Looking Under the Streetlight? A Framework for Differentiating Performance Measures by Level of Care in a Value-Based Payment Environment.
The majority of quality measures used to assess providers and hospitals are based on easily obtained data, focused on a few dimensions of quality, and developed mainly for primary/community care and population health. While this approach supports efforts focused on addressing the triple aim of health care, many current quality report cards and assessments do not reflect the breadth or complexity of many referral center practices.In this article, the authors highlight the differences between population health efforts and referral care and address issues related to value measurement and performance assessment. They discuss why measures may need to differ across the three levels of care (primary/community care, secondary care, complex care) and illustrate the need for further risk adjustment to eliminate referral bias.With continued movement toward value-based purchasing, performance measures and reimbursement schemes need to reflect the increased level of intensity required to provide complex care. The authors propose a framework to operationalize value measurement and payment for specialty care, and they make specific recommendations to improve performance measurement for complex patients. Implementing such a framework to differentiate performance measures by level of care involves coordinated efforts to change both policy and operational platforms. An essential component of this framework is a new model that defines the characteristics of patients who require complex care and standardizes metrics that incorporate those definitions.


Screening of myopic photorefractive keratectomy in eye bank eyes by computerized videokeratography.
In contrast to incisional keratotomy, corneas that have undergone photorefractive keratectomy may be difficult to detect by inspection with slitlamp biomicroscopy alone. Eye bank corneas that have undergone high myopic refractive surgical correction could potentially result in substantial postoperative hyperopic correction if used as donor tissue for corneal transplantation. Surface irregularities or displacement of the treated optical zone within the graft in relation to the entrance pupil of the recipient could result in significant induced astigmatism and distortion. This study examines computerized videokeratographic screening of eye bank globes as a strategy for detecting myopic photorefractive keratectomy. Preoperative and postoperative corneal topographic maps of freshly enucleated human and rabbit eyes that have undergone myopic photorefractive keratectomy with an excimer laser were placed in a globe-fixating device and analyzed using a vertically oriented videokeratoscope. The same system was applied in an actual eye bank setting, and potentially transplantable globes from donors without a history of corneal surgery were analyzed. Computerized videokeratography using a vertically mounted system reliably detected photorefractive keratectomy in 12 of 12 human eye bank corneas treated by excimer photorefractive keratectomy in a range between -1.5 to -6.0 diopters. This method also detected similar changes on lased rabbit corneas enucleated 6 weeks after excimer surgery. Data processed with the tangential mode yielded a "bull's-eye" topography pattern reflecting central corneal flattening that was more sensitive in detecting myopic corrections than the conventional axial formula-based color maps. False-positive results were not detected in 96 cadaver globes sequentially screened in the eye bank. Computerized videokeratography represents a feasible method to screen donor globes for myopic photorefractive keratectomy as shown by the in vitro and rabbit models. However, only whole globes and not corneoscleral sections are amenable to processing with this technique. Tangential maps provided greater sensitivity in detecting low myopic corrections than the axial formula-based color maps.


Toxicology of Physalia's (Portuguese man-o' war) venom.
The venomous pelagic coelentrate Physalia species (Blue bottle) or the Portuguese man-o'war has recently been studied in detail due to their hazardous effects on community. It was observed that the venom of the animal is lethal to man and can also produce cutaneous stings of varying severity. Physalia species also possess significant cardiotoxicity to man, rats, mice and are lethal to lower animals. Thu effect has been attributed to the abnormality in ionic transport across membranes. The cutaneous pain and musculotoxic action in human produced by Physalia venom may be induced by one or several high molecular weight polypeptides. Blockage of specified neurons and neuromuscular junction besides alteration in end plate potential (EPP) and end plate current (EPC) was also attributed to high molecular weight toxic fractions. Survey of enzymatic contents of Physalia venom reveals the presence of a wide variety of enzymes whose presence and actions were similar to that of complex enzyme mixture of snake venom. Besides these clinical manifestations neurotoxicity cytotoxicity and other physiopharmacological effects were also demonstrated.


The orthopedic gender gap: trends in authorship and editorial board representation over the past 4 decades.
The purpose of this study was to quantify the representation of women among the authors and editorial board members of prominent general orthopedics journals and to determine how these proportions have changed over time. Gender was determined for the authors of all original research studies, case reports, and review articles published in 2 prominent general orthopedics journals in 1970, 1980, 1990, 2000, and 2007. Gender was also determined for each individual serving on the editorial boards of these journals during these years. Between 1970 and 2007, the representation of women increased from 0.8% to 6.5% among first authors (P<.001), from 0.0% to 4.3% among last authors (P = .015), and from 1.6% to 5.4% among editorial board members (P = .16). However, the rates of increase observed in orthopedics were lower than those observed in other fields (P<.05). Between 1970 and 2007, female representation increased significantly among physicians publishing in 2 prominent general orthopedics journals, but these rates of increase were lower than those observed in other fields of medicine.


Rapid quantitation of magnetization transfer using pulsed off-resonance irradiation and echo planar imaging.
A technique for producing a quantitative measure of magnetization transfer parameters in a clinically feasible time scale is proposed. The combination of pulsed off-resonance irradiation and echo planar imaging has produced an imaging sequence that negates the need for continuous wave irradiation and allows the approach to steady-state conditions to be studied. Data analysis involves the step-by-step numerical solution of the modified Bloch equations to generate a quantitative model of the measured signal intensity based on the relative size of the bound proton pool and the bound proton pool transverse relaxation time. The sequence and model are applied to the study of a series of agar gels of varying concentrations and the results are compared to those from the literature.


Epigenetic control of retrotransposon expression in human embryonic stem cells.
Long interspersed element 1s (LINE-1s or L1s) are a family of non-long-terminal-repeat retrotransposons that predominate in the human genome. Active LINE-1 elements encode proteins required for their mobilization. L1-encoded proteins also act in trans to mobilize short interspersed elements (SINEs), such as Alu elements. L1 and Alu insertions have been implicated in many human diseases, and their retrotransposition provides an ongoing source of human genetic diversity. L1/Alu elements are expected to ensure their transmission to subsequent generations by retrotransposing in germ cells or during early embryonic development. Here, we determined that several subfamilies of Alu elements are expressed in undifferentiated human embryonic stem cells (hESCs) and that most expressed Alu elements are active elements. We also exploited expression from the L1 antisense promoter to map expressed elements in hESCs. Remarkably, we found that expressed Alu elements are enriched in the youngest subfamily, Y, and that expressed L1s are mostly located within genes, suggesting an epigenetic control of retrotransposon expression in hESCs. Together, these data suggest that distinct subsets of active L1/Alu elements are expressed in hESCs and that the degree of somatic mosaicism attributable to L1 insertions during early development may be higher than previously anticipated.


Development of Endoscopic Diagnosis and Treatment for Chronic Unilateral Hematuria: 35 Years Experience.
Chronic unilateral hematuria (CUH) is also called lateralizing essential hematuria, benign essential hematuria, and benign lateralizing hematuria, which was defined as intermittent or continuous gross hematuria that cannot be diagnosed with standard radiology and hematology studies, together with unilateral bloody efflux by cystoscopy. CUH is rare, but sometimes confused with malignancy or life-threatening hemorrhage. Therefore, it can cause considerable anxiety to not only patients but also urologists. For this study, we summarized articles about endoscopic diagnosis and treatment of CUH, and discussed the development of endourology for CUH. We searched articles related to CUH that were indexed in the PubMed database and published in English. Key terms used were "unilateral," "lateralizing," "chronic," "benign," and "idiopathic" hematuria. We found 15 pertinent articles reporting CUH. Endoscopically, CUH can be classified into three categories: discrete lesion, diffuse lesion, or no (unidentified) lesion. Currently, endoscopic techniques for CUH are similar to the techniques for upper tract urothelial carcinoma, using semi-rigid and flexible ureteroscopes with diathermy fulguration or laser ablation for treatment. The overall success rate of endoscopic treatment for CUH, defined as resolution of gross hematuria after treatment, was 93% (190/205). The recurrence rate, defined as recurrent gross hematuria after treatment, was 10% (19/189). Advancements in endoscopic devices and techniques have enabled more accurate and less invasive diagnosis and treatment of CUH. Once CUH is defined, flexible ureteroscopy is the diagnostic and therapeutic technique of choice.


Primary echinococcus infestation of the bone and muscles.
Hydatid diseases of the bone and muscles are rare, generally are incurable, and have a high level of recurrence. We attempted to ascertain whether the recurrence rate decreased in patients with hydatid disease infestation of the bone and skeletal muscle who were treated with current surgical techniques and antihelminthic chemotherapy, and whether the outcomes for bone infestation were different when compared with outcomes for muscular infestation. We retrospectively reviewed 15 patients with hydatid disease of the bone (eight patients) and muscle (seven patients). The average followup was 30 months (range, 6-69 months). Recurrence was observed in four patients with bone involvement. No patient with muscle involvement had a recurrence after excision. Hydatid disease of the bone often is recurrent and progressive despite using advanced diagnostic studies, improved surgical techniques, and newly developed antihelminthic drugs. The disease status also was not as good as for patients with bone lesions when compared with patients with muscular lesions.


The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes.
Dynamic interactions between components of the outer (OM) and inner (IM) membranes control a number of critical mitochondrial functions such as channeling of metabolites and coordinated fission and fusion. We identify here the mitochondrial AAA(+) ATPase protein ATAD3A specific to multicellular eukaryotes as a participant in these interactions. The N-terminal domain interacts with the OM. A central transmembrane segment (TMS) anchors the protein in the IM and positions the C-terminal AAA(+) ATPase domain in the matrix. Invalidation studies in Drosophila and in a human steroidogenic cell line showed that ATAD3A is required for normal cell growth and cholesterol channeling at contact sites. Using dominant-negative mutants, including a defective ATP-binding mutant and a truncated 50-amino-acid N-terminus mutant, we showed that ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. The capacity of ATAD3A to impact essential mitochondrial functions and organization suggests that it possesses unique properties in regulating mitochondrial dynamics and cellular functions in multicellular organisms.


