Precision medicine and personalized breast cancer: combination pertuzumab therapy.
Trastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer.


Tachyphylaxis to inhaled histamine in asthmatic subjects.
The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.


Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes Assessed by Continuous Glucose Monitoring.
Recurrent hypoglycemia promotes impaired awareness, resulting in an increased risk for asymptomatic hypoglycemia. However, there are no firm data on the frequency of hypoglycemia in daily life needed to initiate this vicious cycle or the role of asymptomatic hypoglycemia. To explore the association between hypoglycemic exposure and proportion of asymptomatic hypoglycemia and relation to risk for severe hypoglycemia. Prospective observational trial. Outpatient clinic. One hundred fifty-three unselected patients with type 1 diabetes mellitus (T1D). Six days of blinded continuous glucose monitoring and recording of hypoglycemia symptoms. Proportion of asymptomatic hypoglycemic events (glucose level ≤70 mg/dL). Patients were grouped by the number of hypoglycemic events during the recording period (group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events), and fractions of asymptomatic events were calculated. Across the four groups, the fraction of asymptomatic hypoglycemia increased: 57% in group 1, 61% in group 2, 65% in group 3, and 80% in group 4 (P < 0.001). Higher fraction of asymptomatic hypoglycemia was positively associated with risk for severe hypoglycemia (incidence rate ratio, 1.3; 95% confidence interval, 1.1 to 1.5; P = 0.003). Group 4 consisted of patients characterized by classic risk factors of severe hypoglycemia (longer duration of diabetes, lower hemoglobin A1c, and more frequent impaired awareness of hypoglycemia). Patients with T1D with hypoglycemic rates corresponding to daily exposure had an increased fraction of asymptomatic events, which was positively associated with risk for severe hypoglycemia; therefore, such patients deserve particular attention in clinical practice.


Rankings of iron, vitamin D, and calcium intakes in relation to maternal characteristics of pregnant Canadian women.
Iron, vitamin D, and calcium intakes in the prenatal period are important determinants of maternal and fetal health. The objective of this study was to examine iron, vitamin D, and calcium intakes from diet and supplements in relation to maternal characteristics. Data were collected in a subsample of 1186 pregnant women from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a cohort study including pregnant women recruited from 10 Canadian sites between 2008 and 2011. A food frequency questionnaire was administered to obtain rankings of iron, calcium, and vitamin D intake (16-21 weeks of pregnancy). Intakes from supplements were obtained from a separate questionnaire (6-13 weeks of pregnancy). Women were divided into 2 groups according to the median total intake of each nutrient. Supplement intake was an important contributor to total iron intake (median 74%, interquartile range (IQR) 0%-81%) and total vitamin D intake (median 60%, IQR 0%-73%), while the opposite was observed for calcium (median 18%, IQR 0%-27%). Being born outside of Canada was significantly associated with lower total intakes of iron, vitamin D, and calcium (p ≤ 0.01 for all). Consistent positive indicators of supplement use (iron, vitamin D, and calcium) were maternal age over 30 years and holding a university degree. In conclusion, among Canadian women, the probability of having lower iron, vitamin D, and calcium intakes is higher among those born outside Canada; supplement intake is a major contributor to total iron and vitamin D intakes; and higher education level and age over 30 years are associated with supplement intake.


Anomalous Slowdown of Polymer Detachment Dynamics on Carbon Nanotubes.
The "wrapping" of polymer chains on the surface of carbon nanotubes allows one to obtain multifunctional hybrid materials with unique properties for a wide range of applications in biomedicine, electronics, nanocomposites, biosensors, and solar cell technologies. We study by means of molecular dynamics simulations the force-assisted desorption kinetics of a polymer from the surface of a carbon nanotube. We find that, due to the geometric coupling between the adsorbing surface and the conformation of the macromolecule, the process of desorption slows down dramatically upon increasing the windings around the nanotube. This behavior can be rationalized in terms of an overdamped dynamics with a frictional force that increases exponentially with the number of windings of the macromolecule, resembling the Euler-Eytelwein mechanism that describes the interplay between applied tension and frictional forces on a rope wrapped around a curved surface. The results highlight the fundamental role played by the geometry to control the dynamics and mechanical stability of hybrid materials in order to tailor properties and maximize performance.


Experimental tissue engineering of fetal skin.
In some human fetuses undergoing prenatal spina bifida repair, the skin defect is too large for primary closure. The aim of this study was to engineer an autologous fetal skin analogue suitable for in utero skin reconstruction during spina bifida repair. Keratinocytes (KC) and fibroblasts (FB) isolated from skin biopsies of 90-day-old sheep fetuses were cultured. Thereafter, plastically compressed collagen hydrogels and fibrin gels containing FB were prepared. KC were seeded onto these dermal constructs and allowed to proliferate using different culture media. Constructs were analyzed histologically and by immunohistochemistry and compared to normal ovine fetal skin. Development of a stratified epidermis covering the entire surface of the collagen gel was observed. The number of KC layers and degree of organization was dependent on the cell culture media used. The collagen hydrogels exhibited a strong tendency to shrink after eight to ten days of culture in vitro. On fibrin gels, we did not observe the formation of a physiologically organized epidermis. Collagen-gel-based ovine fetal cell-derived skin analogues with near normal anatomy can be engineered in vitro and may be suitable for autologous fetal transplantation.


The use of the 4.5 mm 90° titanium cannulated LC-angled blade plate in tibiotalocalcaneal and complex ankle arthrodesis.
Tibiotalocalcaneal arthrodesis is used to manage end stage arthritis, often associated with severe bone loss. The goal is to relieve pain through a stable, well-aligned hindfoot and ankle. We describe our initial results and outcome of ankle and tibiotalocalcaneal arthrodesis using a 90° blade plate. We retrospectively reviewed the records of patients managed at our institution between 2010 and 2014. Twenty cases were identified who had either talocrural (n = 9) or TTC fusion (n = 11) with 1 patient having both ankle and then TTC fusion in separate sittings. Fusion occurred in 18 of the 20 cases (90%) with correction of angular deformity and restoration of hindfoot alignment. None of the 18 patients developed complications and all discharged to follow-up when independently mobile and satisfied with the outcome. This study demonstrated that using a 90° blade plate for ankle or TTC arthrodesis in a diverse group of complex primary and revision indications associated with severe deformity and bone loss resulted in a high rate of bony union and stable deformity correction.


Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ.
Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.


Spatial and temporal variation in nest temperatures forecasts sex ratio skews in a crocodilian with environmental sex determination.
Species displaying temperature-dependent sex determination (TSD) are especially vulnerable to the effects of a rapidly changing global climate due to their profound sensitivity to thermal cues during development. Predicting the consequences of climate change for these species, including skewed offspring sex ratios, depends on understanding how climatic factors interface with features of maternal nesting behaviour to shape the developmental environment. Here, we measure thermal profiles in 86 nests at two geographically distinct sites in the northern and southern regions of the American alligator's (Alligator mississippiensis) geographical range, and examine the influence of both climatic factors and maternally driven nest characteristics on nest temperature variation. Changes in daily maximum air temperatures drive annual trends in nest temperatures, while variation in individual nest temperatures is also related to local habitat factors and microclimate characteristics. Without any compensatory nesting behaviours, nest temperatures are projected to increase by 1.6-3.7°C by the year 2100, and these changes are predicted to have dramatic consequences for offspring sex ratios. Exact sex ratio outcomes vary widely depending on site and emission scenario as a function of the unique temperature-by-sex reaction norm exhibited by all crocodilians. By revealing the ecological drivers of nest temperature variation in the American alligator, this study provides important insights into the potential consequences of climate change for crocodilian species, many of which are already threatened by extinction.


Comparison of Cardiac Computed Tomography With Transesophageal Echocardiography for Identifying Vegetation and Intracardiac Complications in Patients With Infective Endocarditis in the Era of 3-Dimensional Images.
Recent evolution of cardiac computed tomography (CT) provides useful information about valvular and perivalvular structures. We compared the diagnostic performance of CT and transesophageal echocardiography (TEE) with applications of 3-dimensional reconstruction in detecting vegetation and intracardiac complications in patients with infective endocarditis (IE). Seventy-five patients (53 men; age, 58±15 years) with definite IE who underwent TEE and CT with 3-dimensional reconstruction within 3 days were analyzed. The diagnostic performances of the 2 modalities for vegetation and IE-related intracardiac complications (valve perforation, valve aneurysm, perivalvular abscess, pseudoaneurysm, fistula, and prosthetic valve dehiscence) were compared. The detection rate of vegetation in TEE and CT was 97.3% and 72.0%, respectively. The maximum sizes of vegetation identified by TEE and CT were well correlated (r=0.593; P<0.001), especially in patients with large vegetation (≥10 mm), suggestive of a high risk of systemic embolism (r=0.608; P<0.001). However, small vegetation (<10 mm) was underdiagnosed by CT (52.8%) compared with TEE (94.4%), and the sizes of the 2 modalities were poorly correlated (r=0.187; P=0.445). Both modalities showed fair diagnostic performance for detecting IE-related intracardiac complications with excellent agreement. TEE was more useful for diagnosing valve perforation and intracardiac fistula, whereas CT was better for diagnosing perivalvular abscess. Cardiac CT shows a comparable diagnostic performance with TEE for large vegetation and several IE-related complications. TEE is better for detecting small vegetation, valve perforation, and intracardiac fistula, whereas CT is more useful for detecting perivalvular abscess and coronary artery disease.


