Post-operative atrial fibrillation: a maze of mechanisms.
Post-operative atrial fibrillation (POAF) is one of the most frequent complications of cardiac surgery and an important predictor of patient morbidity as well as of prolonged hospitalization. It significantly increases costs for hospitalization. Insights into the pathophysiological factors causing POAF have been provided by both experimental and clinical investigations and show that POAF is 'multi-factorial'. Facilitating factors in the mechanism of the arrhythmia can be classified as acute factors caused by the surgical intervention and chronic factors related to structural heart disease and ageing of the heart. Furthermore, some proarrhythmic mechanisms specifically occur in the setting of POAF. For example, inflammation and beta-adrenergic activation have been shown to play a prominent role in POAF, while these mechanisms are less important in non-surgical AF. More recently, it has been shown that atrial fibrosis and the presence of an electrophysiological substrate capable of maintaining AF also promote the arrhythmia, indicating that POAF has some proarrhythmic mechanisms in common with other forms of AF. The clinical setting of POAF offers numerous opportunities to study its mechanisms. During cardiac surgery, biopsies can be taken and detailed electrophysiological measurements can be performed. Furthermore, the specific time course of POAF, with the delayed onset and the transient character of the arrhythmia, also provides important insight into its mechanisms. This review discusses the mechanistic interaction between predisposing factors and the electrophysiological mechanisms resulting in POAF and their therapeutic implications.


Cell membrane wrapping of a spherical thin elastic shell.
Nanocapsules that can be tailored intelligently and specifically have drawn considerable attention in the fields of drug delivery and bioimaging. Here we conduct a theoretical study on cell uptake of a spherical nanocapsule which is modeled as a linear elastic solid thin shell in three dimensions. It is found that there exist five wrapping phases based on the stability of three wrapping states: no wrapping, partial wrapping and full wrapping. The wrapping phase diagrams are strongly dependent on the capsule size, adhesion energy, cell membrane tension, and bending rigidity ratio between the capsule and membrane. Discussion is made on similarities and differences between the cell uptake of solid nanocapsules and fluid vesicles. The reported results may have important implications for biomedical applications of nanotechnology.


Balanites aegyptiaca ameliorates insulin secretion and decreases pancreatic apoptosis in diabetic rats: Role of SAPK/JNK pathway.
SAPK-JNK pathway performs a significant role in the pathogenesis of type 2 diabetes. Balanites aegyptiaca (BA) is used as an anti-diabetic agent in folk medicine however its hypoglycemic mechanism is not fully elucidated. The current study aimed to evaluate the effect of crude extract, butanol, and dichloromethane fractions from BA on the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK-JNK) pathway in experimental diabetic rats. Six groups of male Wistar rats were included: normal control, diabetic, diabetic rats treated with crude, butanol or dichloromethane fraction from BA (50 mg/kg BW) and diabetic rats treated with gliclazide as a reference drug for one month. Our results suggested a protective role of treatment of diabetic rats with BA against oxidative stress-induced SAPK-JNK pathway. Moreover, BA treatment produced a reduction in plasma glucose, HbA1c, lactic acid, lipid profile, malondialdehyde levels and produced an increase in insulin, reduced glutathione levels, catalase and superoxide dismutase activities compared with untreated diabetic rats. Moreover, it decreased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase 1, protein 53 and increased insulin receptor substrate 1 in rat pancreas while it increased glucose transporter 4 in rat muscle. Analysis of BA extracts by LC-HRMS revealed the presence of different saponins with reported hypoglycemic effect. In conclusion, BA exerted hypoglycemic, hypolipidemic, insulinotropic and antioxidant effects. Additionally, it reduced apoptosis in pancreatic β-cells and increased glucose uptake in muscle. These results suggest that the hypoglycemic effect of BA is due to the inhibition of the SAPK-JNK pathway.


Serum amyloid A levels and alpha 2 and gamma globulins on serum protein electrophoresis in cats exposed to and infected with Leishmania infantum.
Dogs are the main reservoir hosts of Leishmania infantum; nevertheless, recent investigations indicate a likely role for cats in the epidemiology of Leishmania infection. Feline leishmaniosis (FeL) remains poorly characterised, partly due to the lack of suitable diagnostic tools. This study aimed to compare serum amyloid A (SAA) levels and serum protein electrophoresis (SPE) profiles (specifically, alpha 2 and gamma globulins) in cats naturally exposed to or infected by L. infantum from southern Italy versus those of healthy controls and versus cats with neoplastic or inflammatory conditions from non-endemic areas. Serum or plasma samples from four cohorts of cats were analysed for SAA levels and by SPE: (i) G1: healthy controls from Leishmania-non-endemic regions of Switzerland; (ii) G2: cats pre-diagnosed with neoplastic or inflammatory conditions available from the University of Cambridge sample archive; (iii) G3: L. infantum-seropositive, quantitative (q)PCR-negative cats from southern Italy; (iv) G4: L. infantum-seropositive and qPCR-positive cats from southern Italy. SAA data were assessed for normality and homoscedasticity using the Shapiro-Wilk and Levene's tests, respectively; the Kruskall-Wallis test, followed by Dunn's test with Bonferroni correction were subsequently used to compare SAA serum levels between groups. A weighted generalised linear model with a binomial distribution was used to assess statistically significant differences in the numbers of animals displaying elevated gamma globulins and increased alpha 2 globulins between groups. Overall, 68 samples were analysed (G1: n = 16, G2: n = 20, G3: n = 20, G4: n = 12). Cats suffering from neoplastic and inflammatory conditions (G2 ) showed significantly higher SAA levels than healthy controls (G1) (median values [interquartile range]: G1: 0.00 [0.00-0.00] mg/l versus G2: 0.85 [0.00-49.55] mg/l). G2, G3 and G4 cats showed higher percentages of individuals with increased alpha 2 globulins (percentages ± standard error: G1 = 20.0% ± 10.3, G2 = 80.0% ± 8.9, G3 = 70.0% ± 10.2, G4 = 75.0% ± 12.5) and gamma globulins (G1 = 0.0% ± 0, G2 = 65.0% ± 10.7, G3 = 50.0% ± 11.2, G4 = 58.3% ± 14.2) than healthy control cats (G1). For all three markers, no significant difference between cats within G2, G3 and G4 was recorded. This study indicates that the proportions of animals with elevated levels of alpha 2 and gamma globulins are significantly higher in cats exposed to and infected with L. infantum. Levels of SAA and alpha 2 and gamma globulins may not be used to differentiate between L. infantum infection or exposure, and neoplastic and/or inflammatory conditions.


Breed, smaller weight, and multiple injections are associated with increased adverse event reports within three days following canine vaccine administration.
To evaluate patient and vaccine factors associated with adverse events (AEs) recorded within 3 days of vaccine administration in a large cohort of dogs. 4,654,187 dogs vaccinated in 16,087,455 office visits in a 5-year period at 1,119 hospitals of a corporate practice. Electronic medical records of dogs vaccinated between January 1, 2016, and December 31, 2020, were searched for diagnoses of possible AEs recorded within 3 days of administration of vaccines without concurrent injectable heartworm preventative. Patient risk factors (age, sex, breed, and weight) and number and type of vaccine were extracted from records. ORs (and 95% CIs) for risk factors were estimated via multivariable logistic regression mixed models with patient as a random effect. AEs were recorded following 31,197 vaccination visits (0.19%, or 19.4/10,000 visits). Reported AE rates increased from 1 to 4 vaccines administered and among individual vaccines were greatest for rabies vaccine. AE rate was generally inversely related to body weight, with largest rates in dogs ≤ 5 kg. The largest AE rates were noted in French Bulldogs and Dachshunds (ORs > 4 compared to mixed-breed dogs). Risk factor information can be used to update vaccination protocols and client communication. Breed differences may indicate genetics as the primary risk factor for adverse vaccine reactions following vaccinations.


Essentials of Our Current Understanding: Abdominal Wall Blocks.
Abdominal wall blocks rely on the spread of local anesthetic within musculofascial planes to anesthetize multiple small nerves or plexuses, rather than targeting specific nerve structures. Ultrasonography is primarily responsible for the widespread adoption of techniques including transversus abdominis plane and rectus sheath blocks, as well as the introduction of novel techniques such as quadratus lumborum and transversalis fascia blocks. These blocks are technically straightforward and relatively safe and reduce pain and opioid requirements in many clinical settings. The data supporting these outcomes, however, can be inconsistent because of heterogeneity of study design. The extent of sensory blockade is also somewhat variable, because it depends on the achieved spread of local anesthetic and the anatomical course of the nerves being targeted. The blocks mainly provide somatic analgesia and are best used as part of a multimodal analgesic regimen. This review summarizes the anatomical, sonographic, and technical aspects of the abdominal wall blocks in current use, examining the current evidence for the efficacy and safety of each.


Ethical considerations for psychologists in the time of COVID-19.
Psychologists are in a position to respond to the COVID-19 pandemic through research, practice, education, and advocacy. However, concerns exist about the ethical implications associated with transitioning from face-to-face to online or virtual formats as necessitated by stay-at-home orders designed to enforce the social distancing required to flatten the curve of new COVID-19 cases. The purpose of this article is to review potential ethical issues and to provide guidance to psychologists for ethical conduct in the midst of the current crisis and its aftermath. In addition to contextualizing relevant ethical considerations according to the principles and standards of the current American Psychological Association's ethics code, vignettes are presented to exemplify the ethical dilemmas psychologists in various roles may face when responding to COVID-19 and to offer suggestions and resources for resolving potential conflicts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


[A neurochemical analysis of the substance P-induced reordering of the feeding behavior evoked by electrical stimulation of the lateral hypothalamus].
The substance P when administered intracerebroventricularly (15 nmol) led to a transformation of feeding elicited by threshold electrical stimulation of the lateral hypothalamus into an escape reaction in rabbits. Obsidan, Inderal (0.25 and 0.5 mg) and droperidol (0.3 mg) injected intravenously were found to restore the functional properties of the hypothalamic feeding centre. No changes in the escape reaction were observed after kalipsol (ketaminum) administration. The data obtained suggest the important role of the catecholaminergic brain structures in the mechanisms of the transformation of the functional properties of the hypothalamic feeding centre under the influence of the substance P.