A coarse-grained model for the simulations of biomolecular interactions in cellular environments.
The interactions of bio-molecules constitute the key steps of cellular functions. However, in vivo binding properties differ significantly from their in vitro measurements due to the heterogeneity of cellular environments. Here we introduce a coarse-grained model based on rigid-body representation to study how factors such as cellular crowding and membrane confinement affect molecular binding. The macroscopic parameters such as the equilibrium constant and the kinetic rate constant are calibrated by adjusting the microscopic coefficients used in the numerical simulations. By changing these model parameters that are experimentally approachable, we are able to study the kinetic and thermodynamic properties of molecular binding, as well as the effects caused by specific cellular environments. We investigate the volumetric effects of crowded intracellular space on bio-molecular diffusion and diffusion-limited reactions. Furthermore, the binding constants of membrane proteins are currently difficult to measure. We provide quantitative estimations about how the binding of membrane proteins deviates from soluble proteins under different degrees of membrane confinements. The simulation results provide biological insights to the functions of membrane receptors on cell surfaces. Overall, our studies establish a connection between the details of molecular interactions and the heterogeneity of cellular environments.


Induction of anti-DNA antibodies in non autoimmune mice by immunization with a DNA-DNAase I complex.
Recent studies suggest that anti-DNA antibodies may arise from the immune response to a complex of DNA and a DNA-binding protein. One of the protein targets frequently recognized by anti-DNA antibodies is the enzyme DNAase I. To investigate the possible role of DNAase I in the induction of anti-DNA antibodies, we immunized mice with a complex of DNA and DNAase I. Mammalian double strand DNA was crosslinked with DNAase I by ultraviolet light (UV) treatment and emulsified in complete Freund's adjuvant. BALB/c mice were immunized at the base of the tail with the DNA-DNAase complex, boosted after 2 weeks with the immunogen in incomplete adjuvant and bled one week after the boost. Control mice received UV treated DNA in adjuvant. In one-third of the mice immunized with the DNA-DNAase complex, IgG anti-DNA antibodies were detectable in serum; the antibodies reacted with single and double strand DNA. No anti-DNA response was elicited by immunization with DNA alone. These data show that immunization with a DNA-DNAase complex can induce anti-DNA antibodies in non-autoimmune mice strains and suggest that DNA-binding proteins may act as carriers in the immune response that leads to anti-DNA antibody production.


Analysis of factors affecting the accuracy, reproducibility, and interpretation of microbial community carbon source utilization patterns.
We determined factors that affect responses of bacterial isolates and model bacterial communities to the 95 carbon substrates in Biolog microtiter plates. For isolates and communities of three to six bacterial strains, substrate oxidation rates were typically nonlinear and were delayed by dilution of the inoculum. When inoculum density was controlled, patterns of positive and negative responses exhibited by microbial communities to each of the carbon sources were reproducible. Rates and extents of substrate oxidation by the communities were also reproducible but were not simply the sum of those exhibited by community members when tested separately. Replicates of the same model community clustered when analyzed by principal-components analysis (PCA), and model communities with different compositions were clearly separated on the first PCA axis, which accounted for >60% of the dataset variation. PCA discrimination among different model communities depended on the extent to which specific substrates were oxidized. However, the substrates interpreted by PCA to be most significant in distinguishing the communities changed with reading time, reflecting the nonlinearity of substrate oxidation rates. Although whole-community substrate utilization profiles were reproducible signatures for a given community, the extent of oxidation of specific substrates and the numbers or activities of microorganisms using those substrates in a given community were not correlated. Replicate soil samples varied significantly in the rate and extent of oxidation of seven tested substrates, suggesting microscale heterogeneity in composition of the soil microbial community.


Angiotensin II blockade before and after marked sodium depletion in patients with hypertension.
1. Angiotensin II blockade before and after marked sodium depletion in patients with hypertension [unilateral renovascular (eight), bilateral renovascular (four) and essential (four)] was performed by intravenous administration of the angiotensin II antagonist Sar1-Ala8-angiotensin II (saralasin). 2. On normal sodium intake, saralasin decreased mean blood pressure by 8 mmHg in the unilateral renovascular group, by 6 mmHg in the bilateral renovascular group and increased it by 3 mmHg in the essential hypertensive group. After sodium depletion saralasin decreased mean blood pressure by 33 mmHg, 35 mmHg and 18 mmHg respectively. The saralasin-induced decrease in blood pressure significantly correlated with the log of the initial plasma renin activity. 3. Saralasin infusion decreased effective renal plasma flow (ERPF) in all three hypertension subgroups, both on normal sodium intake and after sodium depletion. Glomerular filtration rate decreased in direct relation to the hypotensive effect of saralasin but ERPF showed this relationship only after sodium depletion. On normal sodium intake saralasin increased filtration fraction by 17%, but decreased it by 7% after sodium depletion. 4. It is concluded that the hypotensive action of saralasin closely correlates with the value of circulating plasma renin activity, apparently independent of the aetiology of the hypertension. The decrease in ERPF during saralasin infusion in the patients on normal sodium intake seems mainly related to the agonistic activity of saralasin, but that after sodium depletion to the hypotensive effect of saralasin.


Climate change mitigation: potential benefits and pitfalls of enhanced rock weathering in tropical agriculture.
Restricting future global temperature increase to 2°C or less requires the adoption of negative emissions technologies for carbon capture and storage. We review the potential for deployment of enhanced weathering (EW), via the application of crushed reactive silicate rocks (such as basalt), on over 680 million hectares of tropical agricultural and tree plantations to offset fossil fuel CO2 emissions. Warm tropical climates and productive crops will substantially enhance weathering rates, with potential co-benefits including decreased soil acidification and increased phosphorus supply promoting higher crop yields sparing forest for conservation, and reduced cultural eutrophication. Potential pitfalls include the impacts of mining operations on deforestation, producing the energy to crush and transport silicates and the erosion of silicates into rivers and coral reefs that increases inorganic turbidity, sedimentation and pH, with unknown impacts for biodiversity. We identify nine priority research areas for untapping the potential of EW in the tropics, including effectiveness of tropical agriculture at EW for major crops in relation to particle sizes and soil types, impacts on human health, and effects on farmland, adjacent forest and stream-water biodiversity.


Impact of violence against women on severe acute maternal morbidity in the intensive care unit, including neonatal outcomes: a case-control study protocol in a tertiary healthcare facility in Lima, Peru.
Preventing and reducing violence against women (VAW) and maternal mortality are Sustainable Development Goals. Worldwide, the maternal mortality ratio has fallen about 44% in the last 25 years, and for one maternal death there are many women affected by severe acute maternal morbidity (SAMM) requiring management in the intensive care unit (ICU). These women represent the most critically ill obstetric patients of the maternal morbidity spectrum and should be studied to complement the review of maternal mortality. VAW has been associated with all-cause maternal deaths, and since many women (30%) endure violence usually exerted by their intimate partners and this abuse can be severe during pregnancy, it is important to determine whether it impacts SAMM. Thus, this study aims to investigate the impact of VAW on SAMM in the ICU. This will be a prospective case-control study undertaken in a tertiary healthcare facility in Lima-Peru, with a sample size of 109 cases (obstetric patients admitted to the ICU) and 109 controls (obstetric patients not admitted to the ICU selected by systematic random sampling). Data on social determinants, medical and obstetric characteristics, VAW, pregnancy and neonatal outcome will be collected through interviews and by extracting information from the medical records using a pretested form. Main outcome will be VAW rate and neonatal mortality rate between cases and controls. VAW will be assessed by using the WHO instrument. Binary logistic followed by stepwise multivariate regression and goodness of fit test will assess any association between VAW and SAMM. Ethical approval has been granted by the La Trobe University, Melbourne-Australia and the tertiary healthcare facility in Lima-Peru. This research follows the WHO ethical and safety recommendations for research on VAW. Findings will be presented at conferences and published in peer-reviewed journals.


In vitro antimicrobial potential of infant mouthwashes against streptococcus mutans biofilm: A preliminary study.
Children and teenagers accumulate dental plaque easily due to immature motor coordination present at this specific age. Thus, chemical solutions such as mouthwashes are used for biofilm control. The widespread use of mouthwash could potentially change the oral environment though there is no evidence of its effects on the biofilm. The present study aimed to investigate the in vitro antimicrobial potential of infant mouthwashes on mature Streptococcus mutans biofilm. The susceptibility of S. mutans biofilm UA 159 (ATCC700610) to infant mouthwashes was tested with childrens mouthwashes containing the following active agents: G1-cetylpyridinium chloride, G2-xylitol and triclosan and G3-Malva sylvestris and xylitol. Phosphage-buffered saline (PBS) was used at the negative control (G4). In this study, cariogenic biofilm was exposed once a day for one minute to the mouthwashes over a period of five days. Following this, an aliquot of each mouthwash used was seeded in brain heart infusion (BHI) agar and then incubated at 37°C, 5% CO2 for 48 h. The results were expressed as colony-forming units (CFU) and converted into log10. The results were submitted to ANOVA and Tukey's test at 5%. It was observed 7.75, 7.66, and 7.49 CFUlog10 values to G1, G2, and G3, respectively, with 9.53 CFUlog10 value to G4. Accordingly, all studied mouthwashes showed no significant statistical difference between them but with statistically significant bacterial reduction in comparison to control group. Infant mouthwashes presented a highly significant antimicrobial effect on cariogenic biofilm in an in vitro model, which raises concern when used by a young population.