Linkage of posterior amorphous corneal dystrophy to chromosome 12q21.33 and exclusion of coding region mutations in KERA, LUM, DCN, and EPYC.
To identify the genetic basis of posterior amorphous corneal dystrophy (PACD) segregating in a large pedigree. The authors performed clinical evaluation of a previously unreported pedigree with PACD, light and electron microscopic examination of an excised corneal button, genomewide linkage analysis, fine mapping linkage and haplotype analysis, and screening of four candidate genes (KERA, LUM, DCN, and EPYC). Twenty-one participants were determined to be affected based on the presence of characteristic clinical features of PACD; 15 affected and 39 unaffected individuals from a single pedigree enrolled in the study and provided DNA for analysis. Histopathologic examination of an excised corneal specimen from an affected individual demonstrated disorganized stromal lamellae and stromal staining with colloidal iron. Genomewide analysis demonstrated significant evidence of linkage to chromosome region 12q21.33 and evidence suggestive of linkage to chromosome region 8q22.3. Fine mapping of the chromosome 12 locus confirmed significant linkage; the largest multipoint log odds ratio score was 5.6 at D12S351. The linkage support interval was approximately 3.5 Mb (3.5 cM) in length between flanking markers D12S1812 and D12S95, roughly the entire chromosome band 12q21.33. No coding region mutations were identified in four candidate genes-KERA, LUM, DCN, EPYC-located in the chromosome 12 linkage support interval. Linkage and haplotype analyses identified 12q21.33 as a locus for PACD. However, no mutations were identified in the candidate genes (KERA, LUM, DCN, EPYC) within this region.


The Association between Limited English Proficiency and Sepsis Mortality.
Limited English proficiency (LEP) has been implicated in poor health outcomes. Sepsis is a frequently fatal syndrome that is commonly encountered in hospital medicine. The impact of LEP on sepsis mortality is not currently known. To determine the association between LEP and sepsis mortality. Retrospective cohort study. 800-bed, tertiary care, academic medical center. Electronic health record data were obtained for adults admitted to the hospital with sepsis between June 1, 2012 and December 31, 2016. The primary predictor was LEP. Patients were defined as having LEP if their self-reported primary language was anything other than English and interpreter services were required during hospitalization. The primary outcome was inpatient mortality. Mortality was compared across races stratified by LEP using chi-squared tests of significance. Bivariable and multivariable logistic regressions were performed to investigate the association between mortality, race, and LEP, adjusting for baseline characteristics, comorbidities, and illness severity. Among 8,974 patients with sepsis, we found that 1 in 5 had LEP, 62% of whom were Asian. LEP was highly associated with death across all races except those identifying as Black and Latino. LEP was associated with a 31% increased odds of mortality after adjusting for illness severity, comorbidities, and other baseline characteristics, including race (OR 1.31, 95% CI 1.06-1.63, P = .02). In a single-center study of patients hospitalized with sepsis, LEP was associated with mortality across nearly all races. This is a novel finding that will require further exploration into the causal nature of this association.


Influence of Textured Insoles on Dynamic Postural Balance of Young Dancers.
Postural balance (PB) is a significant factor in dance performance and injury prevention. We aimed to determine whether the use of textured insoles inserted into casual walking shoes of dancers improved their dynamic PB and whether dancers with previous injury manifested different dynamic PB compared with non-injured dancers. In this crossover design study, 26 ballet dancers from the Australian Ballet School, aged 14-19 yrs, were divided into two groups matched by sex and class levels. Group 1 wore the textured insoles in their walking shoes for at least 2 hrs/day during weeks 1 to 4 of the study, and group 2 wore the textured insoles in their walking shoes during weeks 5 to 8. Reports from the school medical staff identified dancers who had previous injuries. All participants were tested pre-intervention and at 4 and 8 weeks by an accelerometer for dynamic PB (average acceleration magnitude, root mean square acceleration, range, and mean frequency) during single-leg fondu, flexing and extending of the knee. Interactions (group x time) were found in dynamic PB measured in the mediolateral direction, indicating significant differences between the groups at the three testing times. Furthermore, both previously injured and noninjured dancers manifested significant time effects from pre-intervention to 8 weeks, indicating a significant improvement in their PB after using the textured insoles. Textured insoles can improve the dynamic PB of ballet dancers and can also be useful as a routine intervention. PB was improved among both dancers with previous injury and non-injured dancers.


Use of designer nucleases for targeted gene and genome editing in plants.
The ability to efficiently inactivate or replace genes in model organisms allowed a rapid expansion of our understanding of many of the genetic, biochemical, molecular and cellular mechanisms that support life. With the advent of new techniques for manipulating genes and genomes that are applicable not only to single-celled organisms, but also to more complex organisms such as animals and plants, the speed with which scientists and biotechnologists can expand fundamental knowledge and apply that knowledge to improvements in medicine, industry and agriculture is set to expand in an exponential fashion. At the heart of these advancements will be the use of gene editing tools such as zinc finger nucleases, modified meganucleases, hybrid DNA/RNA oligonucleotides, TAL effector nucleases and modified CRISPR/Cas9. Each of these tools has the ability to precisely target one specific DNA sequence within a genome and (except for DNA/RNA oligonucleotides) to create a double-stranded DNA break. DNA repair to such breaks sometimes leads to gene knockouts or gene replacement by homologous recombination if exogenously supplied homologous DNA fragments are made available. Genome rearrangements are also possible to engineer. Creation and use of such genome rearrangements, gene knockouts and gene replacements by the plant science community is gaining significant momentum. To document some of this progress and to explore the technology's longer term potential, this review highlights present and future uses of designer nucleases to greatly expedite research with model plant systems and to engineer genes and genomes in major and minor crop species for enhanced food production.


Health service support in the future operating environment 2035.
The period to 2035 is likely to be characterised by instability between states and in relations between groups within states. It is predicted to include climate change, rapid population growth, resource scarcity, resurgence in ideology, and shifts in power from west to east. Many of these changes are likely to have an impact on the health of civil societies and those military personnel deployed by states to counter these challenges. This paper considers the potential impact of emerging global strategic trends on health service support (HSS) in the Future Operating Environment 2035. Global Strategic Trends-Out to 2040, The Future Character of Conflict and NATO Strategic Foresight Analysis Report 2013 provide the foundations of the paper. The study concludes that future impacts on HSS are neither completely predictable nor predetermined, and there is always a possibility of a strategic shock. Knowledge of vulnerability, however, allows an informed approach to the development and evaluation of adaptive strategies to lessen risks to health.


Congenital toxoplasmosis in France in 2007: first results from a national surveillance system.
When immunocompetent people become infected with the parasite Toxoplasma gondii, the disease is generally asymptomatic. However, transplacental transmission of T. gondii may lead to severe congenital infection including in utero abortion, foetal death, or neurological or ocular damage of the foetus. France has had a national programme to prevent congenital toxoplasmosis since 1978. However, although estimated seroprevalence in pregnant women has fallen from 84% in the 1960s to 44% in 2003, no reliable data have been available on the annual number of cases of congenital toxoplasmosis or the severity of infection. In 2006, the French National Institute for Public Health Surveillance (Institut de Veille Sanitaire) and the National Reference Centre for Toxoplasmosis recommended that a national laboratory-based surveillance system be used for the surveillance of the disease. In 2007, 31 laboratories reported at least one congenital case through the surveillance system, giving a total of 272 cases. A total of 11 terminations of pregnancy were reported (six abortions and five foetal deaths). Of the live-born cases, 206 were asymptomatic, 28 were symptomatic and seven had a severe form of the disease. As there were 818,700 births in France and French overseas departments in 2007, the overall prevalence of congenital toxoplasmosis observed that year was 3.3 (95% confidence interval (CI): 2.9 to 3.7) per 10,000 live births and the incidence rate of the disease at birth was 2.9 (95% CI: 2.5 to 3.2) per 10,000 live births; the estimated incidence rate of symptomatic congenital toxoplasmosis was 0.34 (95% CI: 0.2 to 0.5) cases per 10,000 live births.


Variability of control data and relevance of observed group differences in five oral toxicity studies with genetically modified maize MON810 in rats.
The data of four 90-day feeding trials and a 1-year feeding trial with the genetically modified (GM) maize MON810 in Wistar Han RCC rats performed in the frame of EU-funded project GRACE were analysed. Firstly, the data obtained from the groups having been fed the non-GM maize diets were combined to establish a historical control data set for Wistar Han RCC rats at the animal housing facility (Slovak Medical University, Bratislava, Slovakia). The variability of all parameters is described, and the reference values and ranges have been derived. Secondly, the consistency of statistically significant differences found in the five studies was analysed. In order to do so, the body weight development, organ weight, haematology and clinical biochemistry data were compared between the studies. Based on the historical control data, equivalence ranges for these parameters were defined, and the values measured in the GM maize-fed groups were compared with these equivalence ranges. Thirdly, the (statistical) power of these feeding studies with whole food/feed was assessed and detectable toxicologically relevant group differences were derived. Linear mixed models (LMM) were applied, and standardized effect sizes (SES) were calculated in order to compare different parameters as well as to provide an overall picture of group and study differences at a glance. The comparison of the five feeding trials showed a clear study effect in the control data. It also showed inconsistency both in the frequency of statistically significant differences and in the difference values between control and test groups.


Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.
To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. NCT00572195. This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.


Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery.
Both benign prostatic hyperplasia (BPH) and cataract formation are common in older men. The alpha-adrenergic receptor blocker tamsulosin is frequently prescribed to treat BPH, and research suggests this drug may increase the intraoperative difficulty of cataract surgery. No studies have documented whether use of tamsulosin or other alpha-blocker drug therapies affect the risk of serious postoperative adverse events. To assess the risk of adverse events following cataract surgery in older men prescribed tamsulosin or other alpha-blocking drugs used to treat BPH. Nested case-control analysis of a population-based retrospective cohort study using linked health care databases from Ontario, Canada. We included all men aged 66 years or older who had cataract surgery between 2002 and 2007 (N = 96 128). A composite of procedures signifying retinal detachment, lost lens or lens fragment, or endophthalmitis occurring within 14 days after cataract surgery. The risk of these adverse events was compared between men treated with tamsulosin or other alpha-blockers and men with no exposure to these medications in the year prior to cataract surgery. We separately examined the association of drug exposure that was either recent (within the 14 days before surgery) or previous (15-365 days before surgery). Overall, 3550 patients (3.7%) in the cohort had recent exposure to tamsulosin and 7426 patients (7.7%) had recent exposure to other alpha-blockers. Two hundred eighty-four patients (0.3%) had an adverse event. We randomly matched 280 of the cases to 1102 controls according to their age, surgeon, and year of surgery. Adverse events were significantly more common among patients with recent tamsulosin exposure (7.5% vs 2.7%; adjusted odds ratio [OR], 2.33; 95% confidence interval [CI], 1.22-4.43) but were not associated with recent exposure to other alpha-blockers (7.5% vs 8.0%; adjusted OR, 0.91; 95% CI, 0.54-1.54) or to previous exposure to either tamsulosin (< or = 1.8% vs 1%; adjusted OR, 0.94; 95% CI, 0.27-3.34) or other alpha-blockers (2.9% vs 2.1%; adjusted OR, 1.08; 95% CI, 0.47-2.48). This corresponds to an estimated number needed to harm (NNH) of 255 (95% CI, 99-1666). Exposure to tamsulosin within 14 days of cataract surgery was significantly associated with serious postoperative ophthalmic adverse events. There were no significant associations with exposure to other alpha-blocker medications used to treat BPH.


The economics of cardiac surgery.
The coronary artery bypass graft (CABG) is the most costly single surgical procedure in the United States, making bypass surgery a key target for cost containment in the current health care reform environment. This article highlights the relationship between risk factors and costs and describes some of the current initiatives aimed at cost containment and quality enhancement.


A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations.
Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome underlies between 2 and 5% of all colorectal cancer. It is inherited as an autosomal dominant condition due to mutations in the mismatch repair genes. Fifty-four non-related index cases, 21 of them fulfilling Amsterdam criteria I or II, were studied. Ten (10/21 = 47.6%) different pathological mutations were found in this group, two of which had not previously been reported--one in MLH1 and the other in MSH2-. In the remaining patients, we also found another family with one of these new mutations, and four additional changes, two of which were also new--a pathological change in MSH2 and a second change of uncertain significance in MLH1-, while the other two changes had already been reported. Of all mutations, eight were found in MSH2 (8/15 = 53.3%) and seven in MLH1 (7/15 = 46.6%), suggesting a slightly greater involvement of MSH2 in HNPCC than MLH1 in our population, in contrast to the results reported by other authors.


Gene transfer from a parasitic flowering plant to a fern.
The rattlesnake fern (Botrychium virginianum (L.) Sw.) is obligately mycotrophic and widely distributed across the northern hemisphere. Three mitochondrial gene regions place this species with other ferns in Ophioglossaceae, while two regions place it as a member of the largely parasitic angiosperm order Santalales (sandalwoods and mistletoes). These discordant phylogenetic placements suggest that part of the genome in B. virginianum was acquired by horizontal gene transfer (HGT), perhaps from root-parasitic Loranthaceae. These transgenes are restricted to B. virginianum and occur across the range of the species. Molecular and life-history traits indicate that the transfer preceded the global expansion of B. virginianum, and that the latter may have happened very rapidly. This is the first report of HGT from an angiosperm to a fern, through either direct parasitism or the mediation of interconnecting fungal symbionts.


Screening for burn-out in Australian medical students undertaking a rural clinical placement.
To investigate Australian medical student burn-out during rural clinical placement. Second, to examine the association between perceived burn-out and rural career intent at the time of finishing their rural placement. The 2016 Federation of Rural Australian Medical Educators evaluation survey is a cross-sectional study of medical students from 17 Australian universities. Specifically, those medical students who completed a full academic year or more at a Rural Clinical School (RCS). Responses from 638 medical students from regional Australia were analysed in the study of all eligible 756 medical students (response rate 84.3%). The primary objective was to determine self-reported burn-out (emotional exhaustion) in rural placements for medical students. Secondary outcome measures were designed to explore interactions with rural practice self-efficacy and rural intentions. Logistic regression models explored factors associated with burn-out. 26.5% of students reported experiencing burn-out during a rural placement. Factors associated with burn-out were female gender, rural origin, low preference for RCS, stress in the year prior to a rural clinical placement, perceived social isolation during rural placement and lower rural practice self-efficacy. Burn-out was not associated with rural career intentions. Social isolation and low rural self-efficacy were independently associated with burn-out during rural placement and together explained 10% of variance in burn-out (Model Nagelkerke R2=0.23). Burn-out during rural placement may be a consequence of stress prior to a medical school placement. Social isolation and rural self-efficacy are amendable factors to mitigate medical student burn-out during rural placements.


3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1H-Indole Derivatives as New Anticancer Agents in the Treatment of Pancreatic Ductal Adenocarcinoma.
A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 µM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases.


Shame, depressive symptoms and eating, weight and shape concerns in a non-clinical sample.
Shame has been shown to be related both to symptoms of depression and eating pathology. However, the independence of this relationship has not yet been established. The purpose of the present study was to determine whether the relationship between shame and eating disorder symptoms was independent of the relationships of these variables with depression. Seventy non-clinical female participants completed measures of eating disorder-related concerns using the Eating Disorder Examination-Questionnaire version (EDE-Q), depressive symptoms using the Beck Depression Inventory (BDI-II) and two measures of shame, the Other As Shamer Scale (QAS) and the Test of Self-Conscious Affect (TOSCA). Despite a strong association between BDI-II and EDE-Q scores and a moderate relationship between the shame measures, the two measures of shame showed some specificity in their relationships with symptom measures. The OAS was independently related to levels of BDI-II scores while the TOSCA was independently related to scores on the EDE-Q. There are a number of differences between the two measures of shame used in this study. The fact that each was differentially related to eating concerns and depressive symptoms may give clues as to which aspects of shame are important in each of the two types of pathology.


Analysis of incidence and prognosis from 'extreme' case-control designs.
The significant investment in measuring biomarkers has prompted investigators to improve cost-efficiency by sub-sampling in non-standard study designs. For example, investigators studying prognosis may assume that any differences in biomarkers are likely to be most apparent in an extreme sample of the earliest deaths and the longest-surviving controls. Simple logistic regression analysis of such data does not exploit the information available in the survival time, and statistical methods that model the sampling scheme may be more efficient. We derive likelihood equations that reflect the complex sampling scheme in unmatched and matched 'extreme' case-control designs. We investigated the performance and power of the method in simulation experiments, with a range of underlying hazard ratios and study sizes. Our proposed method resulted in hazard ratio estimates close to those obtained from the full cohort. The standard error estimates also performed well when compared with the empirical variance. In an application to a study investigating markers for lethal prostate cancer, an extreme case-control sample of lethal cases and the longest-surviving controls provided estimates of the effect of Gleason score in close agreement with analysis of all the data. By using the information in the sampling design, our method enables efficient and valid estimation of the underlying hazard ratio from a study design that is intuitive and easily implemented.