The pleasures and perils of prophetic advocacy: Henry E. Sigerist and the politics of medical reform.
Henry E. Sigerist, an internationally renowned medical historian, played a surprisingly important and visible role in American medical politics in the 1930s and 1940s. Born in Paris of Swiss parents, he was professor in Leipzig, Germany, before coming to the United States in 1932 as professor of the history of medicine at Johns Hopkins University. Once in America. Sigerist became deeply involved in medical politics and the campaign for national health insurance. He argued that individualized medical practice was outdated and should gradually be superseded by state-run and state-financed health services. National health insurance was but one step in this historical progression. Sigerist thus lent the weight of history itself to the cause of medical care reform. The charming and erudite Sigerist was welcomed by the leaders of academic medicine in America. Soon, he emerged as a spokesman of the left wing of the medical profession, an effective and popular speaker and an impassioned advocate of socialized medicine. This paper traces Sigerist's political ideas and activities, and his contributions toward medical care reform in the United States.


Types and effects of feedback for emergency ambulance staff: a systematic mixed studies review and meta-analysis.
Extensive research has been conducted into the effects of feedback interventions within many areas of healthcare, but prehospital emergency care has been relatively neglected. Exploratory work suggests that enhancing feedback and follow-up to emergency medical service (EMS) staff might provide staff with closure and improve clinical performance. Our aim was to summarise the literature on the types of feedback received by EMS professionals and its effects on the quality and safety of patient care, staff well-being and professional development. A systematic review and meta-analysis, including primary research studies of any method published in peer-reviewed journals. Studies were included if they contained information on systematic feedback to emergency ambulance staff regarding their performance. Databases searched from inception were MEDLINE, Embase, AMED, PsycINFO, HMIC, CINAHL and Web of Science, with searches last updated on 2 August 2022. Study quality was appraised using the Mixed Methods Appraisal Tool. Data analysis followed a convergent integrated design involving simultaneous narrative synthesis and random effects multilevel meta-analyses. The search strategy yielded 3183 articles, with 48 studies meeting inclusion criteria after title/abstract screening and full-text review. Interventions were categorised as audit and feedback (n=31), peer-to-peer feedback (n=3), postevent debriefing (n=2), incident-prompted feedback (n=1), patient outcome feedback (n=1) or a combination thereof (n=4). Feedback was found to have a moderate positive effect on quality of care and professional development with a pooled effect of d=0.50 (95% CI 0.34, 0.67). Feedback to EMS professionals had large effects in improving documentation (d=0.73 (0.00, 1.45)) and protocol adherence (d=0.68 (0.12, 1.24)), as well as small effects in enhancing cardiac arrest performance (d=0.46 (0.06, 0.86)), clinical decision-making (d=0.47 (0.23, 0.72)), ambulance times (d=0.43 (0.12, 0.74)) and survival rates (d=0.22 (0.11, 0.33)). The between-study heterogeneity variance was estimated at σ2=0.32 (95% CI 0.22, 0.50), with an I2 value of 99% (95% CI 98%, 99%), indicating substantial statistical heterogeneity. This review demonstrated that the evidence base currently does not support a clear single point estimate of the pooled effect of feedback to EMS staff as a single intervention type due to study heterogeneity. Further research is needed to provide guidance and frameworks supporting better design and evaluation of feedback interventions within EMS. CRD42020162600.


[Descriptive study of bone and joint infections in children in times of community-acquired methicillin- resistant Staphylococcus aureus (CA-MRSA)].
Bone and joint infections (BJI) are relatively common in children, and community -acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is the leading cause in some countries. To evaluate epidemiological data, clinical and microbiological features and outcome of BJI. A prospective descriptive study was conducted. 40 patients (p) completed the study. Bacterial cultures were positives in 30 p (75%): CA-MRSA was found in 19 p, methicillin-sensitive S. aureus in 6 p, and others in 5 p. Cultures were negatives in 10 p (25%). Median treatment duration was 28 days (r: 21-40 d); Analyzing patients with CA-MRSA positive cultures separately, initial CRP was higher (Md 76 vs 50 mg/L, p < 0.02), normalization occurred later (Md 14 days vs 7days, p < 0.03), and duration of treatment (Md 32 days vs 23, p < 0.004) as well as hospital stay (Md 9 days vs 7, p = 0.12) were longer. Sequelae were present in 3 p and 1 relapsed: All of them with CA-SAMR. CA-MRSA was the leading cause of BJI and was associated with higher CRP on admission, later normalization and longer treatment duration. Complications as drainage requirement, and sequelae were common in those p.


[All about the Pancreas].
All about the Pancreas Abstract. Ultrasound has made tremendous progress with the use of contrast media and elastography, particularly in patients with small, solid pancreatic lesions (SPL) <20mm and cystic tumors (CPL) of any size. In the case of solid and cystic pancreatic lesions, the differential diagnosis must first be evaluated after detection in order to define the indications for radical surgery, strategies for preserving the pancreatic parenchyma or simply for control examinations. Contrast-enhanced transcutaneous (TUS, CEUS) and endoscopic (EUS, CE-EUS) ultrasound and elastography facilitate further characterization of SPL and ZPL. Pancreatic ductal adenocarcinomas (PDAC) show hypoenhancement in contrast-enhanced ultrasound. The majority of the important differential diagnoses, on the other hand, are multi-enhancing. PDAC are almost always harder than healthy pancreatic parenchyma. In contrast, elastographically soft SPL are - with very few exceptions - benign. This review provides an overview of the use of modern ultrasound techniques to detect and characterize solid and cystic pancreatic lesions.


["Transplanted cell antigen" and its detection in different human organs].
A cell membrane antigen was found in the continuous cell lines of epithelial origin, identical to the antigen revealed in the homogenates of human gastric mucosa. The antigen was detected with the aid of an antiserum against the solubilized membrane antigen from Hep-2 cells sorbed with a mixture of homogenates of human tissues--the lung, the liver, papillomatosis of the larynx and of the mammary gland. The described antigen was revealed in some (not all) adenocarcinomas of the stomach; it differs from carcinoembryonic Gold's antigen and from the secretory IgA component, it is not a structural component of D-type oncornoviruses (of primates) produced by Hep-2 cells, and does not seem to be coded by the genom of this virus.


Management of Biliary Strictures: State-of-the-Art Review.
Biliary strictures can be broadly classified as benign or malignant. Benign biliary strictures are most commonly iatrogenic in nature and are a consequence of hepatobiliary surgery. Cholangiocarcinoma and adenocarcinoma of the pancreas are the most common causes of malignant biliary obstruction. This article reviews state-of-the-art minimally invasive techniques used to manage these strictures. In addition, the roles of (a) recently introduced biodegradable biliary stents in the management of benign biliary strictures and (b) intraprocedural imaging and navigation tools, such as cone-beam CT, in percutaneous reconstruction of the biliary-enteric anastomosis are discussed.


Ubp43 gene expression is required for normal Isg15 expression and fetal development.
Isg15 covalently modifies murine endometrial proteins in response to early pregnancy. Isg15 can also be severed from targeted proteins by a specific protease called Ubp43 (Usp18). Mice lacking Ubp43 (null) form increased conjugated Isg15 in response to interferon. The Isg15 system has not been examined in chorioallantoic placenta (CP) or mesometrial (MM) components of implantation sites beyond 9.5 days post coitum (dpc). It was hypothesized that deletion of Ubp43 would cause disregulation of Isg15 in implantation sites, and that this would affect pregnancy rates. Heterozygous (het) Ubp43 mice were mated and MM and CP implantation sites were collected on 12.5 and 17.5 days post-coitum (dpc). Free and conjugated Isg15 were greater on 12.5 versus 17.5 dpc in MM. Free and conjugated Isg15 were also present in CP, but did not differ due to genotype on 12.5 dpc. However, null CP had greater free and conjugated Isg15 when compared to het/wt on 17.5 dpc. Null progeny died in utero with fetal genotype ratios (wt:het:null) of 2:5:1 on 12.5 and 2:2:1 on 17.5 dpc. Implantation sites were disrupted within the junctional zone and spongiotrophoblast, contained less vasculature based on lectin B4 staining and contained greater Isg15 mRNA and VEGF protein in Ubp43 null when compared to wt placenta. It is concluded that Isg15 and its conjugates are present in implantation sites during mid to late gestation and that deletion of Ubp43 causes an increase in free and conjugated Isg15 at the feto-maternal interface. Also, under mixed genetic background, deletion of Ubp43 results in fetal death.


Experimental study of free periosteal autograft. II. Increasing osteogenesis of periosteum.
The difference in osteogenesis of the periosteal graft and the effects of changing the recipient environment were studied in 26 young and 16 adult rabbits. The periosteal grafts from bilateral tibiae were implanted to the right and left sides of the abdominal wall, on the right side a coagulum was added. For quantitative examination, radionuclide, CT, ion-selective electrode, atomic absorption spectrometry and biochemical autoassay methods were used. The results showed that osteogenesis of periosteal grafts may increase by changing the local environments. The amount of periosteal bone formed in the adult rabbits was obviously less than in the young. The bone formation of the periosteal grafts with a coagulum, especially in the adults was increased. The possible mechanism of increasing periosteal osteogenesis by the coagulum is discussed.