An evaluation of the PowerSeq™ Auto System: A multiplex short tandem repeat marker kit compatible with massively parallel sequencing.
Capillary electrophoresis (CE) and multiplex amplification with fluorescent tagging have been routinely used for STR typing in forensic genetics. However, CE-based methods restrict the number of markers that can be multiplexed simultaneously and cannot detect any intra-repeat variations within STRs. Several studies already have indicated that massively parallel sequencing (MPS) may be another potential technology for STR typing. In this study, the prototype PowerSeq(™) Auto System (Promega) containing the 23 STR loci and amelogenin was evaluated using Illumina MiSeq. Results showed that single source complete profiles could be obtained using as little as 62 pg of input DNA. The reproducibility study showed that the profiles generated were consistent among multiple typing experiments for a given individual. The mixture study indicated that partial STR profiles of the minor contributor could be detected up to 19:1 mixture. The mock forensic casework study showed that full or partial profiles could be obtained from different types of single source and mixture samples. These studies indicate that the PowerSeq Auto System and the Illumina MiSeq can generate concordant results with current CE-based methods. In addition, MPS-based systems can facilitate mixture deconvolution with the detection of intra-repeat variations within length-based STR alleles.


Prevalence of severe ADHD: an epidemiological study in the Italian regions of Tuscany and Latium.
The rate with which attention deficit/hyperactivity disorder (ADHD) is diagnosed varies widely across countries, suggesting that cultural factors influence the clinical interpretation of child behaviour. This study estimated the point prevalence of severe ADHD among elementary and middle-school Italian children. An epidemiological sample of 2016 children attending 2nd-8th grade in the Italian regions of Tuscany and Latium was selected based on census distribution of the school-age population. Teachers completed the Italian version of the ADHD Rating Scale for Teachers (SDAI). For children with at least six inattention symptoms and/or at least six hyperactivity/impulsivity symptoms rated 'very often' by the teachers, the parents completed the Italian ADHD Rating Scale for Parents (SDAG). Children with documented ADHD symptoms at both school and home received a complete psychiatric interview with the Kiddie Schedule for Affective Disorders and Schizophrenia-present and lifetime version (K-SADS-PL). Of the 1887 assessed children, 4.45% (95% CI 3.58-5.51) met the ADHD cut-off on teacher ratings, 1.43% (0.96-2.12) had ADHD symptoms endorsed by both teacher and parent, and 1.32% (0.87-1.97) were further confirmed by the psychiatric evaluation. The male:female ratio was 7:1. The inattentive type accounted for about half of the ADHD cases. When applying stringent criteria for both severity and pervasiveness of symptoms, it is estimated that about 1.3% of the Italian elementary and middle-school children suffer from severe ADHD.


Mpox outbreak in France: epidemiological characteristics and sexual behaviour of cases aged 15 years or older, 2022.
BackgroundLocally-acquired mpox cases were rarely reported outside Africa until May 2022, when locally-acquired-mpox cases occurred in various European countries.AimWe describe the mpox epidemic in France, including demographic and behavioural changes among a subset of cases, during its course.MethodsData were retrieved from the enhanced national surveillance system until 30 September 2022. Laboratory-confirmed cases tested positive for monkeypox virus or orthopoxviruses by PCR; non-laboratory-confirmed cases had clinical symptoms and an epidemiological link to a laboratory-confirmed case. A subset of ≥ 15-year-old male cases, notified until 1 August, was interviewed for epidemiological, clinical and sexual behaviour information. Association of symptom-onset month with quantitative outcomes was evaluated by t- or Wilcoxon tests, and with binary outcomes, by Pearson's chi-squared or Fisher exact tests.ResultsA total of 4,856 mpox cases were notified, mostly in Île-de-France region (62%; 3,025/4,855). Cases aged ≥ 15 years were predominantly male (97%; 4,668/4,812), with 37 years (range: 15-81) as mean age. Between May and July, among the subset interviewed, mpox cases increased in regions other than Île-de-France, and mean age rose from 35 (range: 21-64) to 38 years (range: 16-75; p = 0.007). Proportions of cases attending men-who-have-sex-with-men (MSM) meeting venues declined from 60% (55/91) to 46% (164/359; p = 0.012); median number of sexual partners decreased from four (interquartile range (IQR): 1-10) to two (IQR: 1-4; p < 0.001).ConclusionChanges in cases' characteristics during the epidemic, could reflect virus spread from people who were more to less behaviourally vulnerable to mpox between May and July, or MSM reducing numbers of sexual partners as recommended.


Dissemination of behavioural activation for depression to mental health nurses: training evaluation and benchmarked clinical outcomes.
Depression causes significant distress, disability and cost within the UK. Behavioural activation (BA) is an effective single-strand psychological approach which may lend itself to brief training programmes for a wide range of clinical staff. No previous research has directly examined outcomes of such dissemination. A 5-day training course for 10 primary care mental health workers aiming to increase knowledge and clinical skills in BA was evaluated using the Training Acceptability Rating Scale. Depression symptom level data collected in a randomized controlled trial using trainees were then compared to results from meta-analysis of studies using experienced therapists. BA training was highly acceptable to trainees (94.4%, SD 6%). The combined effect size of BA was unchanged by the addition of the results of this evaluation to those of studies using specialist therapists. BA offers a promising psychological intervention for depression that appears suitable for delivery by mental health nurses following brief training.


Two formulations of epoprostenol sodium in the treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection in pulmonary arterial hypertension), a phase IV, open-label, randomized study.
Epoprostenol sodium with arginine-mannitol excipients (epoprostenol AM; Veletri [Actelion Pharmaceuticals Ltd, Allschwil, Switzerland]) and epoprostenol sodium with glycine-mannitol excipients (epoprostenol GM; Flolan [GlaxoSmithKline, Triangle Park, NC]) are intravenous treatments for pulmonary arterial hypertension (PAH). Epoprostenol AM contains different inactive excipients, resulting in greater stability at room temperature compared with epoprostenol GM. In this prospective, multicenter, open-label, randomized, phase IV exploratory study, epoprostenol-naïve patients in need of injectable prostanoid therapy were randomized 2:1 to open-label epoprostenol AM or epoprostenol GM. The study period was 28 days, followed by a 30-day safety follow-up. Study aims were to descriptively compare the safety, tolerability, drug metabolite levels, and treatment effects of epoprostenol AM and epoprostenol GM in PAH. Statistical analysis was descriptive only because of the exploratory nature of the study. Thirty patients with PAH (18-70 years, 24 women, 20 idiopathic PAH) were randomized to epoprostenol AM (n = 20) or epoprostenol GM (n = 10). Most frequently reported adverse events included jaw pain, headache, nausea, and flushing. Two deaths occurred during the study period, and 1 death occurred during the 30-day safety follow-up period, all in patients receiving epoprostenol AM. All deaths were classified by the treating physician as unrelated to epoprostenol AM. The median (range) change from baseline to day 28 in 6-minute walk distance was 36 m (-127 to 210 m) and 49 m (-44 to 110 m) for the epoprostenol AM and epoprostenol GM groups, respectively. In this randomized clinical study of epoprostenol AM in PAH, use of this novel preparation with greater room temperature stability was well tolerated.


An abrupt climate event in a coupled ocean-atmosphere simulation without external forcing.
Temperature reconstructions from the North Atlantic region indicate frequent abrupt and severe climate fluctuations during the last glacial and Holocene periods. The driving forces for these events are unclear and coupled atmosphere-ocean models of global circulation have only simulated such events by inserting large amounts of fresh water into the northern North Atlantic Ocean. Here we report a drastic cooling event in a 15,000-yr simulation of global circulation with present-day climate conditions without the use of such external forcing. In our simulation, the annual average surface temperature near southern Greenland spontaneously fell 6-10 standard deviations below its mean value for a period of 30-40 yr. The event was triggered by a persistent northwesterly wind that transported large amounts of buoyant cold and fresh water into the northern North Atlantic Ocean. Oceanic convection shut down in response to this flow, concentrating the entire cooling of the northern North Atlantic by the colder atmosphere in the uppermost ocean layer. Given the similarity between our simulation and observed records of rapid cooling events, our results indicate that internal atmospheric variability alone could have generated the extreme climate disruptions in this region.


The changing gender ratio in occurrence of deliberate self-harm across the lifecycle.
Overall gender ratios are often quoted in studies of deliberate self-harm (DSH) patients, almost always with higher rates in females than males. Reporting a ratio across all ages may conceal important variations in the gender ratio across the life cycle. Analysis was done of the gender ratio by age groups in rates of DSH in a consecutive sample of DSH patients presenting to a general hospital over a 10-year period. The patients were identified through a well-established monitoring system. The study sample included 2,189 female and 1,439 male patients. While the overall gender rate ratio was 1.5 females to each male, the ratio varied considerably by age group: 8:1 in 10-14-year-olds, 3.1:1 in 15-19-year-olds, 1.6:1 in 20-24-year-olds, approximately 1.3:1 in 25-49-year-olds, and 0.8:1 in people aged 50 years and over. Statements about overall gender ratios for DSH conceal important changes in the ratio across the life cycle. These changes probably reflect differences in development and problems faced in adolescence, changes in motivation for DSH with age, and the closer resemblance of DSH to suicide in older age groups.


