two new genera. Thus the results provide a deeper understanding of the scope of mycoviral diversity while also increasing the distribution of fungal hosts. Further, this study demonstrates the suitability of analyzing RNA-seq data to facilitate rapid discovery of new viruses.


Does physical training reduce fatigue in sarcoidosis?
Sarcoidosis patients frequently experience fatigue, exercise intolerance and muscle weakness, resulting in reduced quality of life (QOL). Scientific studies on the benefits of physical training in sarcoidosis have been scarce, so the aim of this pilot study was to examine the impact of a 13-week physical training program on fatigue, physical functions and QOL in fatigued sarcoidosis patients and/or patients with exercise intolerance. 18 sarcoidosis patients participated in a 13-week physical training program. The Fatigue Assessment Scale (FAS), World Health Organization Quality of Life-BREF assessment instrument (WHOQOL-BREF),Medical Research Council (MRC) dyspnea scale, Visual Analogue Scale (VAS), six-minute walk test (6MWT), submaximal bicycle test and muscle strength of the quadriceps and elbow flexors were assessed at baseline and after the program. FAS scores had decreased (mean difference -2.7 points, 95% CI -4.4 to -1.1) after completion of the training program, along with improvements in WHOQOLBREF psychological health domain (mean difference 0.9 points, 95% CI 0.2 to 1.7) and MRC dyspnea score (mean difference -0.4 points, 95% CI -0.8 to -0.1). 6MWD improved by 34.6 m (95% CI 20.3 to 49.0) and mean heart rate on the bicycle test improved (mean difference 8.4 beats/minute, 95% CI -13.8 to -3.0), as did quadriceps strength (mean difference 10.7 kg, 95% CI 5.5 to 15.9). Fatigue reduced after a period of physical training in sarcoidosis patients. Moreover, psychological health and physical functions improved. Future studies are warranted to assess the benefits of physical training in sarcoidosis.


MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.
Mutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. Seven male Labrador Retrievers, age 14-26 wk, were clinically evaluated for generalized weakness and muscle atrophy. Muscle biopsies showed variability in fiber size, centrally placed nuclei resembling fetal myotubes, and subsarcolemmal ringed and central dense areas highlighted with mitochondrial specific reactions. Ultrastructural studies confirmed the centrally located nuclei, abnormal perinuclear structure, and mitochondrial accumulations. Wild-type triads were infrequent, with most exhibiting an abnormal orientation of T tubules. MTM1 gene sequencing revealed a unique exon 7 variant in all seven affected males, causing a nonconservative missense change, p.N155K, which haplotype data suggest derives from a recent founder in the local population. Analysis of a worldwide panel of 237 unaffected Labrador Retrievers and 59 additional control dogs from 25 other breeds failed to identify this variant, supporting it as the pathogenic mutation. Myotubularin protein levels and localization were abnormal in muscles from affected dogs, and expression of GFP-MTM1 p.N155K in COS-1 cells showed that the mutant protein was sequestered in proteasomes, where it was presumably misfolded and prematurely degraded. These data demonstrate that XLMTM in Labrador Retrievers is a faithful genetic model of the human condition.


Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism.
The glycolytic inhibitor 2-deoxyglucose (2-DG) was tested as a potential chemotherapeutic agent for drug-resistant cancer cells. Previously it was found that Adriamycin-resistant human MCF-7 breast cancer cells (ADR) exhibit an enhanced rate of glycolysis compared to their parent wild-type (WT) cell line (R. C. Lyon et al., Cancer Res., 48: 870-877, 1987). We now describe a specific toxic effect of 2-DG on the ADR cells, which is more than 15-fold greater than for WT cells. Using 31P magnetic resonance spectroscopy of perfused MCF7 cells we continuously monitored the accumulation of 2-deoxyglucose 6-phosphate together with concomitant changes in other phosphate-containing metabolites. Kinetic measurements demonstrated that ADR cells accumulated 2-deoxyglucose 6-phosphate faster and to a greater extent than WT cells, while their depletion of high energy compounds (ATP, phosphocreatine) was more pronounced and became irreversible earlier. The phosphorylation of 2-DG could be followed more effectively by the use of 13C magnetic resonance spectroscopy of 2-DG enriched with 13C at C-6, since the signals of 2-DG and 2-deoxyglucose 6-phosphate are clearly resolved and, unlike 31P magnetic resonance spectroscopy, there are no other interfering signals. With the use of this technique with ADR and WT cells the rate of phosphorylation of 2-DG was found to be 11.2 x 10(-4) and 6.5 x 10(-4) mmol/min/mg protein, respectively. The results of these studies indicate that differences in the biochemistry of energy metabolism of resistant cells may make them targets for energy antimetabolites.


Intrapleural agents for pleural infection: fibrinolytics and beyond.
Pleural infection is a common, increasing clinical problem with a high morbidity and mortality. Medical management of pleural infection often fails, requiring invasive thoracic surgery to drain infected pleural collections, and for many years intrapleural agents have been assessed to reduce the need for surgical drainage and improve clinical outcomes. Randomized trials assessing intrapleural fibrinolytic agents have given conflicting results, and recent evidence provides important information on the role of intrapleural agents in the treatment of pleural infection, and the possible biology associated with infection progression in these patients. Pleural infection is increasing in both the adult and paediatric populations. The combined previous evidence assessing intrapleural fibrinolytics alone in pleural infection suggests lack of efficacy for clinically important outcomes. The Multi-Centre Intrapleural Sepsis Trial 2 (MIST2) study provides the first evidence of a novel treatment combination [intrapleural tissue plasminogen activator (tPA) combined with intrapleural deoxyribonuclease (DNase)], which significantly improves the chest radiograph compared with either agent alone or placebo, and has potentially important benefits to important clinical outcomes (need for surgery and hospital stay). The precise mechanism of action of combination fibrinolytic and DNase in pleural infection is speculative. Fibrinolytic therapy alone has not been proven to be of use in the treatment of pleural infection. The MIST2 study provides clear-cut evidence demonstrating improved chest radiographs, and highly suggestive secondary outcomes suggesting improved clinically important outcomes, using a combination of intrapleural tPA and DNase. This novel treatment combination may represent an important step in our understanding and treatment of pleural infection; however, larger clinical studies specifically addressing important clinical outcomes and further laboratory research describing the potential mechanisms of action are now required.


Analysis of serum magnesium ions in dogs exposed to external stress: A pilot study.
Magnesium ions (Mg2+) are essential for various enzymatic reactions in the body associated with energy production and activation of the muscles and nerves. Mg2+ is also involved in blood pressure regulation, maintenance of body temperature, and glucose metabolism. Although various factors including foods and physical conditions have been reported to change serum Mg2+ status in humans, serum Mg2+ in dogs exposed to external stress has been unclear. In this study, we examined serum levels of Mg2+ in dogs at different conditions using the guide dog candidates for the blind. Serum Mg2+ was decreased in winter and increased in summer. Guide dog candidates in an elementary class of the training showed markedly lower levels of serum Mg2+, compared with that of dogs in an advanced class. When healthy adult dogs were subjected to forced exercise using a treadmill, a significant reduction in serum Mg2+ levels was observed, particularly in winter. These findings suggest that serum levels of Mg2+ may be influenced by weather fluctuation such as air temperature, nervousness in unaccustomed situations, age, and physical stress induced by exercise. The results indicate that Mg2+ supplementation should be considered for working dogs, dogs moving or traveling to a new environment, and dogs during winter.