Effectiveness of herbal oral care products in reducing dental plaque & gingivitis - a systematic review and meta-analysis.
Despite the large number of trials conducted using herbal oral care products for the reduction of dental plaque or gingivitis, results are conflicting and inconclusive. To assess the effectiveness of herbal oral care products compared to conventional products in reducing dental plaque and gingivitis adults. We searched the following databases for Randomised controlled trials (RCTs): MEDLINE Ovid, EMBASE Ovid etc. which yielded 493 trails. Of which 24 RCTs comparing herbal toothpaste or mouth rinse with over the counter toothpaste or mouth rinse in adults aged 18 to 65 years were included. Two authors extracted information and assessed the methodological quality of the included studies using Risk of Bias. Meta-analyses using the random-effects model were conducted for four outcomes for tooth paste and mouth rinse respectively. Mean difference (MD) or standardized mean difference (SMD) were used to estimate the effect, with 95% confidence intervals. A total of 1597 adults participated in 24 RCT studies. These were classified as herbal toothpaste (HTP) (15 trials, 899 participants) and herbal mouth rinse (HMR) (9 trials, 698 participants) compared with non-herbal toothpaste (NHTP) or non-herbal mouth rinse (NHMR). We found that HTP was superior over NHTP (SMD 1.95, 95% CI (0.97-2.93)) in plaque reduction. The long-term use of NHMR was superior in reduction of dental plaque over HMR (SMD -2.61, 95% (CI 4.42-0.80)). From subgroup analysis it showed that HTP was not superior over fluoride toothpaste (SMD 0.99, 95% CI (0.14-2.13)) in reducing dental plaque. However, HTP was favoured over non-fluoride toothpaste (SMD 4.64, 95% CI (2.23-7.05)). For short-term reduction in dental plaque, current evidence suggests that HTP is as effective as compared to NHTP; however, evidence is from low quality studies.


Maternal and Neonatal Morbidity After 4 and 6 Hours of Protracted Active Labor in Nulliparous Term Pregnancies.
To evaluate whether women with protracted active phase labor longer than 6 hours have an increased risk of adverse maternal and neonatal outcomes after the implementation of new labor management guidelines. This was a retrospective study of nulliparous, term, singleton, vertex deliveries at Cedars Sinai Medical Center from August 2016 to September 2017. Women were included if they progressed to active phase labor, defined by cervical dilation of 6 cm or more. Women then were divided into three groups based on the time course of cervical change between 6 and 10 cm: 1) normal active phase: cervical change 1 cm or more within 4 hours throughout active labor; 2) mildly protracted active phase: cervical change 1 cm or less over 4-6 hours; and 3) very protracted active phase: cervical change 1 cm or less over 6 hours. Rate of change was assessed between cervical examinations. Primary outcome was a composite of maternal morbidity by study group. Secondary outcome was a composite of neonatal morbidity. We hypothesized that women with very protracted active phase had higher rates of adverse outcomes when compared with normal active phase. Regression analyses were performed to compare maternal and neonatal outcomes by study group. There were 2,559 deliveries, of which 2,378 (90.8%) were vaginal deliveries. Composite maternal and neonatal morbidity was higher with longer labor. Maternal morbidity-very protracted active phase (42.0%) compared with normal active phase (22.6%) adjusted odds ratio (aOR) 2.15 (95% CI 1.62-2.86); mildly protracted active phase (39.5%) compared with normal active phase (22.6%) aOR 2.18 (95% CI 1.67-2.84). Neonatal morbidity: very protracted active phase (19.8%) compared with normal active phase (13.8%) aOR 1.38 (95% CI 0.98-1.96); mildly protracted active phase (19.4%) compared with normal active phase (13.8%) aOR 1.44; (95% CI 1.04-1.99). Composite maternal and neonatal morbidity was not different between mildly protracted and very protracted groups. Composite maternal morbidity was greater in women with cervical change consistent with mildly protracted (4-6 hours) and very protracted (more than 6 hours) labor compared with cervical change in the normal active phase (less than 4 hours) group. However, composite maternal and neonatal morbidity was not different between mildly protracted and very protracted groups.


Dispensing Pollen via Catapult: Explosive Pollen Release in Mountain Laurel (Kalmia latifolia).
The astonishing amount of floral diversity has inspired countless assumptions about the function of diverse forms and their adaptive significance, yet many of these hypothesized functions are untested. We investigated an often-repeated adaptive hypothesis about how an extreme floral form functions. In this study, we conducted four investigations to understand the adaptive function of explosive pollination in Kalmia latifolia, the mountain laurel. We first performed a kinematic analysis of anther movement. Second, we constructed a heat map of pollen trajectories in three-dimensional space. Third, we conducted field observations of pollinators and their behaviors while visiting K. latifolia. Finally, we conducted a pollination experiment to investigate the importance of pollinators for fertilization success. Our results suggest that insect visitation dramatically improves fertilization success and that bees are the primary pollinators that trigger explosive pollen release.


A retrospective analysis of endocrinopathy manifestations in 136 Chinese patients with POEMS syndrome.
POEMS syndrome is a rare multisystemic disease, with a wide spectrum of clinical endocrinopathies. Patients with POEMS syndrome may present with one or more hormone disorders during the disease course, but such phenomenon has usually been underestimated. In this report, we analyzed the prevalence and clinical characteristics of endocrine abnormalities in a large Chinese cohort with POEMS syndrome. This retrospective review was performed in patients with a definite diagnosis of POEMS syndrome who were hospitalized in our hospital between January 2000 and January 2020. The clinical data about endocrine abnormalities were extracted from their medical records and analyzed. This study comprised 136 patients (95 male, 41 female) with a median age of 48(40-56) years old. Endocrine abnormalities were frequent (127 cases, 93.38%) in patients with POEMS syndrome. The prevalence of single endocrinopathy and multiple endocrinopathies were 12.60% (16/127 cases) and 87.40% (111/127), respectively. The most frequent endocrinopathy was hypogonadism (98/136, 72.06%), followed by hypothyroidism (83/136, 61.03%), hypocalcemia (50/136, 36.76%), hyperprolactinemia (47/136, 34.56%), abnormal glucose metabolism (41/136, 30.15%) and adrenal insufficiency (41/136, 30.15%). In patients with multiple endocrinopathies, the prevalence of 2, 3, 4, 5, and 6 kinds of endocrine axes involved were 29.92% (38/127), 30.71% (39/127), 17.32% (22/127), 7.09% (9/127) and 2.36% (3/127), respectively. Such hormone disorders cause complex clinical presentations, including overt or subclinical situations. Endocrinopathy manifestations in POEMS syndrome are more frequent, and its clinical complicacy should be emphasized in differential diagnosis. For patients with a definite diagnosis of POEMS syndrome, an early and thorough endocrine evaluation should be performed.


Laparoscopic hepatectomy in a patient with uncontrolled polycythaemia vera.
This case report describes the peri-operative course of a patient with uncontrolled polycythaemia vera who underwent a laparoscopic hepatectomy for intrahepatic cholangiocarcinoma. Polycythaemia vera is a chronic condition that results in erythrocytosis and puts patients at risk of peri-operative complications including thrombotic events and paradoxical haemorrhage. Little evidence exists on the ideal peri-operative management of uncontrolled polycythaemia vera when the proposed procedure carries a high risk of haemorrhage. Our patient presented with a pre-operative haemoglobin of 197 g.l-1 (haematocrit 65%) and was not phlebotomised pre-operatively. Intra-operatively he lost 2700 ml of blood, reducing his haematocrit to 48%, and then suffered fatal thrombotic complications postoperatively. The patient did not receive any blood product transfusions during his peri-operative course. We review the available evidence to guide the peri-operative management of patients with polycythaemia vera. The inherent risks of thrombosis and haemorrhage associated with polycythaemia vera need to be weighed against the specific surgical and transfusion-related risks. Phlebotomy to achieve a pre-operative haematocrit under 45% is recommended and intra-operative phlebotomy shows promise for reducing blood loss during hepatectomies. Management of postoperative erythrocytosis may be an important and underappreciated aspect of reducing the peri-operative risk of thrombosis in patients with polycythaemia vera.


The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies.
The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour-associated macrophages (TAMs) can be directly tumouricidal and stimulate the anti-tumour activity of T cells, there is now contrasting evidence that tumour cells are able to block or evade the activity of TAMs at the tumour site. In some cases, tumour-derived molecules even redirect TAM activities to promote tumour survival and growth. Indeed, evidence has emerged for a symbiotic relationship between tumour cells and TAMs, in which tumour cells attract TAMs and sustain their survival, with TAMs then responding to micro-environmental factors in tumours such as hypoxia (low oxygen tension) by producing important mitogens as well as various growth factors and enzymes that stimulate tumour angiogenesis. This review presents evidence for the number and/or distribution of TAMs being linked to prognosis in different types of human malignancy. It also outlines the range of pro- and anti-tumour functions performed by TAMs, and the novel therapies recently devised using TAMs to stimulate host immune responses or deliver therapeutic gene constructs to solid tumours.


Reverse Sural Adipofascial Flaps with Acellular Dermal Matrix and Negative-Pressure Wound Therapy.
The reverse sural adipofascial flap (RSAF) is used to reconstruct challenging wounds of the foot and ankle. It offers several advantages over the traditional reverse sural flap, including less venous congestion. To complete the reconstruction, split-thickness skin grafting (STSG) may be done immediately or in a delayed fashion; however, both scenarios result in suboptimal take rates and prolonged healing. An acellular dermal matrix (ADM; Integra; Ethicon Inc, Somerville, New Jersey) and negative-pressure wound therapy (NPWT) combined with RSAF followed by delayed STSG may decrease wound healing time.In this study, 8 patients underwent reconstruction of lower-extremity wounds with RSAF. Four patients underwent RSAF with immediate STSG, and 4 underwent RSAF with placement of the ADM and a vacuum-assisted closure device, with STSG at a later date.The 4 patients who underwent RSAF and immediate STSG had an average time to heal of 141.2 days, and 2 patients required reoperation. The 4 patients who underwent RSAF with an ADM and NPWT had an average time to heal of 104.5 days, and 1 patient required reoperation. Average time until STSG was 41.5 days. The latter group demonstrated a reduction in time to heal by an average of 36.7 days, or 25%. All 8 patients achieved successful wound closure.The RSAF is a durable option for complex lower-extremity reconstruction. Interim placement of ADM and NPWT may increase STSG take rates. Using this technique in conjunction with RSAF may decrease the overall healing time compared with RSAF with immediate STSG.