Early changes in intervention coverage and mortality rates following the implementation of an integrated health system intervention in Madagascar.
The Sustainable Development Goals framed an unprecedented commitment to achieve global convergence in child and maternal mortality rates through 2030. To meet those targets, essential health services must be scaled via integration with strengthened health systems. This is especially urgent in Madagascar, the country with the lowest level of financing for health in the world. Here, we present an interim evaluation of the first 2 years of a district-level health system strengthening (HSS) initiative in rural Madagascar, using estimates of intervention coverage and mortality rates from a district-wide longitudinal cohort. We carried out a district representative household survey at baseline of the HSS intervention in over 1500 households in Ifanadiana district. The first follow-up was after the first 2 years of the initiative. For each survey, we estimated maternal, newborn and child health (MNCH) coverage, healthcare inequalities and child mortality rates both in the initial intervention catchment area and in the rest of the district. We evaluated changes between the two areas through difference-in-differences analyses. We estimated annual changes in health centre per capita utilisation from 2013 to 2016. The intervention was associated with 19.1% and 36.4% decreases in under-five and neonatal mortality, respectively, although these were not statistically significant. The composite coverage index (a summary measure of MNCH coverage) increased by 30.1%, with a notable 63% increase in deliveries in health facilities. Improvements in coverage were substantially larger in the HSS catchment area and led to an overall reduction in healthcare inequalities. Health centre utilisation rates in the catchment tripled for most types of care during the study period. At the earliest stages of an HSS intervention, the rapid improvements observed for Ifanadiana add to preliminary evidence supporting the untapped and poorly understood potential of integrated HSS interventions on population health.


Transgenic quail as a model for research in the avian nervous system: a comparative study of the auditory brainstem.
Research performed on transgenic animals has led to numerous advances in biological research. However, using traditional retroviral methods to generate transgenic avian research models has proved problematic. As a result, experiments aimed at genetic manipulations on birds have remained difficult for this popular research tool. Recently, lentiviral methods have allowed the production of transgenic birds, including a transgenic Japanese quail (Coturnix coturnix japonica) line showing neuronal specificity and stable expression of enhanced green fluorescent protein (eGFP) across generations (termed here GFP quail). To test whether the GFP quail may serve as a viable alternative to the popular chicken model system, with the additional benefit of genetic manipulation, we compared the development, organization, structure, and function of a specific neuronal circuit in chicken (Gallus gallus domesticus) with that of the GFP quail. This study focuses on a well-defined avian brain region, the principal nuclei of the sound localization circuit in the auditory brainstem, nucleus magnocellularis (NM), and nucleus laminaris (NL). Our results demonstrate that structural and functional properties of NM and NL neurons in the GFP quail, as well as their dynamic properties in response to changes in the environment, are nearly identical to those in chickens. These similarities demonstrate that the GFP quail, as well as other transgenic quail lines, can serve as an attractive avian model system, with the advantage of being able to build on the wealth of information already available from the chicken.


Nephrotic livers secrete normal VLDL that acquire structural and functional defects following interaction with HDL.
Binding of very low-density lipoprotein (VLDL) isolated from serum of nephrotic rats VLDL to endothelial cells is defective. This defect is conferred on normal VLDL by prior incubation with high-density lipoprotein (HDL) from nephrotic, but not control rats. It is not known whether the defect is present in nascent VLDL (nVLDL) or is acquired after secretion. We test the hypothesis that VLDL is normal at the time of secretion from the liver and the defect in binding to endothelium is conferred following secretion through interaction with HDL. nVLDL was synthesized by and collected from isolated perfused livers from either control or nephrotic rats. nVLDL was labeled with 3H-oleate to measure binding and 35S methionine to evaluate apolipoprotein exchange and composition. To test whether HDL conferred a binding defect, nVLDL was incubated with HDL obtained either from control or nephrotic rats prior to measurement of binding. To distinguish the effects of proteinuria from reduced albumin concentration we additionally incubated nVLDL with HDL obtained from rats with hereditary analbuminemia. Both HDL and VLDL were reisolated by centrifugation prior to subsequent binding and lipolysis determination. Exchange of 35S-labeled apolipoprotein E (apoE) among the subsequent VLDL and HDL fractions was determined. To determine the effect of HDL on lipolysis, HDL-treated VLDL was exposed to lipoprotein lipase-coated 96-well plates and 3H-oleate release measured. To establish whether differences in apoE content could explain the differences in binding and lipolysis, apoE was restored to nephrotic VLDL and lipolysis and binding were subsequently measured. Binding of nephrotic nVLDL was greater than control nVLDL (0.58 +/- 0.13 vs. 0.75 +/- 0.07 ng protein bound/mg cell protein) (P= 0.04, N= 6). Lipolysis was similarly elevated (0.091 +/- 0.010 vs 0.064 +/- 0.002 nmol NEFA released/well/hour) (P < 0.05). Prior incubation with nephrotic HDL reduced binding of nVLDL obtained from either nephrotic or control livers (P= 0.02, N= 6). Treatment with nephrotic (vs. control) HDL reduced both binding (control nVLDL + control HDL, 0.64 +/- 0.02; control + nephrotic, 0.43 +/- 0.06; nephrotic + control, 0.69 +/- 0.05; and nephrotic + nephrotic, 0.62 +/- 0.04 mg VLDL protein/mg cell protein) and lipolysis (control nVLDL + control HDL, 0.053 +/- 0.004; control + nephrotic, 0.038 +/- 0.004; nephrotic + control, 0.069 +/- 0.004; and nephrotic + nephrotic, 0.062 +/- 0.004 nmol NEFA/well/hour) (P < 0.05 vs. nVLDL + control HDL) of nVLDL from either source. The apoE content of nVLDL coincubated with control HDL or analbuminemic HDL was increased compared nVLDL incubated with either no HDL or nephrotic HDL (P < 0.05). Similarly, the apoE/apoA-I ratio was reduced in HDL from nephrotic rats but not in HDL from controls (P < 0.05). Reintroduction of apoE to nephrotic VLDL resulted in increased binding. Unlike circulating VLDL, binding of nVLDL from isolated livers from nephrotic rats to endothelial cells is greater and its lipolysis is increased compared to control nVLDL. Decreased binding and lipolysis is conferred following incubation with HDL isolated from control, but not nephrotic rats and binding can be restored by reintroduction of apoE. Thus both defects are conferred on VLDL by exposure to HDL obtained from nephrotic animals, possibly a consequence of a failure of nephrotic HDL to enrich VLDL with apoE during clearance.


Common infections with polyomaviruses and herpesviruses and neuropsychological development at 4 years of age, the Rhea birth cohort in Crete, Greece.
Viral infections of the central nervous system may have detrimental effects for the developing brain, but the effects of less virulent common infections are unclear. We aim to investigate the impact of common viral infections of early childhood on neuropsychological performance of children at age four. We used cross-sectional data on 674 children participating at the 4 years of age follow-up of the Rhea birth cohort in Crete, Greece. Blood levels of IgG antibodies to 10 polyomaviruses (BKPyV, JCPyV, KIPyV, WUPyV, HPyV6, HPyV7, TSPyV, MCPyV, HPyV9, and HPyV10) and four herpesviruses [Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus-1 (HSV-1), and herpes simplex virus-2 (HSV-2)] were measured using multiplex serology. Child's neuropsychological development at age four was assessed using the McCarthy Scales of Children's Abilities, the Attention-Deficit Hyperactivity Disorder Test (ADHDT), and the Strengths and Difficulties Questionnaire (SDQ). Multiple linear regression models were used to explore the associations. Seroprevalence to polyomaviruses ranged from 21% for HPyV9 to 82% for HPyV10. Seroprevalence for EBV was 53%, for CMV 26%, for HSV-1 3.6%, and for HSV-2 1.5%. Children seropositive to ≥8 polyomaviruses had lower score in ADHDT inattention subscale [β = -1.28 (95% CI: -2.56, -0.001)] and lower score in SDQ hyperactivity-inattention subscale [β = -.99 (95% CI: -1.60, -0.37)] versus children seropositive to ≤3 polyomaviruses. Seropositivity to BKPyV, a potential neurotropic virus, was associated with higher score in ADHDT inattention subscale [β = .87 (95% CI: 0.03, 1.71)]. These findings suggest that acquisition of polyomaviruses during development may influence behavioral outcomes in early childhood.


Antiulcer activity of methanol-chloroform extract of Channa striatus fillet.
Channa striatus (Haruan) is Malaysian freshwater fish that is traditionally used to treat ailments related to wound and also ulcers. The aimed of the present study was to determine the mechanisms of anti-ulcer activity of chloroform: methanol extract of C. striatus fillet (CMCS) in rats. The antiulcer profile of CMCS, given orally in the doses of 50, 250 and 500mg/kg, was assessed using the ethanol- and indomethacin-induced gastric ulcer models. The mechanisms of antiulcer of CMCS were determined as follows; i) the antisecretory activity of CMCS was measured using the pyloric ligation rat model, and; ii) the role of nitric oxide (NO) and sulfhydryl compounds in the modulation of CMCS antiulcer activity were determined by pre-treating the rats with L-NAME or NEM, respectively, followed by the pre-treatment of rats with CMCS before subjecting the animals to the ethanol-induced gastric ulcer model. From the results obtained, CMCS exerted significant (P<0.05) antiulcer activity in both models of gastric ulcer wherein the macroscopic and microscopic analysis of the stomach supported the antiulcer claim. With regard to its antisecretory effect, CMCS did not change the volume and pH, but reduce the total acidity only at the lower doses of the gastric juice. Moreover, CMCS demonstrated antiulcer activity was reversed by NEM, but not affected by L-NAME. In conclusion, CMCS shows antiulcer activity that is modulated via its cytoprotective, but not antisecretory effect, and in the presence of sulfhysryl compounds, but not NO.