Immunostimulating and Antimetastatic Effects of Polysaccharides Purified from Ginseng Berry.
Ginseng root has been used in traditional oriental medicine for the enhancement of immune system function. The immunostimulatory effects of ginseng berry polysaccharides, however, remain unclear. Effects of polysaccharides from ginseng berry on the activation of natural killer (NK) cells and inhibition of tumors are reported. A crude polysaccharide was isolated from ginseng berry as a ginseng berry polysaccharide portion (GBPP) and was further fractionated using gel filtration chromatography to obtain the three polysaccharide fractions GBPP-I, -II and -III. GBPP-I consisted of mainly galactose (46.9%) and arabinose (27.5%). GBPP-I showed a high dose-dependent anticomplementary activity. Stimulation of murine peritoneal macrophages by GBPP-I showed the greatest enhancement of interleukin (IL)-6 and IL-12 and tumor necrosis factor (TNF)- α production. In addition, an ex vivo assay of natural killer (NK) cell activity showed that oral ( p.o.) administration of GBPP-I significantly increased NK cell cytotoxicity in YAC-1 tumor cells and production of granzyme B. Prophylactic intravenous ( i.v.) and p.o. administration of GBPP-I significantly and dose-dependently inhibited lung metastatic activity in B16BL6 melanoma cells. Depletion of NK cells after injection of rabbit anti-asialo GM1 partially abolished the inhibitory effect of GBPP-I on lung metastasis, indicating that NK cells play an important role in anticancer effects. GBPP-I exerts a strong immune-enhancing activity and can prevent cancer metastasis through activation of NK cells and other immune-related cells.


Nationwide surveillance study of Clostridium difficile in Australian neonatal pigs shows high prevalence and heterogeneity of PCR ribotypes.
Clostridium difficile is an important enteric pathogen of humans and the cause of diarrhea and enteritis in neonatal pigs. Outside Australia, prevalence in piglets can be up to 73%, with a single PCR ribotype (RT), 078, predominating. We investigated the prevalence and genotype of C. difficile in Australian pig herds. Rectal swabs (n = 229) were collected from piglets aged <7 days from 21 farms across Australia. Selective culture for C. difficile was performed and isolates characterized by PCR for toxin genes and PCR ribotyping. C. difficile was isolated from 52% of samples by direct culture on chromogenic agar and 67% by enrichment culture (P = 0.001). No association between C. difficile recovery or genotype and diarrheic status of either farm or piglets was found. The majority (87%; 130/154) of isolates were toxigenic. Typing revealed 23 different RTs, several of which are known to cause disease in humans, including RT014, which was isolated most commonly (23%; 36/154). RT078 was not detected. This study shows that colonization of Australian neonatal piglets with C. difficile is widespread in the herds sampled.


Effective use of small-interfering RNA to characterize residual B-cell non-Hodgkin lymphoma cells following chemotherapy.
BACKGROUND: Children diagnosed with non-Hodgkin lymphoma (NHL) respond well to therapy resulting in relatively good prognosis. The exceptions are those who continue to have minimal residual disease (MRD). MRD NHL cells have been characterized as having increased mitochondrial DNA (mtDNA) copy numbers with increased expression of citrate synthase and isocitrate dehydrogenase. A proof-of-concept was designed to use small-interfering RNA (siRNA) as a tool to elucidate the relationship between citrate synthase and isocitrate dehydrogenase with cancer cell integrity. METHODS: mtDNA copy number and lactate dehydrogenase activities were assessed in chemotherapy-exposed residual NHL cells after introduction of siRNA against citrate synthase and/or isocitrate dehydrogenase expression. RESULTS: There was a significant decrease in lactate production in cells transfected with citrate synthase siRNA (p=0.02). Citrate synthase-silenced cells had decreased mtDNA copy numbers (p=0.03) compared to isocitrate dehydrogenase-silenced cells or combined citrate synthase- and isocitrate dehydrogenase-silenced cells. CONCLUSION: Inhibition of citrate synthase expression in siRNA-treated NHL cells resulted in decreased mtDNA copy numbers and lactate dehydrogenase expression. This observation needs further validation to determine the role of citrate synthase in mtDNA integrity and if citrate synthase siRNA could be a potential therapeutic modality in eradicating residual B-NHL cells.


Evolution of chloroplast J proteins.
Hsp70 chaperones are involved in multiple biological processes and are recruited to specific processes by designated J domain-containing cochaperones, or J proteins. To understand the evolution and functions of chloroplast Hsp70s and J proteins, we identified the Arabidopsis chloroplast J protein constituency using a combination of genomic and proteomic database searches and individual protein import assays. We show that Arabidopsis chloroplasts have at least 19 J proteins, the highest number of confirmed J proteins for any organelle. These 19 J proteins are classified into 11 clades, for which cyanobacteria and glaucophytes only have homologs for one clade, green algae have an additional three clades, and all the other 7 clades are specific to land plants. Each clade also possesses a clade-specific novel motif that is likely used to interact with different client proteins. Gene expression analyses indicate that most land plant-specific J proteins show highly variable expression in different tissues and are down regulated by low temperatures. These results show that duplication of chloroplast Hsp70 in land plants is accompanied by more than doubling of the number of its J protein cochaperones through adding new J proteins with novel motifs, not through duplications within existing families. These new J proteins likely recruit chloroplast Hsp70 to perform tissue specific functions related to biosynthesis rather than to stress resistance.


Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis.
To investigate which symptoms are indicative of preclinical dementia in general practice and whether subjects with preclinical dementia have an increased contact frequency with their general practitioner (GP). Individuals with preclinical dementia (n = 75) and non-demented controls (n = 125) were selected from the Dutch GP registration network (RNH). Number of visits and odds ratio for the risk of subsequent dementia of various symptoms were analysed. Analyses were done separately for each 12-month period, in the 5 years prior to the diagnosis of dementia. In the 5 years prior to diagnosis, subjects with preclinical dementia visited their GP more often than controls. Gait disturbances were the earliest predictor. Cognitive complaints were predictive for dementia in the 3 years before diagnosis. All other symptoms, except vascular symptoms, were predictive in the year prior to diagnosis. Sensitivity was highest for cognitive symptoms (0.58) and gait disturbances (0.47) in the year before diagnosis. Preclinical dementia is associated with an increased contact frequency between patient and GP at least 5 years prior to the diagnosis of dementia. Gait disturbances and cognitive complaints are the earliest symptoms of preclinical dementia.


Normal serum IgE levels and eosinophil counts exhibited during Strongyloides stercoralis infection.
Infections with parasites, such as Strongyloides stercoralis, typically cause elevated levels of serum immunoglobulin E (IgE) and eosinophils; however, co-infection with human T cell lymphotropic virus type 1 (HTLV-1) can cause lower levels of serum IgE during S. stercoralis infection. We conducted this study to determine whether serum IgE levels and eosinophil counts could also be related to other patient characteristics or symptoms. Between 1991 and 2014, we measured and compared the symptoms of 237 patients and evaluated serum IgE levels and eosinophil counts of 199 patients who were infected with S. stercoralis at the Ryukyu University Hospital and the Nishizaki Hospital. Medical records were reviewed and blood samples were taken before treatment with the anthelminthic, ivermectin, 2weeks following the first dosage, and 2weeks following the second dosage. Commonly reported symptoms included abdominal pain, diarrhea, and general fatigue. Serum IgE levels were found to be normal in patients co-infected with HTLV-1. Additionally, females and patients younger than 70years old exhibited normal serum IgE levels when infected with S. stercoralis. No factor included in our analysis was found to affect eosinophil counts. Serum IgE levels can remain within the normal range for some patients infected with S. stercoralis. Therefore, physicians should not eliminate S. stercoralis infection from the differential diagnosis solely according to findings of normal or low IgE levels.


Celsr1 adhesive interactions mediate the asymmetric organization of planar polarity complexes.
To orchestrate collective polarization across tissues, planar cell polarity (PCP) proteins localize asymmetrically to cell junctions, a conserved feature of PCP that requires the atypical cadherin Celsr1. We report that mouse Celsr1 engages in both trans- and cis-interactions, and organizes into dense and highly stable punctate assemblies. We provide evidence suggesting that PCP-mutant variant of Celsr1, Celsr1Crsh, selectively impairs lateral cis-interactions. Although Celsr1Crsh mediates cell adhesion in trans, it displays increased mobility, diminishes junctional enrichment, and fails to engage in homophilic adhesion with the wild-type protein, phenotypes that can be rescued by ectopic cis-dimerization. Using biochemical and super-resolution microscopy approaches, we show that although Celsr1Crsh physically interacts with PCP proteins Frizzled6 and Vangl2, it fails to organize these proteins into asymmetric junctional complexes. Our results suggest mammalian Celsr1 functions not only as a trans-adhesive homodimeric bridge, but also as an organizer of intercellular Frizzled6 and Vangl2 asymmetry through lateral, cis-interactions.