Strengthening the policy setting process for global malaria control and elimination.
The scale-up of malaria control efforts in recent years, coupled with major investments in malaria research, has produced impressive public health impact in a number of countries and has led to the development of new tools and strategies aimed at further consolidating malaria control goals. As a result, there is a growing need for the malaria policy setting process to rapidly review increasing amounts of evidence. The World Health Organization Global Malaria Programme, in keeping with its mandate to set evidence-informed policies for malaria control, has convened the Malaria Policy Advisory Committee as a mechanism to increase the timeliness, transparency, independence and relevance of its recommendations to World Health Organization member states in relation to malaria control and elimination. The Malaria Policy Advisory Committee, composed of 15 world-renowned malaria experts, will meet in full twice a year, with the inaugural meeting scheduled for 31 January to 2 February 2012 in Geneva. Policy recommendations, and the evidence to support them, will be published within two months of every meeting as part of an open access Malaria Journal thematic series. This article is a prelude to that series and provides the global malaria community with the background and overview of the Committee and its terms of reference.


Laser applications to chemical and environmental analysis: introduction to the feature issue.
This issue of Applied Optics features 14 papers that describe recent advances of laser techniques, including instrumentation, application in combustion research, and detection of pollutants. Most of these contributions were presented at the Eighth Optical Society of America Topical Meeting on Laser Applications to Chemical and Environmental Analysis (8th LACEA), held in Boulder, Colorado, 7-10 February, 2002.


Do we fatten our children at the television set? Obesity and television viewing in children and adolescents.
The association of television viewing and obesity in data collected during cycles II and III of the National Health Examination Survey was examined. Cycle II examined 6,965 children aged 6 to 11 years and cycle III examined 6,671 children aged 12 to 17 years. Included in the cycle III sample were 2,153 subjects previously studied during cycle II. These surveys, therefore, provided two cross-sectional samples and one prospective sample. In all three samples, significant associations of the time spent watching television and the prevalence of obesity were observed. In 12- to 17-year-old adolescents, the prevalence of obesity increased by 2% for each additional hour of television viewed. The associations persisted when controlled for prior obesity, region, season, population density, race, socioeconomic class, and a variety of other family variables. The consistency, temporal sequence, strength, and specificity of the associations suggest that television viewing may cause obesity in at least some children and adolescents. The potential effects of obesity on activity and the consumption of calorically dense foods are consistent with this hypothesis.


The missing N1 or jittered P2: Electrophysiological correlates of pattern glare in the time and frequency domain.
Excessive sensitivity to certain visual stimuli (cortical hyperexcitability) is associated with a number of neurological disorders including migraine, epilepsy, multiple sclerosis, autism and possibly dyslexia. Others show disruptive sensitivity to visual stimuli with no other obvious pathology or symptom profile (visual stress) which can extend to discomfort and nausea. We used event-related potentials (ERPs) to explore the neural correlates of visual stress and headache proneness. We analysed ERPs in response to thick (0.37 cycles per degree [c/deg]), medium (3 c/deg) and thin (12 c/deg) gratings, using mass univariate analysis, considering three factors in the general population: headache proneness, visual stress and discomfort. We found relationships between ERP features and the headache and discomfort factors. Stimulus main effects were driven by the medium stimulus regardless of participant characteristics. Participants with high discomfort ratings had larger P1 components for the initial presentation of medium stimuli, suggesting initial cortical hyperexcitability that is later suppressed. The participants with high headache ratings showed atypical N1-P2 components for medium stripes relative to the other stimuli. This effect was present only after repeated stimulus presentation. These effects were also explored in the frequency domain, suggesting variations in intertrial theta band phase coherence. Our results suggest that discomfort and headache in response to striped stimuli are related to different neural processes; however, more exploration is needed to determine whether the results translate to a clinical migraine population.


Graph theoretical model of a sensorimotor connectome in zebrafish.
Mapping the detailed connectivity patterns (connectomes) of neural circuits is a central goal of neuroscience. The best quantitative approach to analyzing connectome data is still unclear but graph theory has been used with success. We present a graph theoretical model of the posterior lateral line sensorimotor pathway in zebrafish. The model includes 2,616 neurons and 167,114 synaptic connections. Model neurons represent known cell types in zebrafish larvae, and connections were set stochastically following rules based on biological literature. Thus, our model is a uniquely detailed computational representation of a vertebrate connectome. The connectome has low overall connection density, with 2.45% of all possible connections, a value within the physiological range. We used graph theoretical tools to compare the zebrafish connectome graph to small-world, random and structured random graphs of the same size. For each type of graph, 100 randomly generated instantiations were considered. Degree distribution (the number of connections per neuron) varied more in the zebrafish graph than in same size graphs with less biological detail. There was high local clustering and a short average path length between nodes, implying a small-world structure similar to other neural connectomes and complex networks. The graph was found not to be scale-free, in agreement with some other neural connectomes. An experimental lesion was performed that targeted three model brain neurons, including the Mauthner neuron, known to control fast escape turns. The lesion decreased the number of short paths between sensory and motor neurons analogous to the behavioral effects of the same lesion in zebrafish. This model is expandable and can be used to organize and interpret a growing database of information on the zebrafish connectome.


The proximal promoter region of the zebrafish gsdf gene is sufficient to mimic the spatio-temporal expression pattern of the endogenous gene in Sertoli and granulosa cells.
The gonadal soma-derived factor (GSDF) is a new member of the transforming growth factor beta (TGF-beta) superfamily that regulates the proliferation of the primordial germ cells (PGC) in developing embryos and spermatogonia in juvenile male trout. The gsdf transcripts are expressed in the somatic cells supporting germ cell development. In zebrafish, we show that GSDF is encoded by a single copy gene that generates polymorphic transcripts and proteins. We determined that gsdf gene expression occurs before gonadal differentiation and is restricted to the gonads. Gene expression is maintained in adult granulosa cells and Sertoli cells but decreases in the cells that are in contact with meiotic and postmeiotic germ cells. Using zebrafish transgenic lines, we demonstrate that the 2-kb proximal promoter region of the gsdf gene targets high levels of transgene expression in the Sertoli and granulosa cells, and is sufficient to mimic the temporal expression pattern of the endogenous gsdf gene from 16 days postfertilization onward. We identified within the first 500 bp evolutionarily conserved DNA motifs that may be involved in Sertoli and granulosa cell-specific expression. However, the 2-kb proximal promoter region failed to drive efficient expression of the transgene in the gonads in four transgenic medaka lines. We propose that the proximal promoter region can be used to target candidate gene deregulation in zebrafish granulosa and Sertoli cells. Furthermore, the green fluorescent protein-expressing zebrafish lines produced in the present study are new valuable models for cell lineage tracing during sex differentiation and gametogenesis.


Alternative, out-of-frame runt/MTG8 transcripts are encoded by the derivative (8) chromosome in the t(8;21) of acute myeloid leukemia M2.
In the t(8;21) of acute myeloid leukemia (AML) M2, breakpoints are clustered on both chromosomes. The chromosome 21 breakpoint cluster region (bcr) falls within the runt locus, in the intron immediately downstream of the exons encoding an evolutionary conserved domain (the runt box). Transcripts in which the runt box is fused in frame to a novel sequence derived from chromosome 8 (MTG8) have been previously identified and have been assumed to constitute a critical leukemogenic event. Here we show physical linkage of the chromosome 8 bcr to the MTG8 locus. Unexpectedly, not only does the bcr map upstream of the most 5' MTG8 exon found in runt/MTG8 fusion transcripts, but it also maps upstream of a further 5' exon. In addition, we demonstrate the presence of alternative transcripts, originating from the der(8) chromosome, in which runt is out of frame with MTG8. Thus, runt truncation per se, rather than its fusion to MTG8, may be the crucial leukemogenic event.


Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial.
Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score <C3) to receive either individualised duration of elastic compression therapy or standard duration of therapy for 24 months following an initial treatment period of 6 months. Randomisation was done with a web-based automatic randomisation programme (TENALEA) and a random block size (2-12), and was stratified by centre, age, and body-mass index. In the initial phase, compression was applied within 24 h of diagnosis according to three prespecified protocols. All patients received elastic compression stockings (30-40 mm Hg) for 6 months, and were instructed to wear them every day during ambulant hours. Thereafter treatment was tailored on the basis of clinical signs and symptoms scored according to the Villalta post-thrombotic syndrome scale; patients assigned to individualised therapy with two consecutive Villalta scores of 4 or less were instructed to stop using the stockings. Patients were followed up for 2 years and assessed at five clinic visits at study inclusion, and 3, 6, 12, and 24 months after diagnosis (stocking allocation was not revealed to the assessors). The primary outcome was the proportion of patients with post-thrombotic syndrome at 24 months diagnosed according to original Villalta criteria (a score of ≥5 on two consecutive occasions at least 3 months apart) assessed by intention to treat. The predefined non-inferiority margin for the difference in success rates was set at 7·5%. This study has been completed and is registered with ClinicalTrials.gov, number NCT01429714. Between March 22, 2011, and July 1, 2015, we enrolled 865 patients and randomly assigned 437 to individualised duration compression stockings and 428 to standard duration. 283 (66%) of 432 patients in the intervention group were advised before 24 months to stop wearing elastic compression stockings (236 [55%] of 432 patients after 6 months, and 47 [11%] of 432 at 12 months). Post-thrombotic syndrome occurred in 125 (29%) of 432 patients receiving individualised duration of therapy and in 118 (28%) of 424 receiving standard duration of therapy (odds ratio for difference 1·06, 95% CI 0·78 to 1·44). The absolute difference was 1·1% (95% CI -5·2 to 7·3), thus meeting the non-inferiority margin. 24 patients died, 17 (4%) in the individualised treatment group and seven (2%) in the standard duration group, but no deaths were related to treatment. No serious adverse events related to the intervention occurred. Individualised therapy with elastic compression stockings for the prevention of post-thrombotic syndrome was non-inferior to standard duration of therapy of 24 months. Individualising the duration is effective and could shorten the length of therapy needed, potentially enhancing patients' wellbeing. ZonMw (Netherlands).