Tolerance-Inducing dose of 3-nitropropionic acid modulates bcl-2 and bax balance in the rat brain: a potential mechanism of chemical preconditioning.
Many studies have reported ischemia protection using various preconditioning techniques, including single dose 3-nitropropionic acid (3-NPA), a mitochondrial toxin. However, the cellular signal transduction cascades resulting in ischemic tolerance and the mechanisms involved in neuronal survival in the tolerant state still remain unclear. The current study investigated the mRNA and protein expression of the antiapoptotic bcl-2 and the proapoptotic bax. two antagonistic members of the bcl-2 gene family, in response to a single dose of 3-NPA, to global cerebral ischemia-reperfusion. and to the combination of both 3-NPA-pretreatment and subsequent global cerebral ischemia-reperfusion. Brain homogenates of adult Wistar rats (n = 25) were analyzed for bcl-2 and bax mRNA expression using a new highly sensitive and quantitative polymerase chain reaction (PCR) technique that allows real-time fluorescence measurements of the PCR product (LightCycler; Roche Diagnostics, Mannheim, Germany). Animals for mRNA analysis received 3-NPA (20 mg/kg, intraperitoneal; "chemical preconditioning") or vehicle (normal saline), and were either observed for 24 plus 3 hours or were subjected to 15 minutes of global cerebral ischemia 24 hours after the pretreatment and observed for 3 hours of reperfusion. Immunohistochemistry was applied to serial brain sections of additional rats (n = 68) to determine amount and localization of the respective Bcl-2 and Bax protein expression in various brain areas. One set of animals was injected with 3-NPA and observed for 3, 12, 24, and 96 hours; a second set was exposed to 15 minutes global cerebral ischemia, 3, 12, and 24 hours reperfusion; and a third set was pretreated with 3-NPA or saline 24 hours before the ischemic brain insult and observed for 96 hours of reperfusion. The authors found single dose 3-NPA treatment to be associated with an elevated bcl-2:bax ratio (increased bcl-2 expression, decreased bax expression), both on the transcriptional (mRNA) and the translational (protein) level. The differential influence of 3-NPA was maintained during early recovery from global cerebral ischemia (3 hours), when 3-NPA pretreated animals showed higher bcl-2 and lower bax mRNA levels compared with rats with saline treatment. Respective changes in protein expression were localized predominately in neurons vulnerable to ischemic damage. Compared with baseline, Bcl-2 protein was significantly higher in surviving neurons at 96 hours after the insult, whereas Bax protein remained unchanged. However, at this late time of postischemic recovery (96 hours), the protein expression pattern of surviving neurons was not different between animals with and without 3-NPA pretreatment. To the authors' knowledge, the current study is the first report on the differential expression of pro- and antiapoptotic genes after a single, nonlethal dose of 3-NPA. The current results suggest alterations in the balance between pro- and antiapoptotic proteins as a potential explanation for the reported protection provided by chemical preconditioning using 3-NPA in rats.


Cognitive processing in putative functional gastrointestinal disorder: rumination yields orientation to social threat not pain.
Two possible roles of selective attention in the development and maintenance of functional gastrointestinal disorders (FGID) such as irritable bowel syndrome (IBS) were examined. First, hypervigilance to pain within FGID may exacerbate pain perception and pain-related distress. Second, hypervigilance to socially threatening stimuli could account for the disrupted social functioning reported by patients. Furthermore, stress-related variations in reported symptom severity and functioning impairments may reflect changes in cognitive bias with psychological state. Patterns of selective attention were probed within a sample of putative FGID participants (pFGID). The effect of rumination induction on performance on a modified exogenous cueing task was examined. Thirty-three women with pFGID and 27 matched controls responded to dot probes following pain, social threat and neutral word cues, both before and after rumination (passive self-focused thought), or distraction induction. Reaction times revealed that after rumination but not neutral distraction, pFGID participants showed enhanced attention to social threat words, but not to pain or neutral words. Between-group differences in mood, anxiety or depression could not account for these effects. These results implicate selective attention in social but not pain-related idiosyncrasies in FGID including IBS.