Major side effects of antipsychotic drugs.
Since the introduction of phenothiazines into clinical practice in 1952, over 250 million people have received these drugs for the treatment of psychotic states. In addition to the phenothiazines, five other classes of neuroleptic medications are now in use: butyrophenones, thioxanthenes, dihydroindolones, diphenylbutylpiperidines, and dibenzoxazepines. Besides their use in the treatment of psychosis, these drugs have been used in the treatment of anxiety, depression, nausea, alcoholic withdrawal, and pain, and are often administered in combination with other medications. Through the use of these drugs, many psychotic patients have been able to move back into the community, and the family physician is coming into contact with more patients on maintenance dosages of neuroleptics. He/she may wish to prescribe these drugs or may, in the treatment of a medical problem, need to prescribe other medication to an individual already receiving neuroleptics. It is important, therefore, for the family physician to be aware of the side effects of these drugs and of complications which can arise when neuroleptics are given in combination with other families of drugs.


Immunohistochemical localization of transforming growth factor-beta 1, -beta 2, and -beta 3 latency-associated peptide in human cornea.
To study spatial distribution of TGF-beta isoforms (TGF-beta 1, -beta 2, and -beta 3) in the human cornea and to elucidate their biologic roles in corneal maintenance. Frozen sections obtained from eight human autopsy eyes were placed on gelatin-coated slides. After blocking of nonspecific binding sites, the slides were incubated with rabbit polyclonal antibody to the latency-associated peptide (LAP) region of human TGF-beta 1, TGF-beta 2, and TGF-beta 3 precursors, followed by the incubation with biotinylated swine anti-rabbit IgG. Subsequently, a streptavidin-labeled alkaline phosphatase technique was used. In the corneal region, beta 1-LAP antibody did not stain either epithelium or stroma, beta 2-LAP antibody stained all epithelial cell layers and the corneal stroma, and beta 3-LAP antibody stained the subepithelial region alone. The staining pattern in the limbal region was almost the same as in the corneal region, except in the limbal stroma, which was stained with beta 1-LAP antibody in three of eight samples. In the trabecular meshwork, all samples showed clear staining with beta 2-LAP antibody, whereas beta 1-LAP and beta 2-LAP antibody stained faintly in five of eight and four of eight samples, respectively. beta 2-LAP was found in the corneal epithelium and stroma and beta 3-LAP in the subepithelial region, suggesting that TGF-beta 2 and TGF-beta 3 may play essential roles in normal corneal epithelial maintenance in vivo.


Effects of increasing levothyroxine on pregnancy outcomes in women with uncontrolled hypothyroidism.
Uncontrolled hypothyroidism has been associated with an increased risk of adverse pregnancy outcomes. We aimed to assess the effectiveness of increasing levothyroxine (LT4) dose on reducing the risk of adverse outcomes for pregnant women with TSH level greater than the recommended 1st trimester limit. We reviewed the electronic medical records of pregnant women evaluated from January 2011 to December 2013, who had history of LT4-treated hypothyroidism and were found to have TSH > 2·5 mIU/l in 1st trimester. Women were divided into two groups: group A - LT4 dose was increased within two weeks from the TSH test, group B - LT4 dose remained stable. We compared the frequency of pregnancy loss (primary outcome) and other prespecified pregnancy-related adverse outcomes between groups. There were 85 women in group A (median TSH: 5·0, interquartile range 3·8-6·8 mIU/l) and 11 women in group B (median TSH: 4·5, interquartile range 3·2-4·9 mIU/l). The groups were not different in baseline clinical and socioeconomic characteristics. The mean interval between TSH test and LT4 dose increase was 4·5 (SD 4·6) days. Pregnancy loss was significantly lower in group A (2/85, 2·4%) vs group B (4/11, 36·4%) (P = 0·001). Other pregnancy-related adverse outcomes were similar between groups. Increasing LT4 dose for women with uncontrolled hypothyroidism in the 1st trimester of pregnancy was associated with a decreased risk of pregnancy loss. Given the limitations of our study, this association awaits further confirmation from larger studies.


Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts.
CD22 is a membrane glycophosphoprotein found on nearly all healthy B-lymphocytes and most B-cell lymphomas. Recent in vitro studies have identified several anti-CD22 monoclonal antibodies (mAbs) that block the interaction of CD22 with its ligand. One of these mAbs, HB22.7, has been shown to effectively induce apoptosis in several B-cell lymphoma cell lines. Lymphoma xenograft studies with Raji-xenograft mice were used to assess the toxicity and efficacy of HB22.7 alone and with combined modality immunotherapy (CMIT) with yttrium (90)Y-DOTA-peptide-Lym-1 radioimmunotherapy (RIT). The effect of the sequence of these agents on the combined treatment was assessed by administering HB22.7 24 hours before, simultaneously with, or 24 hours after RIT. Within the groups treated with RIT alone or with RIT and HB22.7 (CMIT), the reduction in tumor volume was the greatest when HB22.7 was administered simultaneously with and 24 hours after RIT, and in the RIT treatment groups, this translated into the greatest overall response and survival, respectively. Overall survival rates at the end of the 84-day CMIT trial were 67% and 50% in the groups treated with HB22.7 simultaneously and 24 hours after RIT, respectively. This compared favorably with the untreated and the RIT alone groups, which had survival rates of 38% and 43% at the end of the trial. Surprisingly, when compared with untreated controls and all other treatment groups, the greatest cure and overall survival rates were observed in the group treated with HB22.7 alone, with 47% cured and 76% surviving at the end of the 84-day trial. RIT clearance was not affected by treatment with HB22.7. When compared with RIT alone, there was no significant additional hematologic (white blood cell, red blood cell, or platelet count) toxicity when HB22.7 was added to RIT. Nonhematologic toxicity (assessed as change in body weight) was also unchanged when HB22.7 was added to RIT. Thus the anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of (90)Y-DOTA-peptide-Lym-1 in lymphoma xenografts without significant toxicity.


Patch test study of 90 patients with tattoo reactions: negative outcome of allergy patch test to baseline batteries and culprit inks suggests allergen(s) are generated in the skin through haptenization.
Tattoo reactions, especially in red tattoos, are often suggested as allergic in nature, however, systematic evaluation by patch testing has not performed in the past. To report the results of patch testing in 90 patients with non-infectious chronic tattoo reactions. From 2009 to 2013 at the 'Tattoo Clinic', Department of Dermatology, Bispebjerg University Hospital, 90 patients were patch tested with batteries of baseline allergens, disperse dyes/textile allergens, and a selection of tattoo ink stock products, which, according to case observations, were problematic, supplemented with individual culprit inks when accessible. Patients with reactions to the tattoo colour red, the most predominant colour associated with skin reactions, showed negative patch test results with common allergens. Outcomes were also negative in patients who had experienced concomitant reactions in another hitherto tolerated tattoo of the same colour as the problematic tattoo. The allergen or allergens responsible for tattoo reactions are not present directly in tattoo ink stock products. This is despite the fact that clinical histories suggest that the vast majority of clinical reactions, especially reactions to red and red nuances, are likely to be allergic events caused by the injected inks. We suggest that the responsible allergen results from a complicated and slow process of haptenization, which may even include photochemical cleavage of red azo pigment.


The COOH-terminal domain of the RNA polymerase alpha subunit in transcriptional enhancement and deactivation at the bacteriophage T4 late promoter.
Many activator proteins generate their positive control of transcription through interactions with the COOH-terminal domain of the Escherichia coli RNA polymerase alpha subunit. We have examined the participation of this alpha-domain in transcriptional enhancement and suppression at bacteriophage T4 late promoters. Enhancement is generated by the T4 gene 45 protein, which is the DNA-tracking processivity factor of viral DNA replication; suppression of unenhanced transcription is generated by the RNA polymerase-binding co-activator T4 gene 33 protein. Enhanced and unenhanced transcription by RNA polymerase reconstituted with intact and truncated alpha subunits and by RNA polymerase containing ADP-ribosylated alpha has been compared; the internal structures of transcription complexes formed with these RNA polymerases have also been analyzed by footprinting and photocross-linking. Comparison of these structural and functional analyses suggests that enhancement of T4 late transcription by gp45 is not compatible with any significant role of the COOH-terminal domain of the RNA polymerase core alpha subunit in transcriptional initiation. Suppression of unenhanced T4 late transcription by the gene 33 protein also does not require the COOH-terminal domain of alpha.


Quantitative immunofluorescence reveals the signature of active B-cell receptor signaling in diffuse large B-cell lymphoma.
B-cell receptor (BCR)-mediated signaling is important in the pathogenesis of a subset of diffuse large B-cell lymphomas (DLBCL) and the BCR-associated kinases SYK and BTK have recently emerged as potential therapeutic targets. We sought to identify a signature of activated BCR signaling in DLBCL to aid the identification of tumors that may be most likely to respond to BCR-pathway inhibition. We applied quantitative immunofluorescence (qIF) using antibodies to phosphorylated forms of proximal BCR signaling kinases LYN, SYK, and BTK and antibody to BCR-associated transcription factor FOXO1 on BCR-cross-linked formalin-fixed paraffin-embedded (FFPE) DLBCL cell lines as a model system and on two clinical cohorts of FFPE DLBCL specimens (n = 154). A robust signature of active BCR signaling was identified and validated in BCR-cross-linked DLBCL cell lines and in 71/154 (46%) of the primary DLBCL patient specimens. Further analysis of the primary biopsy samples revealed increased nuclear exclusion of FOXO1 among DLBCL with qIF evidence of active BCR signaling compared with those without (P = 0.004). Nuclear exclusion of FOXO1 was also detected in a subset of DLBCL without evidence of proximal BCR signaling suggesting that alternative mechanisms for PI3K/AKT activation may mediate FOXO1 subcellular localization in these cases. This study establishes the feasibility of detecting BCR activation in primary FFPE biopsy specimens of DLBCL. It lays a foundation for future dissection of signal transduction networks in DLBCL and provides a potential platform for evaluating individual tumors in patients receiving novel therapies targeting the BCR pathway.