A systematic review and meta-analysis of the prevalence and complications of paraphenylenediamine-containing hair dye poisoning in developing countries.
Suicide is a public health problem, and the number of paraphenylenediamine (PPD)-containing hair dye poisoning with suicidal intentions is increasing in developing countries. In order to better understand this situation, we aimed to conduct a systematic review and meta-analysis to estimate the prevalence and complications associated with hair dye poisoning in developing countries. We conducted a systematic review of epidemiological studies using MeSh terms and text keywords to identify studies from the inception to March 2016 about hair dye poisoning with suicidal intentions in developing countries. A meta-analysis was used to calculate the pooled prevalence proportion of hair dye poisoning and its major complications. Data extraction, data analysis, and risk of bias assessment were performed. Thirty-two studies were included in the systematic review and 29 of these studies containing 5,559 subjects covering six countries were included in the meta-analysis. The pooled prevalence proportion of hair dye poisoning with suicidal intentions was 93.5% (95% confidence interval [CI] = 91.6-95.4) with a mortality rate of 14.5% (95% CI = 11.1-17.9). Of these, 73.8% were female, and 26.2% were male (sex ratio: 2.7:1). The occurrence of angioneurotic edema in hair poisoning patients was 67.1% (95% CI = 56.6-77.6), and tracheostomy intervention was considered in 47.9% (95% CI = 22.7-73.2) patients with respiratory distress. Acute renal failure was noticed in 54.7% (95% CI = 34.5-74.9) of the pooled samples and mortality rates were 14.5% (95% CI = 11.1-17.9). The pooled rate of the population studied from Asia and Africa showed 94.6% (95% CI = 92.5-96.7) and 82.9% (95% CI = 70.6-95.3), respectively, ingested hair dye with suicidal intentions. Further, studies carried out in Africa showed slightly higher mortality of 15.1% (95% CI = 6.56-23.7) than the Asians 14.3% (95% CI = 10.5-18.1). This meta-analysis provided clear evidence of the prevalence of hair dye poisoning among individuals with suicidal intentions and had given robust evidence for policy making to curtail emerging PPD-containing hair dye poisoning in developing countries.


Trends in hospital admission rates for whooping cough in England across five decades: database studies.
Our aim was to report on trends in hospitalisation rates for pertussis in England from the 1960s to 2011; and to provide context for the recent unexpected activity of Bordetella pertussis in the UK. A retrospective analysis of English national Hospital Episode Statistics (HES, 1968-2011) and the Oxford Record Linkage Study (ORLS, 1963-2011) for people admitted to hospital with whooping cough. England and the Oxford Record Linkage Study area. Age- and gender-specific hospital admission rates, and summary age- and sex-standardised rates, for people aged under 25 years per 100,000 population in each age group. Admission rates declined from the 1960s to the early 1970s. For example, the standardised rates were 12.8 (95% confidence interval 11.2-14.5) per 100,000 in England in 1968 and 4.0 (3.0-4.9) per 100,000 in 1973. They then increased to reach 45.0 (41.4-48.6) per 100,000 in 1978 and 47.4 (43.7-51.1) in 1982. From the late 1980s, admission rates continued to decline, falling to between 1 and 4 per 100,000 in each of the years between 2003 and 2011. While the trend in hospital admissions closely followed that in notifications, the annual ratio between these two measures was not consistent ranging from 1.07 (95% confidence interval 1.00-1.14) to 4.03 (3.79-4.27) notifications per admission over the last 10 years. Epidemics of whooping cough in the late 1970s and early 1980s were associated with a significant rise in hospital admission rates. Current admission rates are low, by historical comparison. Vaccine programmes must continue to be fully implemented in order to improve control of pertussis activity.


Targeting sequences of UBXD8 and AAM-B reveal that the ER has a direct role in the emergence and regression of lipid droplets.
Lipid droplets are sites of neutral lipid storage thought to be actively involved in lipid homeostasis. A popular model proposes that droplets are formed in the endoplasmic reticulum (ER) by a process that begins with the deposition of neutral lipids between the membrane bilayer. As the droplet grows, it becomes surrounded by a monolayer of phospholipid derived from the outer half of the ER membrane, which contains integral membrane proteins anchored by hydrophobic regions. This model predicts that for an integral droplet protein inserted into the outer half of the ER membrane to reach the forming droplet, it must migrate in the plane of the membrane to sites of lipid accumulation. Here, we report the results of experiments that directly test this hypothesis. Using two integral droplet proteins that contain unique hydrophobic targeting sequences (AAM-B and UBXD8), we present evidence that both proteins migrate from their site of insertion in the ER to droplets that are forming in response to fatty acid supplementation. Migration to droplets occurs even when further protein synthesis is inhibited or dominant-negative Sar1 blocks transport to the Golgi complex. Surprisingly, when droplets are induced to disappear from the cell, both proteins return to the ER as the level of neutral lipid declines. These data suggest that integral droplet proteins form from and regress to the ER as part of a cyclic process that does not involve traffic through the secretory pathway.


Generating an in vitro 3D cell culture model from zebrafish larvae for heart research.
We describe here a novel, fast and inexpensive method for producing a 3D 'heart' structure that forms spontaneously, in vitro, from larval zebrafish (ZF). We have named these 3D 'heart' structures 'zebrafish heart aggregate(s)' (ZFHAs) and have characterised their basic morphology and structural composition using histology, immunohistochemistry, electron microscopy and mass spectrometry. After 2 days in culture, the ZFHA spontaneously form and become a stable contractile syncytium consisting of cardiac tissue derived by in vitro maturation, which beats rhythmically and consistently for more than 8 days. We propose this model as a platform technology, which can be developed further to study in vitro cardiac maturation, regeneration, tissue engineering and safety pharmacological/toxicology testing.


BMCGM: A Behavior Economics-Based Message Transmission Cooperation Guarantee Mechanism in Vehicular Ad-hoc NETworks.
Vehicular Ad-hoc NETwork (VANET) is a special mobile ad hoc network that composed of facilities such as vehicle nodes and roadside units. Message transfer among vehicle nodes has been a great challenge due to the network's highly variable topology and the selfish nature of vehicle nodes. Thus, it is very necessary to propose a mechanism to improve the cooperation among vehicle nodes to guarantee the effective message transmission. Currently, incentive-based cooperation mechanisms are commonly used to encourage nodes to participate in message transmission. Those mechanisms are based on traditional economics and generally assume that the decision-making behavior of nodes is completely independent. Also, the cooperation of nodes depends on whether the cooperation behavior can obtain the higher utility. But researches in behavioral economics have shown that due to the existence of altruistic reciprocity, the behavior of nodes is affected by not only their utility but also the behavioral motives of other nodes, so as to obtain different results from traditional incentive-based mechanisms. Therefore, the paper introduces the reciprocal altruistic from behavioral economics and proposes the reciprocal altruistic factor to reconstruct the utility function of nodes. The reconstructed utility function reflects the interaction of behavioral motives among nodes, which promotes the node's cooperative behavior. Also, since the Network Formation Game (NFG) is a common mathematical model for studying the interaction and communication links formation among network nodes, hence the paper regards NFG in traditional economics as the research object. A Behavior Economics-based Message Transmission Cooperation Guarantee Mechanism named BMCGM is proposed, which motivates nodes to participate in the message transmission to reduce the transmission delay ratio. The simulation results show that the BMCGM reduces message transmission delay by at least 30.3% compared with the recent representative cooperation transmission mechanism.


Management of steroid-induced hyperglycemia in hospitalized patients with cancer: a review.
Glucocorticoids are prescribed for hospitalized patients with cancer for a variety of reasons, including cerebral edema, treatment and prevention of nausea, and as part of cancer treatment regimens. Glucocorticoids are known to cause hyperglycemia. The purpose of this study was to integrate the published research on the management and the effects of steroid-induced hyperglycemia in hospitalized adult patients with cancer with or without preexisting diabetes. MEDLINE®, PubMed, EMBASE, CINAHL®, and Scopus electronic databases were used to identify relevant articles. Bibliographies of included studies were reviewed for any pertinent studies that were not obtained through database search.Data Evaluation: 1,392 studies were identified. A total of 18 studies that met criteria were fully reviewed, 6 of which met all of the inclusion criteria. Data were abstracted from the included studies using a systematic code sheet to document characteristics of the studies and findings on management of hyperglycemia. Characteristics of the studies and findings on management of hyperglycemia were organized into three tables: the patients did not have preexisting diabetes, the patients had preexisting diabetes, and patients with or without preexisting diabetes were both included in the study. Management and effects of management of hyperglycemia were then compared and synthesized.Presentation of Findings: Hyperglycemia occurs in hospitalized patients with cancer irrespective of whether patients have a prior history of diabetes. Hyperglycemia resulting from steroids is treated in a variety of ways, but the resulting glycemic control has not been consistently documented. However, this review suggests that scheduled insulin (basal-bolus) is effective in attainment of glucose targets. Nurses should be aware of the effect that steroids have on glycemic control in patients and should be empowered to request or perform blood glucose monitoring when appropriate. Nurses can identify those patients receiving steroids and assess for signs and symptoms of hyperglycemia. They also can review routine laboratory results and assess for hyperglycemia in patients receiving steroids.


Modelling the vascular response to sympathetic postganglionic nerve activity.
This paper explores the influence of burst properties of the sympathetic nervous system on arterial contractility. Specifically, a mathematical model is constructed of the pathway from action potential generation in a sympathetic postganglionic neurone to contraction of an arterial smooth muscle cell. The differential equation model is a synthesis of models of the individual physiological processes, and is shown to be consistent with physiological data. The model is found to be unresponsive to tonic (regular) stimulation at typical frequencies recorded in sympathetic efferents. However, when stimulated at the same average frequency, but with repetitive respiratory-modulated burst patterns, it produces marked contractions. Moreover, the contractile force produced is found to be highly dependent on the number of spikes in each burst. In particular, when the model is driven by preganglionic spike trains recorded from wild-type and spontaneously hypertensive rats (which have increased spiking during each burst) the contractile force was found to be 10-fold greater in the hypertensive case. An explanation is provided in terms of the summative increased release of noradrenaline. Furthermore, the results suggest the marked effect that hypertensive spike trains had on smooth muscle cell tone can provide a significant contribution to the pathology of hypertension.