New insights into the photocycle of Ectothiorhodospira halophila photoactive yellow protein: photorecovery of the long-lived photobleached intermediate in the Met100Ala mutant.
There are previously two known intermediates (I1 and I2) in the room-temperature photocycle of the photoactive yellow protein (PYP) from Ectothiorhodospira halophila. The three-dimensional structures of ground-state PYP and of I2 have shown that light-induced conformational changes are localized to the active site. Previous site-specific mutagenesis studies of PYP in our laboratories have characterized two active site mutants (Glu46Gln and Arg52Ala). We now report the construction and characterization of a mutant at a third active site position (Met100Ala) in order to establish the role of this residue in the photocycle. Met100Ala PYP has an absorption spectrum which is very similar to wild-type (WT) PYP, but exhibits very different kinetic properties. At pH 7.0, the light-induced bleaching reaction (I2 formation) has a half-life <1 microseconds and the recovery in the dark has a half-life of 5.5 min, as compared with half-lives of 100 microseconds and 140 ms for the same reactions in WT PYP. The slow rate of recovery from I2 for Met100Ala results in the accumulation of the bleached intermediate even under room light illumination. These results are qualitatively similar to what has been observed with the Arg52Ala mutant of PYP, and with WT PYP in the presence of alcohols or urea, and suggest that Met100 acts to stabilize the ground state of the protein. The midpoint for guanidine denaturation confirms this. The slow recovery of I2 in the Met100Ala mutant has allowed us to obtain direct evidence that this intermediate species is also photoactive and can be returned to the ground state by a 365 nm laser flash, with kinetics (half-life = 160 microseconds; k = 6300 s-1) which are 6 orders of magnitude faster than dark recovery. This implies that chromophore reisomerization limits the rate of conversion of I2 to the ground state in PYP. Met100 is in van der Waals contact with the chromophore in the I2 state, and we suggest that the sulfur atom catalyzes cis-trans isomerization in WT PYP.


Clinical and prognostic implications of atrial fibrillation in patients undergoing transcatheter aortic valve implantation.
To study a cohort of consecutive patients undergoing transcatheter aortic valve implantation (TAVI) and compare the outcomes of atrial fibrillation (AF) patients vs patients in sinus rhythm (SR). All consecutive patients undergoing TAVI in our hospital were included. The AF group comprised patients in AF at the time of TAVI or with history of AF, and were compared with the SR group. Procedural, echocardiographic and follow-up variables were compared. Likewise, the CHA(2)DS(2)-VASC stroke risk score and HAS-BLED bleeding risk score and antithrombotic treatment at discharge in AF patients were compared with that in SR patients. From a total of 34 patients undergoing TAVI, 17 (50%) were allocated to the AF group, of whom 15 (88%) were under chronic oral anticoagulation. Patients in the AF group were similar to those in the SR group except for a trend (P = 0.07) for a higher logistic EuroSCORE (28% vs 19%), and a higher prevalence of hypertension (82% vs 53%) and chronic renal failure (17% vs 0%). Risk of both stroke and bleeding was high in the AF group (mean CHA(2)DS(2)-VASC 4.3, mean HAS-BLED 2.9). In the AF group, treatment at discharge included chronic oral anticoagulation in all except one case, and in association with an antiplatelet drug in 57% of patients. During a mean follow-up of 11 mo (maximum 32), there were only two strokes, none of them during the peri-procedural period: one in the AF group at 30 mo and one in the SR group at 3 mo. There were no statistical differences in procedural success, and clinical outcome (survival at 1 year 81% vs 74% in AF and SR groups, respectively, P = NS). Patients in AF undergoing TAVI show a trend to a higher surgical risk. However, in our cohort, patients in AF did not have a higher stroke rate compared to the SR group, and the prognosis was similar in both groups.


Visualization of [3H]docosahexaenoic acid trafficking through photoreceptors and retinal pigment epithelium by electron microscopic autoradiography.
[3H]docosahexaenoic (DHA) acid was followed through the retinal pigment epithelial cells and photoreceptors for up to 5 days after injection to specifically determine which membrane systems of the retinal pigment epithelial cells are used in the handling of [3H]DHA after shedding and phagocytosis of rod tips. Frogs (Rana pipiens) were injected with [3H]DHA in the dorsal lymph sacs, and maintained for up to 5 days. Retinas were processed for electron microscopic autoradiography, stored for various periods of time, and then analyzed by transmission electron microscopy. After 1 day, [3H]DHA had accumulated within photoreceptor ellipsoids, and had begun to appear as dense label in newly formed discs. By day 5, the basal region of dense label had expanded apically. Newly shed rod outer segment tips were diffusely labeled; but occasionally after several hours, they acquired additional label as they moved near Bruch's membrane. Retinal pigment epithelial cytoplasm maintained a constant level of label, with myeloid bodies sometimes slightly labeled. Oil droplets of the retinal pigment epithelium accumulated dense label throughout this study. When [3H]DHA enters the retinal pigment epithelium, some is retained within oil droplets, whereas the rest is passed on to the photoreceptors. [3H]DHA is initially taken up by inner segments and then dispersed to photoreceptor synaptic terminals as well as to ellipsoids where discs are assembled. Phagosomal labeling exactly matches rod outer segment tips, but occasionally increases as degradation occurs near Bruch's membrane. Normally, density of label remains constant throughout the degradation process.


Jejunal atresia in an infant with triple-X syndrome.
A 33-year-old woman presented at 31 weeks' gestation with polyhydramnios that required repeated amniodrainage. An antenatal scan at 32 weeks showed dilated fetal bowel loops, which were not confirmed on subsequent scans. The amniotic fluid karyotype confirmed 47,XXX. After birth, jejunal obstruction was confirmed. To our knowledge, this is the first report of an association of triple-X syndrome and jejunal atresia.


A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.
Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH(2)) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001), all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer's disease.


Association of diabetes and cancer mortality in American Indians: the Strong Heart Study.
The metabolic abnormalities that accompany diabetes mellitus are associated with an increased risk of many cancers. These associations, however, have not been well studied in American Indian populations, which experience a high prevalence of diabetes. The Strong Heart Study is a population-based, prospective cohort study with extensive characterization of diabetes status. Among a total cohort of 4,419 participants who were followed for up to 20 years, 430 cancer deaths were identified. After adjusting for sex, age, education, smoking status, drinking status, and body mass index, participants with diabetes at baseline showed an increased risk of gastric (HR 4.09; 95% CI 1.42-11.79), hepatocellular (HR 2.94; 95% CI 1.17-7.40), and prostate cancer mortality (HR 3.10; 95% CI 1.22-7.94). Further adjustment for arsenic exposure showed a significantly increased risk of all-cause cancer mortality with diabetes (HR 1.27; 95% CI 1.03-1.58). Insulin resistance among participants without diabetes at baseline was associated with hepatocellular cancer mortality (HR 4.70; 95% CI 1.55-14.26). Diabetes mellitus, and/or insulin resistance among those without diabetes, is a risk factor for gastric, hepatocellular, and prostate cancer in these American Indian communities, although relatively small sample size suggests cautious interpretation. Additional research is needed to evaluate the role of diabetes and obesity on cancer incidence in American Indian communities as well as the importance of diabetes prevention and control in reducing the burden of cancer incidence and mortality in the study population.


Genetic variability for temperament indicators of Nellore cattle.
The aim of this study was to estimate genetic parameters of 4 temperament indicator traits for Nellore cattle and evaluate the possibility of using such traits as selection criteria in breeding programs. Temperament was assessed for 23,420 male and female animals at 550 d of age, which were born between 2002 and 2009. A temperament score (TS) was used, which is based on a scale from 1 to 5 and considers the reaction of animals after exiting the crush. Moreover, 9,150 individuals born in 2008 and 2009 were measured for these characteristics: movement score (MOV), where animals were scored from 1 to 5 according to their movement inside the crush; crush score (CS), which assigns scores from 1 to 4 for the general reactivity inside the crush; and flight speed (FS), which is a recording of the speed (m/s) at which animals exit the crush after being weighed. The weaning weight (WW) was included in the multitrait analysis to reduce the effect of the selection performed at weaning. Bayesian inference using Gibbs sampling was applied to estimate (co)variance components and breeding values of the animals. The model included random direct additive genetic and residual effects, fixed effects of contemporary groups, age of the dam (classes), and age of the animal as covariate (linear and quadratic effects for WW and TS, and only linear effects for the other traits). A linear model was applied to WW and FS, whereas a threshold model was used for TS, CS, and MOV. Heritability estimates for FS, TS, CS, and MOV were 0.35, 0.15, 0.19, and 0.18, respectively. The genetic correlation estimates of FS with TS (0.85), CS (0.85), and MOV (0.76) were high, although the phenotypic correlations were low (between 0.18 and 0.25). For CS and MOV, the genetic and phenotypic correlation estimates were high (0.99 and 0.71, respectively). We concluded that all of the temperament indicator traits addressed in this study presented enough genetic variability to respond to selection; however, the use of FS would result in a faster genetic gain. With regard to the practical applicability in breeding programs, the use of FS is also favorable because it produces data on a continuous scale, allows for recording of the data electronically, and requires low investment.


Range-adapting representation of economic value in the orbitofrontal cortex.
While making economic choices, individuals assign subjective values to the available options. Values computed in different behavioral conditions, however, can vary substantially. The same person might choose some times between goods worth a few dollars, and other times between goods worth thousands of dollars, or more. How does the brain system that computes values -- the "valuation system" -- handle this large variability? Here we show that the representation of value in the orbitofrontal cortex (OFC), an area implicated in value assignment during economic choice, adapts to the behavioral condition of choice and, more specifically, to the range of values available in any given condition. In the experiments, monkeys chose between different juices and their choice patterns provided a measure of subjective value. Value ranges were varied from session to session and, in each session, OFC neurons encoded values in a linear way. Across the population, the neuronal sensitivity (defined as the change in neuronal activity elicited by the increase in one value unit) was inversely proportional to the value range. Conversely, the neuronal activity range did not depend on the value range. This phenomenon of range adaptation complements that of menu invariance observed in a previous study. Indeed, the activity of each neuron adapts to the range values it encodes but does not depend on other available goods. Our results thus suggest that the representation of value in the OFC is at one time instantiative of preference transitivity (menu invariance) and computationally efficient (range adaptation).