On focusing the slit-lamp: Part I. An inaccurate ocular setting--what is there to lose?
Adjustments of the diopter rings on the slit-lamp oculars compensate for three independent factors: the observer's refractive error, the observer's state of accommodation, and any instrument misalignment. An inaccurate setting of these rings will significantly affect the slit-lamp image quality, as well as the precision and accuracy of slit-lamp mounted lasers, such as are used for retinal photocoagulation, YAG capsulotomy, and laser trabeculoplasty. For each slit-lamp and microscope-related examination technique, photographic technique, and laser procedure, the consequences of an incorrect ocular setting are discussed. Data are presented on the preferred ocular settings of several random observers, highlighting both interobserver and intraobserver variability. Finally, photographs demonstrate the image deterioration that occurs when an incorrect ocular setting is used. It is shown that for younger observers, one's distance refraction is only seldom the correct setting of the slit-lamp oculars, and that on different instruments, one should not be surprised to find somewhat different settings. Examiners are urged to check the accuracy of their habitual setting, if only to find out whether the improvement in image quality is worth the extra bother.


A Markovian Entropy Measure for the Analysis of Calcium Activity Time Series.
Methods to analyze the dynamics of calcium activity often rely on visually distinguishable features in time series data such as spikes, waves, or oscillations. However, systems such as the developing nervous system display a complex, irregular type of calcium activity which makes the use of such methods less appropriate. Instead, for such systems there exists a class of methods (including information theoretic, power spectral, and fractal analysis approaches) which use more fundamental properties of the time series to analyze the observed calcium dynamics. We present a new analysis method in this class, the Markovian Entropy measure, which is an easily implementable calcium time series analysis method which represents the observed calcium activity as a realization of a Markov Process and describes its dynamics in terms of the level of predictability underlying the transitions between the states of the process. We applied our and other commonly used calcium analysis methods on a dataset from Xenopus laevis neural progenitors which displays irregular calcium activity and a dataset from murine synaptic neurons which displays activity time series that are well-described by visually-distinguishable features. We find that the Markovian Entropy measure is able to distinguish between biologically distinct populations in both datasets, and that it can separate biologically distinct populations to a greater extent than other methods in the dataset exhibiting irregular calcium activity. These results support the benefit of using the Markovian Entropy measure to analyze calcium dynamics, particularly for studies using time series data which do not exhibit easily distinguishable features.


Seven thousand years of records on the mining and utilization of metals from lake sediments in central China.
A 268 cm section of sediment core from Liangzhi Lake in Hubei province in central China was used to assess the use and accumulation of metals in the lake in the past 7,000 years. The concentrations of trace metals, including Cu, Pb, Ni, and Zn, and major elements, Ca, Fe, and Mg, in a 14C- dated segment of sediment core were analyzed. Historical trends on the input of metals to Liangzhi Lake from around 5000 BC to the present were recorded in the sediments, representing about 7,000 years of history on the mining and utilization of metals in central China. The concentrations of Cu, Ni, Pb, and Zn increased gradually from about 3000 +/- 328 BC, indicating the start of the Bronze Age in ancient China. During the period 467 +/- 257 to 215 +/- 221 AD, there was a rapid increase in the concentrations of these metals in the sediments, indicating enormous inputs of these metals at that time. This era corresponded to China's Warring States Period (475- 221 BC) and the early Han Dynasty (206 BC-220 AD), during which copper and lead were extensively used in making bronze articles such as vessels, tools, and weapons. From 1880 +/- 35 AD to the early 1900s, there was also a significant increase in the concentrations of metals such as Cu, Ni, and Pb, which probably reflected the metal emissions and utilization during the early period of industrial development and weapon manufacture during the wars in China. The Pb isotopic analysis showed that the surface and subsurface sediments had lower 206Pb/207Pb and 208Pb/ 207Pb ratios than the deeper layers, reflecting the additional input of Pb from mining activities that took place during the Bronze Age era and in modern times. This study provides direct evidence of the environmental impact of the mining and utilization of metals in the last 7,000 years in one of the important regions of Chinese civilization.


Neonatal and infant mortality associated with spina bifida: A systematic review and meta-analysis.
A systematic review was conducted in high-income country settings to analyse: (i) spina bifida neonatal and IMRs over time, and (ii) clinical and socio-demographic factors associated with mortality in the first year after birth in infants affected by spina bifida. PubMed, Embase, Ovid, Web of Science, CINAHL, Scopus and the Cochrane Library were searched from 1st January, 1990 to 31st August, 2020 to review evidence. Population-based studies that provided data for spina bifida infant mortality and case fatality according to clinical and socio-demographical characteristics were included. Studies were excluded if they were conducted solely in tertiary centres. Spina bifida occulta or syndromal spina bifida were excluded where possible. Independent reviewers extracted data and assessed their quality using MOOSE guideline. Pooled mortality estimates were calculated using random-effects (+/- fixed effects) models meta-analyses. Heterogeneity between studies was assessed using the Cochrane Q test and I2 statistics. Meta-regression was performed to examine the impact of year of birth cohort on spina bifida infant mortality. Twenty studies met the full inclusion criteria with a total study population of over 30 million liveborn infants and approximately 12,000 spina bifida-affected infants. Significant declines in spina bifida associated infant and neonatal mortality rates (e.g. 4.76% decrease in IMR per 100, 000 live births per year) and case fatality (e.g. 2.70% decrease in infant case fatality per year) were consistently observed over time. Preterm birth (RR 4.45; 2.30-8.60) and low birthweight (RR 4.77; 2.67-8.55) are the strongest risk factors associated with increased spina bifida infant case fatality. Significant declines in spina bifida associated infant/neonatal mortality and case fatality were consistently observed, advances in treatment and mandatory folic acid food fortification both likely play an important role. Particular attention is warranted from clinicians caring for preterm and low birthweight babies affected by spina bifida.


Elevated Sensitivity to Tactile Stimuli in Stereotypic Horses.
Although stereotypic behaviors are a common problem in captive animals, why certain individuals are more prone to develop them remains elusive. In horses, individuals show considerable differences in how they perceive and react to external events, suggesting that this may partially account for the emergence of stereotypies in this species. In this study, we focused on crib-biting, the most common stereotypy displayed by horses. We compared how established crib-biters ("CB" = 19) and normal controls ("C" = 18) differed in response to a standard "personality" assessment test battery, i.e., reactivity to humans, tactile sensitivity, social reactivity, locomotor activity, and curiosity vs. fearfulness (both in novel and suddenness situations). Our analyses showed that crib-biters only differed from control horses in their tactile sensitivity, suggesting an elevated sensitivity to tactile stimuli. We suggest that this higher tactile sensitivity could be due to altered dopamine or endogenous opioid physiology, resulting from chronic stress exposition. We discuss these findings in relation to the hypothesis that there may be a genetic predisposition for stereotypic behavior in horses, and in relation to current animal husbandry and management practices.


A million little pieces of broken trust.
In April 2015, the Union Cabinet approved the Juvenile Justice (Care and Protection of Children) Bill, 2014, which proposes to bring about regressive changes in the law, that would not only be unconstitutional but also unethical. In May 2015, the Ministry of Women and Child Development introduced the Bill in the Lok Sabha, where it was passed. If the Rajya Sabha, passes the Bill and the President gives his assent to it, the youth of this country will be harmed in a manner that could break the very fabric of the nation.


Induction of apoptosis in skeletal tissues: phosphate-mediated chick chondrocyte apoptosis is calcium dependent.
In an earlier study, we have shown that Pi induced apoptosis of terminally differentiated hypertrophic chondrocytes. To ascertain whether Ca2+ modulates Pi-induced cell death, we asked the following two questions: First, can we prevent Pi-induced apoptosis by removing Ca2+ from the culture medium; alternatively, can we potentiate cell death by increasing the Ca2+ concentration? Second, can we inhibit chondrocyte apoptosis by blocking Pi transport? We also explored the mechanism of apoptosis by evaluating mitochondrial activity and reactive oxygen species (ROS) generation in cells treated with the ion pair. We noted that EDTA and EGTA blocked Pi-induced apoptosis in a dose-dependent manner. While high levels of Ca2+ alone had little effect on chondrocyte viability, the cation enhanced Pi-dependent cell death and greatly increased Pi uptake. When Pi transport was blocked, there was complete inhibition of cell killing. The process of cell death was characterized by mitochondrial hyperpolarization; two hours following apoptogen treatment, there was a significant decrease in the mitochondrial membrane potential. Coincident with the changes in mitochondrial function, there was an increase in intracellular Ca2+ that was maintained throughout the experimental period. A raised Ca2+ signal was observed in blebs at the cell membrane. Finally, we noted that, 75 minutes after treatment with the ion pair, there was a six-fold elevation in ROS levels. This increase declined to baseline values after three hours. Based on these observations, we suggest that, at the cartilage mineralization front, an elevation in local environmental Ca2+ and Pi concentrations modulates oxidative metabolism, and triggers apoptosis of terminally differentiated chondrocytes.