Supportive and nonsupportive family behaviors: relationships to adherence and metabolic control in persons with type I diabetes.
The Diabetes Family Behavior Checklist (DFBC) was administered to 54 adults and 18 adolescents (less than 19 yr of age) with insulin-dependent diabetes mellitus (IDDM). Subjects and family members completed parallel forms of the DFBC at initial and 6-mo follow-up home interviews. During each of these periods, adherence was assessed via self-report, 1 wk of self-monitoring, and 24-h dietary recalls. The results showed reliable differences between adolescents and adults. More negative interactions with family members were reported by adolescents and their family members, and adolescents were in poorer metabolic control. For adults but not adolescents, negative DFBC scores were prospectively predictive of poorer regimen adherence over the 6-mo interval for measures of glucose testing, insulin injection, and dietary adherence. In addition, higher negative DFBC scores for adults were marginally associated with higher HbA1 levels (P less than 0.10). We conclude that the DFBC is a promising measure of family interaction related specifically to the IDDM regimen and that, for adults, higher levels of nonsupportive family behaviors may be related to reduced regimen adherence and poor control.


Perineuronal net expression in the brain of a hibernating mammal.
During hibernation, mammals like the 13-lined ground squirrel cycle between physiological extremes. Most of the hibernation season is spent in bouts of torpor, where body temperature, heart rate, and cerebral blood flow are all very low. However, the ground squirrels periodically enter into interbout arousals (IBAs), where physiological parameters return to non-hibernating levels. During torpor, neurons in many brain regions shrink and become electrically quiescent, but reconnect and regain activity during IBA. Previous work showed evidence of extracellular matrix (ECM) changes occurring in the hypothalamus during hibernation that could be associated with this plasticity. Here, we examined expression of a specialized ECM structure, the perineuronal net (PNN), in the forebrain of ground squirrels in torpor, IBA, and summer (non-hibernating). PNNs are known to restrict plasticity, and could be important for retaining essential connections in the brain during hibernation. We found PNNs in three regions of the hypothalamus: ventrolateral hypothalamus, paraventricular nucleus (PVN), and anterior hypothalamic area. We also found PNNs throughout the cerebral cortex, amygdala, and lateral septum. The total area covered by PNNs within the PVN was significantly higher during IBA compared to non-hibernating and torpor (P < 0.01). Additionally, the amount of PNN coverage area per Nissl-stained neuron in the PVN was significantly higher in hibernation compared to non-hibernating (P < 0.05). No other significant differences were found across seasons. The PVN is involved in food intake and homeostasis, and PNNs found here could be essential for retaining vital life functions during hibernation.


Broadening the Biocatalytic Toolbox-Screening and Expression of New Unspecific Peroxygenases.
Unspecific peroxygenases (UPOs) catalyze the selective transfer of single oxygen atoms from peroxides to a broad range of substrates such as un-activated hydrocarbons. Since specific oxyfunctionalizations are among the most-desired reactions in synthetic chemistry, UPOs are of high industrial interest. To broaden the number of available enzymes, computational and experimental methods were combined in this study. After a comparative alignment and homology modelling, the enzymes were expressed directly in P. pastoris. Out of ten initially selected sequences, three enzymes (one from Aspergillus niger and two from Candolleomyces aberdarensis) were actively expressed. Cultivation of respective expression clones in a bioreactor led to production titers of up to 300 mg L-1. Enzymes were purified to near homogeneity and characterized regarding their specific activities and pH-optima for typical UPO substrates. This work demonstrated that directed evolution is not necessarily required to produce UPOs in P. pastoris at respective titers. The heterologous producibility of these three UPOs will expand the toolbox of available enzymes and help to advance their synthetic application.


Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.
Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10(-11)). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P = 7 x 10(-5)) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is approximately 16%. The overall evidence for association for these variants (P = 4.4 x 10(-14) combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance.


A synthetic consortium of 100 gut commensals modulates the composition and function in a colon model of the microbiome of elderly subjects.
Administration of cultured gut isolates holds promise for modulating the altered composition and function of the microbiota in older subjects, and for promoting their health. From among 692 initial isolates, we selected 100 gut commensal strains (MCC100) based on emulating the gut microbiota of healthy subjects, and retaining strain diversity within selected species. MCC100 susceptibility to seven antibiotics was determined, and their genomes were screened for virulence factor, antimicrobial resistance and bacteriocin genes. Supplementation of healthy and frail elderly microbiota types with the MCC100 in an in vitro colon model increased alpha-diversity, raised relative abundance of taxa including Blautia luti, Bacteroides fragilis, and Sutterella wadsworthensis; and introduced taxa such as Bifidobacterium spp. Microbiota changes correlated with higher levels of branched chain amino acids, which are health-associated in elderly. The study establishes that the MCC100 consortium can modulate older subjects' microbiota composition and associated metabolome in vitro, paving the way for pre-clinical and human trials.


Cytokinin-deficient transgenic Arabidopsis plants show multiple developmental alterations indicating opposite functions of cytokinins in the regulation of shoot and root meristem activity.
Cytokinins are hormones that regulate cell division and development. As a result of a lack of specific mutants and biochemical tools, it has not been possible to study the consequences of cytokinin deficiency. Cytokinin-deficient plants are expected to yield information about processes in which cytokinins are limiting and that, therefore, they might regulate. We have engineered transgenic Arabidopsis plants that overexpress individually six different members of the cytokinin oxidase/dehydrogenase (AtCKX) gene family and have undertaken a detailed phenotypic analysis. Transgenic plants had increased cytokinin breakdown (30 to 45% of wild-type cytokinin content) and reduced expression of the cytokinin reporter gene ARR5:GUS (beta-glucuronidase). Cytokinin deficiency resulted in diminished activity of the vegetative and floral shoot apical meristems and leaf primordia, indicating an absolute requirement for the hormone. By contrast, cytokinins are negative regulators of root growth and lateral root formation. We show that the increased growth of the primary root is linked to an enhanced meristematic cell number, suggesting that cytokinins control the exit of cells from the root meristem. Different AtCKX-green fluorescent protein fusion proteins were localized to the vacuoles or the endoplasmic reticulum and possibly to the extracellular space, indicating that subcellular compartmentation plays an important role in cytokinin biology. Analyses of promoter:GUS fusion genes showed differential expression of AtCKX genes during plant development, the activity being confined predominantly to zones of active growth. Our results are consistent with the hypothesis that cytokinins have central, but opposite, regulatory functions in root and shoot meristems and indicate that a fine-tuned control of catabolism plays an important role in ensuring the proper regulation of cytokinin functions.


Testing alleged mediumship: methods and results.
Mediums claim to be able to communicate with the deceased. Such claims attract a considerable amount of public interest and, if valid, have important implications for many areas of psychology. For over 100 years, researchers have tested alleged mediums. This work has obtained mixed results and provoked a considerable amount of methodological debate. This paper reviews the key issues in this debate, describes how the authors devised a method of testing that aimed to prevent the many problems that have hindered past research, and how they then used this method to test several professional mediums. The results of this work did not support the existence of genuine mediumistic ability. Competing interpretations of these results are discussed, along with ways in which the methodology presented in the paper could be used to assess conceptually similar, but non-paranormal, claims made in clinical, occupational and forensic contexts.


Differential Contribution of Subunit Interfaces to α9α10 Nicotinic Acetylcholine Receptor Function.
Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementary component of the adjacent subunit. Compared with neuronal nicotinic acetylcholine cholinergic receptors (nAChRs) assembled from α and β subunits, the α9α10 receptor is an atypical member of the family. It is a heteromeric receptor composed only of α subunits. Whereas mammalian α9 subunits can form functional homomeric α9 receptors, α10 subunits do not generate functional channels when expressed heterologously. Hence, it has been proposed that α10 might serve as a structural subunit, much like a β subunit of heteromeric nAChRs, providing only complementary components to the agonist binding site. Here, we have made use of site-directed mutagenesis to examine the contribution of subunit interface domains to α9α10 receptors by a combination of electrophysiological and radioligand binding studies. Characterization of receptors containing Y190T mutations revealed unexpectedly that both α9 and α10 subunits equally contribute to the principal components of the α9α10 nAChR. In addition, we have shown that the introduction of a W55T mutation impairs receptor binding and function in the rat α9 subunit but not in the α10 subunit, indicating that the contribution of α9 and α10 subunits to complementary components of the ligand-binding site is nonequivalent. We conclude that this asymmetry, which is supported by molecular docking studies, results from adaptive amino acid changes acquired only during the evolution of mammalian α10 subunits.