Centaurin-like protein Cnt5 contributes to arsenic and cadmium resistance in fission yeast.
Arsenic (As) and cadmium (Cd) are two of the most hazardous substances in the environment and have been implicated in a number of human diseases including cancer. Their mechanisms of toxicity and subsequent carcinogenesis are not understood. To identify the genes involved in As/Cd detoxification, we screened a random insertional mutagenesis library of Schizosaccharomyces pombe for mutants that are hypersensitive to As/Cd. Mutations were mapped to spc1(+) (sty1(+)) and SPBC17G9.08c. Spc1 is a stress-activated protein kinase orthologous to human p38. A fragment of SPBC17G9.08c was previously identified as csx2, a high-copy suppressor of cut6 that encodes an acetyl-CoA carboxylase involved in fatty acid biosynthesis. SPBC17G9.08c is a member of the centaurin ADP ribosylation factor GTPase activating protein family found in a variety of fungi, plants and metazoans, but not in Saccharomyces cerevisiae. Cnt5, so named because its closest human homolog is centaurin beta-5, binds to phosphatidic acid and phosphatidyl serine in vitro. Microscopic localization of Cnt5-GFP indicates significant redistribution of Cnt5 from the cytoplasm to the cell membranes in response to As stress. These data suggest a model in which Cnt5 contributes to As/Cd resistance by maintaining membrane integrity or by modulating membrane trafficking.


Risk factors for pelvic floor repair after hysterectomy.
Having demonstrated that prior history of prolapse was a risk factor for pelvic floor repair procedures after hysterectomy, the objective of this study was to assess medical risk factors for pelvic floor repair after hysterectomy. Using the Rochester Epidemiology Project database of 8,220 Olmsted County, Minnesota, women who had hysterectomy for benign indications from 1965-2002, we conducted a nested case-control study in 144 pairs, comparing women who underwent pelvic floor repair after hysterectomy (case group) with women matched for known risk factors (ie, age, pelvic floor disorders at baseline, year and type of hysterectomy, and pelvic floor repair during hysterectomy) (control group). The median duration between hysterectomy and pelvic floor repair was 13 years. Chronic pulmonary disease (odds ratio [OR] 14.3, 95% confidence interval [CI] 1.2-178), but not obstetric history, obesity, indication for hysterectomy, or chronic constipation, was associated with an increased risk of pelvic floor repair after hysterectomy. Between the hysterectomy and subsequent pelvic floor repair, overall pelvic organ prolapse severity changed by one grade or less in 54 case patients (38%, group A) but increased by two or more grades in 72 case patients (50%, group B). In group A, but not group B, uterine prolapse (OR 25, 95% CI 2.1-300) and chronic pulmonary disease (OR 22, 95% CI 1.5-328) at baseline remained risk factors for pelvic floor repair after hysterectomy. In this matched case-control study, chronic pulmonary disease was the only risk factor for pelvic floor repair after hysterectomy for benign indications, underscoring the need to address pulmonary status before surgery.


Factors predicting the transition from acute to persistent pain in people with 'sciatica': the FORECAST longitudinal prognostic factor cohort study protocol.
Sciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with 'sciatica') will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica. We will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence. The FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts. ISRCTN18170726; Pre-results.


Usual Cruciferous Vegetable Consumption and Ovarian Cancer: A Case-Control Study.
Ovarian cancer is the fifth leading cause of cancer-related deaths among women, primarily due to diagnosis at late stages. Therefore, identification of modifiable risk factors for this disease is warranted. Using the Patient Epidemiology Data System (PEDS), collected from 1981 to 1998 at Roswell Park Cancer Institute, Buffalo, NY, we conducted a hospital-based, case-control analysis of self-reported cruciferous vegetable intake and ovarian cancer among 675 women with primary, incident ovarian cancer, and 1275 without cancer. Cruciferous vegetable intake was queried using a 44-item food frequency questionnaire (FFQ). Odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression, adjusting for age, body mass index (BMI), education, smoking status, parity, family history of ovarian cancer, total fruit consumption, total meat consumption, and total noncruciferous vegetable consumption. We observed a significant inverse association for women with highest vs. lowest intakes of total vegetables (OR = 0.65, 95% CI = 0.46-0.92), cooked cauliflower (OR = 0.82, 95% CI = 0.67-0.99), and cooked greens (OR = 0.63, 95% CI = 0.46-0.86) and an inverse, dose-dependent association between cooked cruciferous vegetables intake and ovarian cancer (for each additional ten servings per month, OR = 0.85, 95% CI = 0.76-0.96). These findings suggest that a diet that includes cruciferous vegetables could be an important modifiable risk factor for ovarian cancer.


Isolation and renaturation of alpha 2-macroglobulin receptor from diploid human fibroblasts.
alpha 2-Macroglobulin receptor was extracted from human diploid fibroblasts and purified by affinity chromatography in a single step. The receptor had mol.wt. 125 000 after sodium dodecyl sulphate (SDS)/polyacrylamide-gel electrophoresis. The isolated receptor was separated by SDS/polyacrylamide-gel electrophoresis, transferred on to nitrocellulose sheets and subsequently renatured, as shown by a specific binding test, by incubation with Nonidet P40.


School-level correlates of physical activity intensity in 10-year-old children.
Little is known about school environmental factors that promote or inhibit activity, especially from studies using objective measures in large representative samples. We therefore aimed to study associations between activity intensities and physical and social school environmental factors. A population-based sample of 1 908 British children (SPEEDY study), mean age 10.3 years (Standard deviation [SD]: 0.3), recruited from 92 schools across Norfolk, UK, with valid activity data (assessed with Actigraph accelerometers). Outcome measures were school-based (8 am-4 pm on weekdays) time (in minutes) spent in sedentary (<100 counts/min), moderate (2 000-3 999 counts/min) and vigorous (≥4 000 counts/min) activity. A total of 40 school physical and social environmental factors were assessed. Multivariable multilevel linear regression analyses adjusted for children's sex and body mass index were conducted; interactions with sex were investigated. Availability of a 'Park and Stride' scheme was negatively associated with sedentary minutes (-7.74; 95% CI: -14.8; -0.70). Minutes of moderate activity were associated with the availability of a lollypop person (1.33, 95% CI: 0.35; 2.62) and objectively-assessed walking provision (1.70, 95% CI: 0.85; 2.56). The number of sports facilities of at least medium quality (0.47, 95% CI: 0.16; 0.79), not having a policy on physical activity (-2.28, 95% CI: -3.62; -0.95), and, in boys only, provision of pedestrian training (1.89; 95% CI: 0.77; 3.01) were associated with minutes of vigorous activity. Only a small number of school-level factors were associated with children's objectively-measured physical activity intensity, giving few pointers for potential future intervention efforts. Further research should focus on using objective measures to elucidate what factors may explain the school-level variance in activity levels.


Single particle reconstruction and validation using Bsoft for the map challenge.
The Bsoft package is aimed at processing electron micrographs for the determination of the three-dimensional structures of biological specimens. Recent advances in hardware allow us to solve structures to near atomic resolution using single particle analysis (SPA). The Map Challenge offered me an opportunity to test the ability of Bsoft to produce reconstructions from cryo-electron micrographs at the best resolution. I also wanted to understand what needed to be done to work towards full automation with validation. Here, I present two cases for the Map Challenge using Bsoft: ß-galactosidase and GroEL. I processed two independent subsets in each case with resolution-limited alignment. In both cases the reconstructions approached the expected resolution within a few iterations of alignment. I further validated the results by coherency-testing: i.e., that the reconstructions from real particles give better resolutions than reconstructions from the same number of aligned noise images. The key operations requiring attention for full automation are: particle picking, faster accurate alignment, proper mask generation, appropriate map sharpening, and understanding the amount of data needed to reach a desired resolution.


[Redusome hypothesis of aging: cardioepidemiology].
Diurnal analysis of database (n=5223) on myocardial infarction in Syktyvkar for 1998-2006 has revealed the following regularities. All phase extremes of the Moon, including new moon, are accompanied in men and women by the reliable growing of the myocardial infarction number by 25-35%. "Age" of myocardial infarction in men is less than that in women by 10 years. This factor complies with the gender difference in the average life expectancy in the region. Men have myocardial infarction oftener than women by 1.7 times. The critical month for development of the myocardial infarction in both sexes is June.


Combined approaches to the skull base for intracranial extension of tumors via perineural spread can improve patient outcomes.
Many neoplasms of the head and neck extend centripetally, gaining access to the central nervous system via nerves through the skull base foramina. Often patients with perineural spread have been excluded from aggressive interventions given the overall poor prognosis and technical difficulty when addressing the perineural components. However, in carefully selected patients combined surgical approaches can provide the greatest potential for disease control as well as neural decompression for symptom relief. We performed a retrospective chart review of 20 consecutive patients who underwent skull base approaches for resection of tumors with intracranial extension via perineural spread from 2011 to 2014. Patients were evaluated for symptom change, surgical approaches, histopathology, adjuvant therapy, outcome, and prognosis. The most common presenting symptoms were pain or cranial nerve palsies. 55% of patients underwent endoscopic endonasal approaches, 50% transcranial approaches, and 15% underwent transfacial approaches. Overall 85% of patients reported symptom improvement in the post-operative period while 40% were completely asymptomatic following surgical resection. Ultimately, we observed a 45% mortality rate with an average survival of 8 months after diagnosis. In carefully selected patients, an aggressive multidisciplinary approach using a combination of surgical avenues to the skull base for the treatment of intracranial tumor via perineural extension can improve patient quality of life.


[Drug combinations of lithium: reasons and limitations].
Lithium is widely used in the treatment of several psychiatric diseases-bipolar mood disorder, in particular. It is often necessary to have lithium combined with other psychopharmacological agents when efforts are aimed at either enhancing a less-than-optimal therapeutic effect or treating other symptoms as well. A therapist should be familiar with every possibility, limitation, and probable risk such pharmacological combinations are likely to lead to.


Guar gum in insulin-dependent diabetes: effects on glycemic control and serum lipoproteins.
We examined the effect of guar gum on glycemic control and serum lipid and lipoprotein profiles in mildly hypercholesterolemic patients with insulin-dependent diabetes. The study was done in a randomized, double-blind fashion with either guar gum or placebo added to the diet four times per day for 6 wk each. Fasting blood glucose and hemoglobin A1c decreased significantly during the guar-gum diet, whereas the diurnal glucose profile was unchanged. In addition, serum low-density-lipoprotein (LDL) cholesterol decreased by 20% and the ratio of LDL cholesterol to high-density-lipoprotein cholesterol by 28% during guar-gum therapy. No changes were seen in the placebo group. In conclusion, guar gum can improve glycemic control and decrease serum LDL-cholesterol concentrations in mildly hypercholesterolemic insulin-dependent diabetic patients and thus reduce risk factors for both micro- and macroangiopathic complications.