Birth of a new gene on the Y chromosome of Drosophila melanogaster.
Contrary to the pattern seen in mammalian sex chromosomes, where most Y-linked genes have X-linked homologs, the Drosophila X and Y chromosomes appear to be unrelated. Most of the Y-linked genes have autosomal paralogs, so autosome-to-Y transposition must be the main source of Drosophila Y-linked genes. Here we show how these genes were acquired. We found a previously unidentified gene (flagrante delicto Y, FDY) that originated from a recent duplication of the autosomal gene vig2 to the Y chromosome of Drosophila melanogaster. Four contiguous genes were duplicated along with vig2, but they became pseudogenes through the accumulation of deletions and transposable element insertions, whereas FDY remained functional, acquired testis-specific expression, and now accounts for ∼20% of the vig2-like mRNA in testis. FDY is absent in the closest relatives of D. melanogaster, and DNA sequence divergence indicates that the duplication to the Y chromosome occurred ∼2 million years ago. Thus, FDY provides a snapshot of the early stages of the establishment of a Y-linked gene and demonstrates how the Drosophila Y has been accumulating autosomal genes.


Digital technologies for social inclusion of individuals with disabilities.
Information technology can be an important facilitator of social inclusion for people with disabilities into society. However, the goals specified in this area by organizations such as the European Commission have not yet been achieved in their totality. The aim of this paper is to explore which types of information communication technology-based applications and/or digital services have been suggested to facilitate the social integration of people who suffer from different types of disabilities. We performed a literature review that included studies published during a period of 6 years (2010-2016). The results show that, in the data we have had access to, no concrete patterns can be identified regarding the type of technology or technological trends that can be used to support the social integration of individuals with disabilities. This literature review is of relevance to the identification of further research areas and to the identification of issues which have to be considered in the context of the development and implementation of technological innovations that are aimed at promoting or facilitating social inclusion of individuals with disabilities.


Hand problems among endourologists.
Endourology has evolved rapidly for the management of both benign and malignant disease of the upper urinary tract. Limited data exist, however, on the occupational hazards posed by complex endourologic procedures. The aim of this study was to determine the prevalence and possible causes of hand problems among endourologists who routinely perform flexible ureteroscopy compared with controls. An online computer survey targeted members of the Endourological Society and psychiatrists in academic and community settings. A total of 600 endourologists and 578 psychiatrists were contacted by e-mail. Invited physicians were queried regarding their practice settings and symptoms of hand pain, neuropathy, and/or discomfort. Survey responses were obtained from 122 (20.3%) endourologists and 74 (12.8%) psychiatrists. Of endourologists, 61% were in an academic setting and 70% devoted their practice to endourology. Endourologists were in practice for a mean 13 years, performing 4.5 ureteroscopic cases per week with a mean operative time of 50 minutes. Hand/wrist problems were reported by 39 (32%) endourologists compared with 14 (19%) psychiatrists (P=0.0486, relative risk [RR]=1.69). Surgeons who preferred counterintuitive ureteroscope deflection were significantly more likely to have problems (56%) compared with intuitive users (27%) (RR 2.07, P=0.0139) or those with no preference (26%) (RR 2.15, P=0.0451). Overall, most respondents (85%) with hand/wrist problems needed either medical or surgical intervention. Hand and wrist problems are very common among endourologists. Future studies are needed to develop more ergonomic platforms and thereby reduce the endourologist's exposure to these occupational hazards.


Possible existence of a novel amphipathic immunostimulator in the phenol-water extracts of Mycobacteriaceae.
The extracts having diverse immunostimulating activities were obtained as a water-phase fraction from four bacterial species representing the 4 genera (Mycobacterium, Nocardia, Gordona, and Rhodococcus) of Mycobacteriaceae by the phenol-water method, which is commonly used for extraction of endotoxic lipopolysaccharides (LPS) from gram-negative bacteria and amphipathic substances from gram-positives. These fractions, especially those of G. aurantiaca and R. terrae, showed strong stimulatory effects on murine splenocytes, macrophages of mice and guinea pigs, the immunoadjuvant activities in guinea pigs and mice, and the distinct activities inducing a tumor necrosis factor and interferons alpha/beta and gamma in primed mice. The fractions from G. aurantiaca and R. terrae exhibited potent pyrogenicity and the ability to activate the clotting enzyme cascade of the horseshoe crab (Tachypleus tridentatus). Some of these biological activities were not very different from the potency of the reference endotoxic LPS derived from Escherichia coli or Fusobacterium nucleatum. But the test fractions neither showed the activity to prepare rabbit skin to the local Shwartzman reaction, nor reacted with anti-lipid A conventional and monoclonal antibodies. Furthermore, unlike LPS, these fractions stimulated the splenocytes of C3H/HeJ mice (LPS-Nonresponder). Although the fractions showing the above biological activities have not yet been adequately purified, they contained polysaccharides, whose main constituent sugar is mannose with a smaller amount of arabinose, fatty acids consisting primarily of palmitic, stearic, and tuberculostearic acids, and small amounts of peptides and amino sugars. Since components characteristic of known immunomodulators of bacterial origin, namely endotoxins (lipid A's), cell wall peptidoglycans, lipoteichoic acids, cord factors (trehalose dimycolates), or deoxyribonucleic acids, were practically not detected in these fractions, the agent responsible for the above bioactivities is considered to be a novel substance different from the known, bacterial immunomodulators.


Pheromone Lure and Trap Color Affects Bycatch in Agricultural Landscapes of Utah.
Aerial traps, using combinations of color and attractive lures, are a critical tool for detecting and managing insect pest populations. Yet, despite improvements in trap efficacy, collection of nontarget species ("bycatch") plagues many insect pest surveys. Bycatch can influence survey effectiveness by reducing the available space for target species and increasing trap screening time, especially in areas where thousands of insects are captured as bycatch in a given season. Additionally, bycatch may negatively impact local nontarget insect populations, including beneficial predators and pollinators. Here, we tested the effect of pheromone lures on bycatch rates of Coccinellidae (Coleoptera), Apoidea (Hymenoptera), and nontarget Lepidoptera. Multicolored (primarily yellow and white) bucket traps containing a pheromone lure for capturing one of three survey target species, Spodoptera litura (F.), S. littoralis (Boisduval), or Helicoverpa armigera (Hübner), were placed in alfalfa and corn fields, and compared to multicolored traps without a pheromone lure. All-green traps with and without H. armigera lures were employed in a parallel study investigating the effect of lure and trap color on bycatch. Over 2,600 Coccinellidae representing seven species, nearly 6,400 bees in 57 species, and >9,000 nontarget moths in 17 genera were captured across 180 traps and seven temporal sampling events. Significant effects of lure and color were observed for multiple taxa. In general, nontarget insects were attracted to the H. armigera lure and multicolored trap, but further studies of trap color and pheromone lure specificity are needed to better understand these interactions and to minimize nontarget captures.


Detection of Fusarium oxysporum f. sp. melonis Race 1 in Soil in Colima State, Mexico.
During the winters of 2002 and 2003, a wilt occurred in melons cultivated on 1,500 ha in Colima State, Mexico. Yield losses reached 25% of final production, despite soil disinfestation with 60% methyl bromide and 40% chloropicrin. On the basis of the observation of plants with necrotic xylem, yellowing, and wilting of leaves, this disease was identified provisionally as Fusarium wilt. During February 2003, four soil samples from affected fields were plated onto a Fusarium-selective medium (1), which resulted in the detection of 2,260 ± 357, 179 ± 76, 668 ± 357, and 1,391 ± 256 CFU/g of F. oxysporum (3). Thirty-one randomly chosen isolates were used to inoculate differential cultivars of melon as described by Risser et al. (4). The cultivars were Amarillo Canario (susceptible to all races), Diana (resistant to races 0 and 2), Tango (resistant to races 0 and 1), and Vulcano (resistant to races 0, 1, and 2) (2). Ten plants of each cultivar, grown on sterilized vermiculite, were inoculated at the first true-leaf stage by drenching with 200 ml of a conidial suspension (1 × 105 CFU/ml) of each isolate. Noninoculated plants of each cultivar served as controls. Plants were maintained in a growth chamber with a 16-h photoperiod (18 × 103 lux) and temperatures at 23 to 25°C. Yellowing, wilt, and vascular discoloration symptoms developed on cvs. Amarillo Canario and Diana following inoculation with each of the 31 isolates, while noninoculated plants remained symptomless. F. oxysporum was consistently reisolated on potato dextrose agar from the affected plants. On the basis of the combination of affected cultivars, all isolates were identified as F. oxysporum f. sp. melonis race 1. To our knowledge, this is the first report of F. oxysporum f. sp. melonis race 1 in Colima State, Mexico. References: (1) H. Komada. Rev. Plant Prot. Res. 8:114, 1975. (2) J. Marín Rodríquez. Portagrano 2004. Vadmecum de Variedades Hortícolas. Agrobook, Spain. 2004. (3) P. E. Nelson et al. Fusarium Species: An Illustrated Manual for Identification. Pennsylvania State University Press, University Park, 1983. (4) G. Risser et al. Phytopathology 66:1105, 1976.


Cystic duplication of transverse colon: an unusual case of abdominal pain and bowel obstruction.
Gatrointestinal duplications are rare congenital anomalies, usually detected prenatally or in the first two years of life, although they can be diagnosed even in older age. Within the abdomen, a small bowel location is the most frequent (more than 50% of cases), while colonic site accounts for 17% of patients; transverse colonic location is very rare. These lesions can vary in shape, being cystic or tubular, and typically show the same structure of the adjacent normal bowel, with which they can have direct communication. The most of case of intestinal duplication in adults present with acute abdomen and bowel obstruction, and are more common in the ileum than in the colon. When diagnosed these lesions should be surgically resected to avoid future possible complications. The Authors present a case of cystic duplication of transverse colon in a young adult male, cause of acute abdominal pain and intestinal obstruction, thus requiring urgent surgery.