Giant dural venous sinus ectasia in neonates.
In this report, the authors describe 4 recent cases of posterior giant dural venous sinus ectasia in neonates diagnosed during pregnancy and encountered at 3 different institutions. Posterior giant venous sinus ectasia was diagnosed in 4 patients using antenatal ultrasonography and confirmed in 2 patients using prenatal MR imaging and in 3 patients using postnatal MR angiography. In 2 children angiography was performed at the age of 6 months. The pregnancy was terminated in 1 case, and the fetus underwent an autopsy. The 3 children who were born presented with various degree of cardiac insufficiency and were admitted to the intensive care unit after birth. Signs of increased intracranial pressure were present immediately after birth, including a bulging fontanel. No endovascular treatment was used in these cases. Surgery was performed in 2 cases as an attempt to alleviate increased intracranial pressure symptoms, without any real benefit. A slow venous flow in the ectasia was shown by ultrasonography in the case in which the pregnancy was terminated. Angiography or MR angiography did not show an obvious arteriovenous malformation in any of the cases, but an arteriovenous fistula secondary or contributing to the formation of the venous ectasia is one of the physiopathological hypotheses of the cause of this condition. Interestingly, spontaneous progressive thrombosis and regression of the intravascular component of the venous sinus ectasia was observed in all cases. The clinical outcome was acceptable in 1 child (who had a moderate handicap after the surgery) and good for the other 2 children (who had normal neurological development). Stratified thrombi of different ages are found in these giant venous ectasias and develop within the leaves of the dura close to the confluence of the major posterior venous sinuses. Therefore, it appears that the formation of a progressive thrombosis represents the normal evolution of these giant dural venous sinus ectasias, which explains the favorable outcome in some cases without specific surgical treatment, except for resuscitation techniques.


Production, optimisation and characterisation of angiotensin converting enzyme inhibitory peptides from sea cucumber (Stichopus japonicus) gonad.
In this study, production of bioactive peptides with angiotensin converting enzyme (ACE) inhibitory activity from sea cucumber (Stichopus japonicus) gonad using commercial protamex was optimised by response surface methodology (RSM). As a result, the optimal condition to achieve the highest ACE inhibitory activity in sea cucumber gonad hydrolysate (SCGH) was hydrolysis for 1.95 h and E/S of 0.75%. For further characterisation, three individual peptides (EIYR, LF and NAPHMR) were purified and identified. The peptide NAPHMR showed the highest ACE inhibitory activity with IC50 of 260.22 ± 3.71 μM. NAPHMR was stable against simulated gastrointestinal digestion and revealed no significant cytotoxicity toward Caco-2 cells. Molecular docking study suggested that Arg, His and Asn residues in NAPHMR interact with the S2 pocket or Zn2+ binding motifs of ACE via hydrogen or π-bonds, potentially contributing to ACE inhibitory effect. Sea cucumber gonad is thus a potential resource to produce ACE inhibitory peptides for preparation of functional foods.


Can video playback provide social information for foraging blue tits?
Video playback is becoming a common method for manipulating social stimuli in experiments. Parid tits are one of the most commonly studied groups of wild birds. However, it is not yet clear if tits respond to video playback or how their behavioural responses should be measured. Behaviours may also differ depending on what they observe demonstrators encountering. Here we present blue tits (Cyanistes caeruleus) videos of demonstrators discovering palatable or aversive prey (injected with bitter-tasting Bitrex) from coloured feeding cups. First we quantify variation in demonstrators' responses to the prey items: aversive prey provoked high rates of beak wiping and head shaking. We then show that focal blue tits respond differently to the presence of a demonstrator on a video screen, depending on whether demonstrators discover palatable or aversive prey. Focal birds faced the video screen more during aversive prey presentations, and made more head turns. Regardless of prey type, focal birds also hopped more frequently during the presence of a demonstrator (compared to a control video of a different coloured feeding cup in an empty cage). Finally, we tested if demonstrators' behaviour affected focal birds' food preferences by giving individuals a choice to forage from the same cup as a demonstrator, or from the cup in the control video. We found that only half of the individuals made their choice in accordance to social information in the videos, i.e., their foraging choices were not different from random. Individuals that chose in accordance with a demonstrator, however, made their choice faster than individuals that chose an alternative cup. Together, our results suggest that video playback can provide social cues to blue tits, but individuals vary greatly in how they use this information in their foraging decisions.


Predicting disease progression after regional therapy for in-transit melanoma.
Although approximately 30% to 50% of patients experience a complete response after regional chemotherapy for in-transit melanoma, a subset of patients will develop rapidly progressive disease. In the current era of an expanding armamentarium, including both regional and systemic options for treating advanced melanoma, identifying perioperative factors that predict disease progression may obviate unnecessary morbidity associated with regional therapy and avoid delays in systemic therapy. To identify patient-related clinical and pathological variables, as well as procedural factors, that correlate with disease progression. Using a prospectively maintained database, we identified patients who either underwent first-time melphalan-based isolated limb infusion (ILI) or first-time hyperthermic isolated limb perfusion (HILP) for in-transit melanoma. Response was defined using modified Response Evaluation Criteria in Solid Tumors for cutaneous disease at 3 months after treatment. Survival analyses were performed using the Kaplan-Meier method, with the differences in survival curves compared using a log-rank test. Potential preoperative and procedural predictors of in-field progressive disease were analyzed using logistic regression. Of the 258 patients included in the database, 215 were identified as having undergone first-time regional therapy. Of these 215 patients, 134 underwent ILI, and 81 underwent HILP. Regional therapy (ILI or HILP). Complete response or progressive disease. Of 134 patients who underwent ILI, 43 (32.1%) experienced in-field progressive disease. Of 81 patients who underwent HILP, 9 (11.1%) experienced in-field progressive disease. The median survival for patients with in-field progressive disease was 20.3 months for the ILI cohort and 15.0 months for the HILP cohort. In general, patients with progressive disease were younger, with advanced-stage melanoma and increased tumor burden. Compared with patients who experienced a complete response, patients with in-field progressive disease after ILI were younger (odds ratio, 1.06 [95% CI, 0.90-0.98]; P = .002). For patients who underwent HILP, no clinically relevant preoperative predictors of in-field progressive disease were identified. Procedural variables, including chemotherapeutic dosing, degree of acidosis or base deficit achieved, and peak temperature attained, were not predictors of in-field progressive disease after ILI or HILP. Patient, clinical, and procedural factors are unreliable predictors of in-field progressive disease after regional therapy in patients with in-transit melanoma. Defining the potential utility of molecular markers in predicting response or failure of regional therapy should be the focus of future research efforts.


Polymerization of tubulin in vivo: direct evidence for assembly onto microtubule ends and from centrosomes.
Microtubule assembly in vivo was studied by hapten-mediated immunocytochemistry. Tubulin was derivatized with dichlorotriazinylaminofluorescein (DTAF) and microinjected into living, interphase mammalian cells. Sites of incorporation were determined at the level of individual microtubules by double-label immunofluorescence. The haptenized tubulin was localized by an anti-fluorescein antibody and a second antibody conjugated with fluorescein. Total microtubules were identified by anti-tubulin and a secondary antibody conjugated with rhodamine. Contrary to recent studies (Salmon, E. D., et al., 1984, J. Cell Biol., 99:2165-2174; Saxton, W. M., et al., 1984, J. Cell Biol., 99:2175-2186) which suggest that tubulin incorporates all along the length of microtubules in vivo, we found that microtubule assembly in interphase cells was in vivo, as in vitro, an end-mediated process. Microtubules that radiated out toward the cell periphery incorporated the DTAF-tubulin solely at their distal, that is, their plus ends. We also found that a proportion of the microtubules connected to the centrosomes incorporated the DTAF-tubulin along their entire length, which suggests that the centrosome can nucleate the formation of new microtubules.


Plasticity and heterogeneity of lymphoid organs. What are the criteria to call a lymphoid organ primary, secondary or tertiary?
Lymphoid organs are generally classified in a hierarchy with primary lymphoid organs such as the thymus and bone marrow for the production of receptor specific T and B lymphocytes, respectively, independent of antigens. In secondary lymphoid organs such as lymph nodes, spleen, and tonsils, the lymphocytes are expanded due to antigen exposure, producing memory T cells and effector B cells, resulting in plasma cells. Tertiary lymphoid tissues are often defined as aggregations of lymphoid cells in autoimmune diseases. It will be outlined that all these organs have a high plasticity and also the thymic medulla is included in the route of migrating mature T cells and the bone marrow, not only in the traffic of CD4+ but also of CD8+ lymphocytes. The mucosa-associated lymphoid organs depend to a much larger extent on microbial antigen and are much more diverse than often described. The role of structural elements as well as blood and lymphatic vessels as an entry and exit site of lymphocytes will be outlined. Using a precise terminology, taking account of the plasticity of these organs at different ages and considering species differences will reduce misunderstandings among immunologists.