The effect of potassium on exocytosis of transmitter at the frog neuromuscular junction.
1. Electrophysiology and morphology have been combined to investigate the time course of the exocytosis of quanta of neurotransmitter induced by elevated concentrations of K+ at the frog neuromuscular junction. 2. Replicas of freeze-fractured resting nerve terminals fixed in the presence of 20 mM-K+ showed images of fusion of synaptic vesicles with the presynaptic axolemma which were closely associated with the active zones. After 1 min in 20 nM-K+ fusions appeared also outside the active zones, and by 5 min they became uniformly distributed over the presynaptic membrane. 3. The average total density of fusions was not significantly different at the various times examined since it decreased at the active zones while it increased over the rest of the membrane. 4. Resting terminals fixed in 20 mM-K+ released 33,000-45,000 quanta after the addition of fixative; terminals stimulated by 20 mM-K+ for 1-5 min released 50,000-100,000 quanta during fixation. The fixative potentiated K+-induced transmitter release. 5. Fusions were uniformly distributed in terminals pre-incubated for 5 min in 20 mM-K+ without added Ca2+, stimulated by adding Ca2+ for 30 s, and then fixed. Conversely, after 5 min stimulation in hypertonic Ringer solution fusions remained predominantly located near the active zones. A similar distribution was observed after 15 min stimulation by a lower concentration of K+ (15 mM). 6. At all concentrations of K+ tested (10, 15, 20, 25 mM) miniature end-plate potential (MEPP) rate attained a steady-state value within 10-15 min. Values from a single junction were generally lower at higher concentrations of K+, which indicates partial inactivation of the secretion-recycling process. 7. The data indicate that K+ initially activates exocytosis at the active zones. Subsequently, ectopic exocytosis is activated while sites at the active zones appear to undergo partial inactivation. These phenomena are not related to the intensity or to the amount of previous secretion.


Selective inhibition of Erwinia amylovora by the herbicidally active germination-arrest factor (GAF) produced by Pseudomonas bacteria.
The germination-arrest factor (GAF) produced by Pseudomonas fluorescens WH6, and identified as 4-formylaminooxyvinylglycine, specifically inhibits the germination of a wide range of grassy weeds. This study was undertaken to determine whether GAF has antimicrobial activity in addition to its inhibitory effects on grass seed germination. Culture filtrate from Ps. fluorescens WH6 had little or no effect on 17 species of bacteria grown in Petri dish lawns, but the in vitro growth of Erwinia amylovora, the causal agent of the disease of orchard crops known as fire blight, was strongly inhibited by the filtrate. The anti-Erwinia activity of WH6 culture filtrate was shown to be due to its GAF content, and a commercially available oxyvinylglycine, 4-aminoethoxyvinylglycine (AVG), exhibited anti-Erwinia activity similar to that of GAF. The effects of GAF on Erwinia were reversed by particular amino acids. The biological properties of GAF include a rather specific antimicrobial activity against Erw. amylovora. This may be a general property of oxyvinylglycines as AVG exhibited similar activity. The ability of particular amino acids to reverse GAF inhibition is consistent with a potential effect of this compound on the activity of aminotransferases. The results presented here demonstrate a novel antimicrobial activity of oxyvinylglycines and suggest that GAF and/or GAF-producing bacteria may have potential for the control of fire blight.


Improved PCR based methods for detecting C9orf72 hexanucleotide repeat expansions.
Due to the GC-rich, repetitive nature of C9orf72 hexanucleotide repeat expansions, PCR based detection methods are challenging. Several limitations of PCR have been reported and overcoming these could help to define the pathogenic range. There is also a need to develop improved repeat-primed PCR assays which allow detection even in the presence of genomic variation around the repeat region. We have optimised PCR conditions for the C9orf72 hexanucleotide repeat expansion, using betaine as a co-solvent and specific cycling conditions, including slow ramping and a high denaturation temperature. We have developed a flanking assay, and repeat-primed PCR assays for both 3' and 5' ends of the repeat expansion, which when used together provide a robust strategy for detecting the presence or absence of expansions greater than ∼100 repeats, even in the presence of genomic variability at the 3' end of the repeat. Using our assays, we have detected repeat expansions in 47/442 Scottish ALS patients. Furthermore, we recommend the combined use of these assays in a clinical diagnostic setting.


A 12-Year Retrospective Study of Avulsion Cases in a Public Brazilian Dental Trauma Service.
This study assessed the epidemiological characteristics and management of the permanent teeth avulsion cases attended in a Brazilian dental trauma service from December 2005 to August 2016. A retrospective study was conducted of case records of 93 patients involving 139 avulsed teeth. Data included sex, age, trauma etiology, location of the accident, number and position of avulsed teeth, and presence and type of associated traumatic lesions. Management of the avulsed teeth was addressed as: time elapsed until teeth were retrieved from the accident's location; teeth's cleaning method and storage media; time elapsed until seeking treatment and replantation. The majority of the patients were children from 6-10 (31.2%) and 11-15 years old (26.9%). Male patients were more affected than female. Bicycle accident was the main etiological factor (31.2%). In 56 (60.2%) cases, traumatic lesions to neighboring teeth were present. In 55 (59.1%) cases, lesions to adjacent soft tissues were reported. In 82 (88.2%) cases, patients requested treatment at the same day of the accident. Sixty-four teeth (46.0%) were immediately retrieved and 28 (20.1%) were not found. Forty-two teeth (30.2%) were kept dry. Only one tooth (0.7%) was immediately replanted at the accident's site, while 51 teeth (36.7%) were not replanted. Numerous avulsed teeth were inappropriately managed and immediate replantation was not frequent. Public policies must be created to raise awareness towards the particularities of avulsion cases.


Mouse liver contains a Pseudomonas aeruginosa exotoxin A-binding protein.
The opportunistic pathogen Pseudomonas aeruginosa produces several potential virulence factors, including the ADP-ribosylating toxin, exotoxin A (PE). Studies using a burned mouse model have shown that PE consistently inhibits protein synthesis and depletes elongation factor 2 in mouse liver and variably in other organs. One reason for toxin sensitivity could be the presence of a PE receptor on the surface of cells. Therefore we examined detergent extracts of mouse tissues for the presence of toxin-binding proteins. Proteins which specifically bind PE were present in extracts from liver, kidney, lung, spleen, and heart. Because liver appears to be a prominent target for the toxin in a burned animal, we choose to isolate the PE-binding protein from mouse liver and compare this protein to the recently characterized toxin-binding protein from toxin-sensitive mouse LM fibroblasts. The toxin-binding proteins from both sources have a molecular mass of approximately 350 kDa, share similar protease digestion profiles, and are glycosylated. However the glycosylation patterns for the two species are quite different. Both glycoproteins bind toxin with high avidity. The toxin-binding moiety is located, at least in part, on the plasma membrane and thus could represent the receptor involved in internalization of toxin molecules responsible for cell death.


[Alternative means of drug therapy for cancer: antineoplastons--antitumor properties and mechanisms of action].
This review presents data on the antitumor properties of antineoplastons--alternative means of treatment for cancer originally isolated from human blood and urine. It was assumed that antineoplastons (derivatives of peptides and amino acids) are natural regulators of cell differentiation. In experimental studies it was showed that synthetic antineoplastons (A10-3-phenyl-acetyl-amino-2,6-piperidinedione and AS2-1--a mixture of phenylacetic acid and phenylacetylglutamine) were able to prevent the introduction of glutamine into the cell, to block the action of Bcl-2, to activate p53 and p21, to inhibit histone deacetylase, to induce apoptosis. In experiments in vitro and in vivo in several studies it was registered antitumor activity, mainly on models of hepatocellular carcinoma and glioma. Clinical data are limited by reports of individual clinical cases or series of cases and the results of several clinical trials Phase I-II, indicating a possible antitumor activity.


The relationship between urban environment and the inflammatory bowel diseases: a systematic review and meta-analysis.
The objective of this study was to conduct a systematic review with meta-analysis of studies assessing the association between living in an urban environment and the development of the Crohn's disease (CD) or ulcerative colitis (UC). A systematic literature search of MEDLINE (1950-Oct. 2009) and EMBASE (1980-Oct. 2009) was conducted to identify studies investigating the relationship between urban environment and IBD. Cohort and case-control studies were analyzed using incidence rate ratio (IRR) or odds ratio (OR) with 95 % confidence intervals (CIs), respectively. Stratified and sensitivity analyses were performed to explore heterogeneity between studies and assess effects of study quality. The search strategy retrieved 6940 unique citations and 40 studies were selected for inclusion. Of these, 25 investigated the relationship between urban environment and UC and 30 investigated this relationship with CD. Included in our analysis were 7 case-control UC studies, 9 case-control CD studies, 18 cohort UC studies and 21 cohort CD studies. Based on a random effects model, the pooled IRRs for urban compared to rural environment for UC and CD studies were 1.17 (1.03, 1.32) and 1.42 (1.26, 1.60), respectively. These associations persisted across multiple stratified and sensitivity analyses exploring clinical and study quality factors. Heterogeneity was observed in the cohort studies for both UC and CD, whereas statistically significant heterogeneity was not observed for the case-control studies. A positive association between urban environment and both CD and UC was found. Heterogeneity may be explained by differences in study design and quality factors.


An intramolecular N-H...(mu-H)Re2 dihydrogen bond and a novel mu 3-eta 2 coordination mode of the pyrazolate anion on a triangular cluster face.
The quantitative addition of pyrazole (Hpz) to the 44 valence-electron, triangular cluster anion [Re3(mu 3-H)-(mu-H)3(CO)9]- gives the novel unsaturated anion [Re3(mu-H)4(CO)9(Hpz)]- (1, 46 valence electrons), which contains a pyrazole molecule that is terminally coordinated on a cluster vertex. Solidstate X-ray and IR analyses reveal a rather weak hydrogen-bonding interaction between the NH proton and one of the hydrides bridging the opposite triangular cluster edge (delta H degree = -3.1 kcal mol-1 from the Iogansen equation). Both IR and NMR data indicate that such a proton-hydride interaction is maintained in the major conformer present in CD2Cl2, but also provide evidence of the presence of minor conformers of 1 in which the NH proton is involved in an intermolecular hydrogen bond with the solvent. The mu-H...HN bond length evaluated in solution through the T1 minimum value (2.07 A) and that determined in the solid state by X-ray diffraction (2.05 A) are in good agreement. NMR experiments show that, in acetone, intermolecular N-H...solvent interactions replace the intramolecular dihydrogen bond. At room temperature in CH2Cl2, the pyrazole ligand in 1 is labile and 1 slowly "disproportionates" to [Re3(mu 3-H)-(mu-H)3(CO)9]- and [Re3(mu-H)3(CO)9-(mu-eta 2-pz)(Hpz)]-, with H2 evolution. Slow H2 evolution also leads to the formation of the anion [Re3(mu-H)3-(CO)9(pz)]- (5), in which the pyrazolate anion adopts a novel mu 3-eta 2-coordination mode, as revealed by a single-crystal X-ray analysis. The analysis of the bond lengths indicates that the pyrazolate anion in 5 acts as a six-electron donor, with loss of the aromaticity. The formation of 5 from 1 is much faster in solvents with a high dielectric constant, such as acetone or DMF. Anion 5 was also obtained from the reaction of pyrazole with [Re3(mu-H)3(CO)9(mu 3-CH3)]- through the intermediate formation of two isomeric addition derivatives and following CH4 evolution.


Topical Therapy for non-invasive penile cancer (Tis)-updated results and toxicity.
Penile cancer is a rare malignancy estimated to affect 26,000 men globally each year. The association with penile cancer, in particular non-invasive disease, and human papilloma virus (HPV) is well known. Ninety-five percent of cases of penile cancer are squamous cell carcinoma (SCC), which are staged using the TNM staging system. Terminology describing the histological appearance of non-invasive penile cancer has changed with all cases grouped under the umbrella term of penile intraepithelial neoplasia (PeIN); either undifferentiated or differentiated. This replaces previous terms such as carcinoma in situ (CIS) and eponymous names such as Bowen's disease. This change is recognised by the World Health Organisation (WHO). The topical treatments most commonly used for PeIN are 5-fluorouracil (5-FU) and imiquimod (IQ). Other treatments such as photodynamic therapy (PDT) are used but to a lesser degree. The evidence for all of these treatments is heterogenous with no randomised data available. Overall up to 57% complete response has been reported with a low number of serious adverse events. In this article, we aim to review the available evidence for the topical treatment of non-invasive penile cancer specifically regarding its efficacy and toxicity.


Intracellular heavy metal nanoparticle storage: progressive accumulation within lymph nodes with transformation from chronic inflammation to malignancy.
A 25-year-old man had complained of sudden fever spikes for two years and his blood tests were within the normal range. In 1993, a surgical biopsy of swollen left inguinal lymph nodes was negative for malignancy, but showed reactive lymphadenitis and widespread sinus histiocytosis. A concomitant needle biopsy of the periaortic lymph nodes and a bone marrow aspirate were also negative. In 1994, after an emergency hospital admission because of a sport-related thoracic trauma, a right inguinal lymph node biopsy demonstrated Hodgkin's lymphoma Stage IVB (scleronodular mixed cell subtype). Although it was improved by chemotherapy, the disease suddenly relapsed, and a further lymph node biopsy was performed in 1998 confirming the same diagnosis. Despite further treatment, the patient died of septic shock in 2004, at the age of 38 years. Retrospective analysis of the various specimens showed intracellular heavy metal nanoparticles within lymph node, bone marrow, and liver samples by field emission gun environmental scanning electron microscopy and energy dispersive spectroscopy. Heavy metals from environmental pollution may accumulate in sites far from the entry route and, in genetically conditioned individuals with tissue specificity, may act as cofactors for chronic inflammation or even malignant transformation. The present anecdotal report highlights the need for further pathologic ultrastructural investigations using serial samples and the possible role of intracellular nanoparticles in human disease.


Evaluation of Sorption Mechanism of Pb (II) and Ni (II) onto Pea (Pisum sativum) Peels.
The present study was carried out to know the sorption mechanism of Pb (II) and Ni (II) in aqueous solution using pea peels under the influence of sorbent dose, pH, temperature, initial metal ion concentration and contact time. SEM and FTIR were used for characterization of pea peels. The study showed that solution pH affects sorption process and the optimum pH for Pb (II) was 6.0 while for that of Ni (II) was 7.0. Pseudo-second order kinetic model was found to be the most suitable one to explain the kinetic data not only due to high value of R2 (>0.99) but also due to the closeness of the experimental sorption capacity values to that of calculated sorption capacity values of pseudo second order kinetic model. It can be seen from the results that Freundlich isotherm explains well the equilibrium data (R2>0.99). Sorption capacity of pea peels was 140.84 and 32.36 for Pb (II) and Ni (II) mg g-1 respectively. The positive value of ΔH° and negative values of ΔG° suggest that sorption of Pb (II) and Ni (II) onto pea peels is an endothermic and spontaneous process respectively.


Picolinamides as effective ligands for copper-catalysed aryl ether formation: structure-activity relationships, substrate scope and mechanistic investigations.
The use of picolinic acid amide derivatives as an effective family of bidentate ligands for copper-catalysed aryl ether synthesis is reported. A fluorine-substituted ligand gave good results in the synthesis of a wide range of aryl ethers. Even bulky phenols, known to be very challenging substrates, were shown to react with aryl iodides with excellent yields using these ligands. At the end of the reaction, the first examples of end-of-life Cu species were isolated and identified as Cu(II) complexes with several of the anionic ligands tested. A preliminary mechanistic investigation is reported that suggests that the substituents on the ligands might have a crucial role in determining the redox properties of the metal centre and, consequently, its efficacy in the coupling process. An understanding of these effects is important for the development of new efficient and tunable ligands for copper-based chemistry.


Cervical lateral glide increases nociceptive flexion reflex threshold but not pressure or thermal pain thresholds in chronic whiplash associated disorders: A pilot randomised controlled trial.
Sensory hypersensitivity indicative of augmented central pain processing is a feature of chronic whiplash associated disorders (WAD). This study investigated the immediate effects of a cervical spine manual therapy (SMT) technique on measures of central hyperexcitability. In a randomised, single blind, clinical trial, 39 participants with chronic WAD were randomly assigned to a cervical SMT (lateral glide) or manual contact intervention. The Neck Disability Index (NDI) and GHQ-28 were administered at baseline. Pressure pain thresholds (PPTs), thermal pain thresholds (TPTs) and Nociceptive Flexion Reflex (NFR) responses (threshold and VAS of pain) were measured pre and post intervention. There was a significantly greater increase in NFR threshold following SMT compared to the manual contact intervention (p = 0.04). PPTs at the cervical spine increased following both SMT (mean +/- SE: 24.1 +/- 7.3%) and manual contact (21 +/- 8.4%) with no difference between interventions. There was no difference between interventions for pain ratings with the NFR test, PPTs at the Median Nerve or Tibialis Anterior, heat or cold TPT. SMT may be effective in reducing spinal hyperexcitability in chronic WAD.


Role of RelA and SpoT in Burkholderia pseudomallei survival, biofilm formation and ceftazidime tolerance during nutritional stress.
Burkholderia pseudomallei a saprophyte found in soil and stagnant water is the causative agent of human melioidosis, an often cause fatal disease. B. pseudomallei is intrinsically resistant to many antibiotics. The stringent response is a global bacterial adaptation process in response to nutritional limitation and is mediated by the alarmone (p)ppGpp, which is produced by two proteins, RelA and SpoT. In order to test whether the stringent response is involved in ceftazidime tolerance, biofilm formation, and bacterial survival in the soil microcosm, B. pseudomallei strain K96243 and its isogenic ΔrelA and ΔrelAΔspoT mutants were grown in rich and nutrient-limited media. In nutrient-limiting conditions, both the wild type and mutants were found to be up to 64-times more tolerant to ceftazidime than when grown in rich culture conditions. Moreover, the biofilm formation of all bacterial isolates tested were significantly higher under nutrient-limiting conditions than under nutrient-rich conditions. The ΔrelAΔspoT mutant produced less biofilm than its wild type or ΔrelA mutant under nutrient-limiting conditions. The survival of the ΔrelAΔspoT double mutant cultured in 1% moisture content soil was significantly decreased compared to the wild type and the ΔrelA mutant. Therefore, the RelA/SpoT protein family might represent a promising target for the development of novel antimicrobial agents to combat B. pseudomallei.


Improving PCR efficiency for accurate quantification of 16S rRNA genes.
Quantitative real-time PCR is a valuable tool for microbial ecologists. To obtain accurate absolute quantification it is essential that PCR efficiency for pure standards is close to amplification efficiency for test samples. Counter to normal expectation that PCR efficiency might be lower in environmental DNA, due to the presence of PCR inhibitors, we report the counterintuitive observation that PCR efficiency of pure standards can be lower than for environmental DNA. This can lead to overestimation of gene abundances if not corrected. SYBR green-based qPCR assays of 16S rRNA genes targeting Bacteria, Syntrophus and Smithella spp., Marinobacter spp., Methanomicrobiales, Methanosarcinaceae, and Methanosaetaceae in samples from methanogenic crude oil biodegradation enrichments were tested. In five out of the six assays, PCR efficiency was lower with pure standards than with environmental DNA samples. We developed a solution to this problem based on amending pure clone standards with a background of non-target environmental 16S rRNA genes which significantly improved PCR efficiency of standards in the qPCR assays that exhibited this phenomenon. Overall this method of qPCR standard preparation achieved a more reliable and robust quantification of 16S rRNA genes. We believe this may be a potentially common issue in microbial ecology that often goes unreported, as intuitively one would not expect standards to have poorer PCR efficiency than samples.