Comparison of two angles of approach for trigger point dry needling of the lumbar multifidus in human donors (cadavers).
Descriptive comparison study. To assess the accuracy of two needle angle approaches for dry needling of the lumbar multifidus. Low back pain is a leading cause of disability around the world; the lumbar multifidus plays a vital role in low back health. Manual therapy such as dry needling can improve pain mediation and motor control activation of the lumbar multifidus. Clinicians practicing dry needling at the lumbar multifidus typically use an inferomedial approach considered non-controversial. Clinicians practicing electromyography and nerve conduction studies commonly sample the lumbar multifidus in a directly posteroanterior approach that may provide another option for dry needling technique. Four human donors were used for a total of eight needle placements-four with an inferomedial orientation and four with a posteroanterior orientation. Each needle was placed from 1 to 1.5 cm lateral to the spinous process of L4 to the depth of the lumbar lamina. Each lower lumbar spine was then dissected to determine the structures that the needle traversed and the needle's final resting place. All four inferomedial approach needles ended at the lamina of the vertebrae below. All four posterior-anterior approach needles ended in the lamina of the same level. All eight needles traversed the lumbar multifidus and ended in the lumbar lamina with little possibility of the needle entering the subarachnoid space. Thus both the inferomedial and the posteroanterior angles of approach are efficacious for clinicians to use in dry needling of the lumbar mulifidus.


Child abuse and dentistry: what you should know.
Dentistry must become more aware of its moral, legal and ethical responsibilities in recognizing and reporting child abuse and neglect. All dental professionals must be aware of the seriousness of the problems of child maltreatment, and understand that children do not just get hurt in abuse and neglect, they often die as a direct result of their maltreatment. It has been said that victims of child abuse and neglect fall into only two categories--those who lived through it, and those who did not.


Binaural pitch fusion: Comparison of normal-hearing and hearing-impaired listeners.
Binaural pitch fusion is the fusion of dichotically presented tones that evoke different pitches between the ears. In normal-hearing (NH) listeners, the frequency range over which binaural pitch fusion occurs is usually <0.2 octaves. Recently, broad fusion ranges of 1-4 octaves were demonstrated in bimodal cochlear implant users. In the current study, it was hypothesized that hearing aid (HA) users would also exhibit broad fusion. Fusion ranges were measured in both NH and hearing-impaired (HI) listeners with hearing losses ranging from mild-moderate to severe-profound, and relationships of fusion range with demographic factors and with diplacusis were examined. Fusion ranges of NH and HI listeners averaged 0.17 ± 0.13 octaves and 1.7 ± 1.5 octaves, respectively. In HI listeners, fusion ranges were positively correlated with a principal component measure of the covarying factors of young age, early age of hearing loss onset, and long durations of hearing loss and HA use, but not with hearing threshold, amplification level, or diplacusis. In NH listeners, no correlations were observed with age, hearing threshold, or diplacusis. The association of broad fusion with early onset, long duration of hearing loss suggests a possible role of long-term experience with hearing loss and amplification in the development of broad fusion.


Both male and female identity influence variation in male signalling effort.
Male sexual displays play an important role in sexual selection by affecting reproductive success. However, for such displays to be useful for female mate choice, courtship should vary more among than within individual males. In this regard, a potentially important source of within male variation is adjustment of male courtship effort in response to female traits. Accordingly, we set out to dissect sources of variation in male courtship effort in a fish, the desert goby (Chlamydogobius eremius). We did so by designing an experiment that allowed simultaneous estimation of within and between male variation in courtship, while also assessing the importance of the males and females as sources of courtship variation. Although males adjusted their courtship depending on the identity of the female (a potentially important source of within-male variation), among-male differences were considerably greater. In addition, male courtship effort towards a pair of females was highly repeatable over a short time frame. Despite the plasticity in male courtship effort, courtship displays had the potential to reliably convey information about the male to mate-searching females. Our experiment therefore underscores the importance of addressing the different sources contributing to variation in the expression of sexually-selected traits.


Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility.
Creatine kinases are important in maintaining cellular-energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine-like compounds. Herein we examine whether ablation of the cytosolic brain-type creatine kinase (B-CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B-CK (B-CK-/-) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra- and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr left arrow over right arrow ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B-CK-/- animals showed diminished open-field habituation. In the water maze, adult B-CK-/- mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24-month-old, aged B-CK-/- mice, on top of the age-related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole-induced seizures (creating a high-energy demand) was observed in B-CK-/- mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho-creatine shuttle provides compensation for the loss of B-CK in the brain. Our studies indicate a role for the creatine-phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B-CK can be compensated for by other systems in the versatile and robust metabolic-energy network of the brain.


Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV) closely resembles lung cancer in sheep infected with JSRV.
Jaagsiekte sheep retrovirus (JSRV) causes a lethal lung cancer in sheep and goats. Expression of the JSRV envelope (Env) protein in mouse lung, by using a replication-defective adeno-associated virus type 6 (AAV6) vector, induces tumors resembling those seen in sheep. However, the mouse and sheep tumors have not been carefully compared to determine if Env expression alone in mice can account for the disease features observed in sheep, or whether additional aspects of virus replication in sheep are important, such as oncogene activation following retrovirus integration into the host cell genome. We have generated mouse monoclonal antibodies (Mab) against JSRV Env and have used these to study mouse and sheep lung tumor histology. These Mab detect Env expression in tumors in sheep infected with JSRV from around the world with high sensitivity and specificity. Mouse and sheep tumors consisted mainly of well-differentiated adenomatous foci with little histological evidence of anaplasia, but at long times after vector exposure some mouse tumors did have a more malignant appearance typical of adenocarcinoma. In addition to epithelial cell tumors, lungs of three of 29 sheep examined contained fibroblastic cell masses that expressed Env and appeared to be separate neoplasms. The Mab also stained nasal adenocarcinoma tissue from one United States sheep, which we show was due to expression of Env from ovine enzootic nasal tumor virus (ENTV), a virus closely related to JSRV. Systemic administration of the AAV6 vector encoding JSRV Env to mice produced numerous hepatocellular tumors, and some hemangiomas and hemangiosarcomas, showing that the Env protein can induce tumors in multiple cell types. Lung cancers induced by JSRV infection in sheep and by JSRV Env expression in mice have similar histologic features and are primarily characterized by adenomatous proliferation of peripheral lung epithelial cells. Thus it is unnecessary to invoke a role for insertional mutagenesis, gene activation, viral replication, or expression of other viral gene products in sheep lung tumorigenesis, although these processes may play a role in other clinically less important sequelae of JSRV infection such as metastasis observed with variable frequency in sheep.


Mycoplasma genitalium P140 and P110 cytadhesins are reciprocally stabilized and required for cell adhesion and terminal-organelle development.
Mycoplasma genitalium is a human pathogen that mediates cell adhesion by a complex structure known as the attachment organelle. This structure is composed of cytadhesins and cytadherence-associated proteins, but few data are available about the specific role of these proteins in M. genitalium cytadherence. We have deleted by homologous recombination the mg191 and mg192 genes from the MgPa operon encoding the P140 and P110 cytadhesins. Molecular characterization of these mutants has revealed a reciprocal posttranslational stabilization between the two proteins. Loss of either P140 or P110 yields a hemadsorption-negative phenotype and correlates with decreased or increased levels of cytoskeleton-related proteins MG386 and DnaK, respectively. Scanning electron microscopy analysis reveals the absolute requirement of P140 and P110 for the proper development of the attachment organelle. The phenotype described for these mutants resembles that of the spontaneous class I and class II cytadherence-negative mutants [G. R. Mernaugh, S. F. Dallo, S. C. Holt, and J. B. Baseman, Clin. Infect. Dis. 17(Suppl. 1):S69-S78, 1993], whose genetic basis remained undetermined until now. Complementation assays and sequencing analysis demonstrate that class I and class II mutants are the consequence of large deletions affecting the mg192 and mg191-mg192 genes, respectively. These deletions originated from single-recombination events involving sequences of the MgPa operon and the MgPa island located immediately downstream. We also demonstrate the translocation of MgPa sequences to a particular MgPa island by double-crossover events. Based on these observations, we propose that in addition to being a source of antigenic variation, MgPa islands could be also involved in a general phase variation mechanism switching on and off, in a reversible or irreversible way, the adhesion properties of M. genitalium.


Degradation of histamine by Bacillus polymyxa isolated from salted fish products.
Histamine is the causative agent of scombroid poisoning, a foodborne chemical hazard. Histamine is degraded by the oxidative deamination activity of certain microorganisms. In this study, eight histamine-degrading bacteria isolated from salted fish products were identified as Rummeliibacillus stabekisii (1 isolate), Agrobacterium tumefaciens (1 isolate), Bacillus cereus (2 isolates), Bacillus polymyxa (1 isolate), Bacillus licheniformis (1 isolate), Bacillus amyloliquefaciens (1 isolate), and Bacillus subtilis (1 isolate). Among them, B. polymyxa exhibited the highest activity in degrading histamine than the other isolates. The ranges of temperature, pH, and salt concentration for growth and histamine degradation of B. polymyxa were 25-37°C, pH 5-9, and 0.5-5% NaCl, respectively. B. polymyxa exhibited optimal growth and histamine-degrading activity at 30°C, pH 7, and 0.5% NaCl in histamine broth for 24 hours of incubation. The histamine-degrading isolate, B. polymyxa, might be used as a starter culture in inhibiting histamine accumulation during salted fish product fermentation.