The candidate phylum 'Termite Group 1' of bacteria: phylogenetic diversity, distribution, and endosymbiont members of various gut flagellated protists.
The candidate phylum 'Termite Group 1' (TG1) of bacteria, which is abundant in termite guts but has no culturable representative, was investigated with respect to the in situ localization, distribution, and diversity. Based on the 16S rRNA gene sequence analyses and FISH in termite guts, a number of lineages of TG1 members were identified as endosymbionts of a variety of gut flagellated protists from the orders Trichonymphida, Cristamonadida, and Oxymonadida that are mostly unique to termites. However, the survey in various environments using specific PCR primers revealed that TG1 members were also present in termites, a cockroach, and the bovine rumen that typically lack these protist orders. Most of the TG1 members from gut flagellates, termites, cockroaches, and the rumen formed a monophyletic subcluster that showed a shallow branching pattern in the phylogenetic tree, suggesting their recent diversification. Although endosymbionts of the same protist genera tended to be closely related, the endosymbiont lineages were often independent of the higher level classifications of their host protist and were dispersed in the phylogenetic tree. It appears that their cospeciation is not the sole rule for the diversification of TG1 members of endosymbionts.


A validation of questionnaire information on occupational exposure and smoking.
Occupational exposure information obtained via a questionnaire to close relatives of 160 deceased smelter workers was compared with data from employee registers. The data from the questionnaire regarding employment at the smelter had a very high validity, ie, a sensitivity of 98% and a specificity of 99%. When an assessment of arsenic exposure was made from information in the questionnaire, the sensitivity was only 40%, but the specificity was over 90%. Data on smoking habits were available from medical files for only 14 of the subjects. For all 14, the information was identical to the data in the questionnaires. It appears that questionnaires may sometimes be of use for exposure assessments in occupational health epidemiology.


Determinants of the CmoB carboxymethyl transferase utilized for selective tRNA wobble modification.
Enzyme-mediated modifications at the wobble position of tRNAs are essential for the translation of the genetic code. We report the genetic, biochemical and structural characterization of CmoB, the enzyme that recognizes the unique metabolite carboxy-S-adenosine-L-methionine (Cx-SAM) and catalyzes a carboxymethyl transfer reaction resulting in formation of 5-oxyacetyluridine at the wobble position of tRNAs. CmoB is distinctive in that it is the only known member of the SAM-dependent methyltransferase (SDMT) superfamily that utilizes a naturally occurring SAM analog as the alkyl donor to fulfill a biologically meaningful function. Biochemical and genetic studies define the in vitro and in vivo selectivity for Cx-SAM as alkyl donor over the vastly more abundant SAM. Complementary high-resolution structures of the apo- and Cx-SAM bound CmoB reveal the determinants responsible for this remarkable discrimination. Together, these studies provide mechanistic insight into the enzymatic and non-enzymatic feature of this alkyl transfer reaction which affords the broadened specificity required for tRNAs to recognize multiple synonymous codons.


An inducible knockout mouse to model the cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias.
PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The role of PTEN in carcinogenesis has been validated by knockout mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has inhibited the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional knockout mice with transgenic mice expressing a tamoxifen-inducible Cre-ER(T) under the control of a chicken actin promoter, we have generated a tamoxifen-inducible mouse model that allows temporal control of PTEN deletion. Interestingly, administration of a single dose of tamoxifen resulted in PTEN deletion mainly in epithelial cells, but not in stromal, mesenchymal or hematopoietic cells. Using the mT/mG double-fluorescent Cre reporter mice, we demonstrate that epithelial-specific PTEN excision was caused by differential Cre activity among tissues and cells types. Tamoxifen-induced deletion of PTEN resulted in extremely rapid and consistent formation of endometrial in situ adenocarcinoma, prostate intraepithelial neoplasia and thyroid hyperplasia. We also analyzed the role of PTEN ablation in other epithelial cells, such as the tubular cells of the kidney, hepatocytes, colonic epithelial cells or bronchiolar epithelium, but those tissues did not exhibit neoplastic growth. Finally, to validate this model as a tool to assay the efficacy of anti-tumor drugs in PTEN deficiency, we administered the mTOR inhibitor everolimus to mice with induced PTEN deletion. Everolimus dramatically reduced the progression of endometrial proliferations and significantly reduced thyroid hyperplasia. This model could be a valuable tool to study the cell-autonomous mechanisms involved in PTEN-loss-induced carcinogenesis and provides a good platform to study the effect of anti-neoplastic drugs on PTEN-negative tumors.


[Clinicopathological features of sporadic frontotemporal lobar degeneration with TDP-43-positive inclusions].
Frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) and Pick's disease are common pathological substrates in FTLD patients. Because most Japanese FTLD-TDP patients lack a family history, characterizing clinical features in sporadic FTLD-TDP is important to infer the underlying pathologies in FTLD patients. Our recent study suggested that these two diseases tended to show different clinical pictures. Early impairment of semantic memory was frequent in sporadic FTLD-TDP, but very rare in Pick's disease. In contrast, early impairment of speech output, including non-fluent aphasia and speech apraxia, was more frequent in Pick's disease. Asymmetric motor disturbances (e.g., pyramidal signs, parkinsonism, and contracture) were frequent in sporadic FTLD-TDP, but rare in Pick's disease. The most common first syndrome in FTLD-TDP was semantic dementia (39%), but that in Pick's disease was frontotemporal dementia (64%). Pathologically, consistent with clinical features, the temporal cortex, striatum, globus pallidus, substantia nigra, and pyramidal tract were more severely degenerated in sporadic FTLD-TDP. These findings suggest that the early impairment of semantic memory and asymmetric motor disturbances in sporadic FTLD patients predict FTLD-TDP rather than Pick's disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick's disease rather than FTLD-TDP.


Adjuvant chemotherapy with carboplatin and taxane compared with single drug carboplatin in early stage epithelial ovarian carcinoma.
The objective of the present study was to compare recurrence-free survival (RFS) in early stages (FIGO stages I-II) of epithelial ovarian cancer after adjuvant chemotherapy with carboplatin and a taxane (113 patients) and with carboplatin alone (27 patients). The distribution of clinical and pathological prognostic factors as well as type of primary surgery were comparable in the two groups. Recurrence rate was 21% and RFS was 79% in the series of patients treated with taxane-based chemotherapy and 19% and 81%, respectively, in the series of patients who received single drug carboplatin. Thus, no significant differences were recorded. The major toxicities in the present study were myelosuppression (46%) and neuro-toxicity (26%). Neuro-toxicity was more frequently (P=0.007) recorded and of higher grade (P=0.011) for patients in the carboplatin-taxane series compared with patients in the carboplatin series. RFS for patients in FIGO-stage I was 85% and for patients in FIGO-stage II only 47%. In a multivariate logistic regression analysis of predictive factors for tumor recurrence in the complete series (n=140) the FIGO stage was the only independent and significant (P=0.0006) predictive factor with an odds ratio of 6.4 (95% CI: 2.2-18.9) for stage II versus IA-C. Age, tumor grade and type of adjuvant chemotherapy (+/- taxane) were not significant predictive factors. In the present study, although based on a limited number of patients, we could not find any improvement in recurrence rate or recurrence-free survival for patients treated with a carboplatin-taxane combination regimen compared with patients treated with carboplatin monotherapy. The spectrum of side effects was also in favor of the monotherapy regimen. Further, larger randomized studies are needed to give a final and fully conclusive answer to this question.


Characteristics of first suicide attempts in single versus multiple suicide attempters with bipolar disorder.
Although suicidality remains highly prevalent among patients with bipolar disorder, little research exists examining the characteristics of successive attempts among individuals who make and survive a first suicide attempt. We compared bipolar subjects with a history of one suicide attempt to those with multiple attempts and assessed demographic characteristics, family histories, psychopathology, and clinical dimensions of suicidal behavior. Fifty-two DSM-IV bipolar patients (age 21 to 74 years) with a history of at least one suicide attempt were consecutively evaluated in the Bipolar Disorders Research Clinic of the New York Presbyterian Hospital. Circumstances surrounding each lifetime suicide attempt were assessed by direct interviews, questionnaires, and chart reviews along with family psychiatric histories, substance abuse histories, current psychopathology, and features of impulsivity and aggression. Multiple suicide attempts occurred in approximately two thirds of the study group. Single attempters were significantly more likely than multiple attempters to show high seriousness of intent at their first attempt (OR = 0.65, 95% CI = 0.43 to 0.99), and tended to be less likely than multiple attempters to exhibit mixed states at their first attempt (OR = 0.54, 95% CI = 0.28 to 1.01). Seriousness of intent was consistent across the first and second attempts (r =.48, P <.01) and second and third attempts (r =.74, P <.05). Single and multiple attempters differed in no other clinical or demographic characteristics studied. We conclude that multiple suicide attempts are common among bipolar patients. Those who survive an initial suicide attempt involving high seriousness of intent appear less likely than those with low intent to make subsequent attempts. Consequently, single attempters may represent a group more closely resembling those who complete suicide on a first attempt, in terms of the risk for death associated with their first attempt. However, multiple suicide attempts among bipolar patients are not necessarily associated with a higher risk for lethality in first suicide attempt survivors.


Nonfatal acute myocardial infarction in Costa Rica: modifiable risk factors, population-attributable risks, and adherence to dietary guidelines.
Cardiovascular disease, including myocardial infarction (MI), is increasing in developing countries. Knowledge of risk factors and their impact on the population could offer insights into primary prevention. We estimated the population-attributable risk (PAR) for major MI risk factors among Costa Ricans without a history of diabetes, hypertension, or regular use of medication (889 MI cases, 1167 population-based controls). Lifestyle and dietary variables were measured with validated questionnaires. In multivariate analyses, abdominal obesity (PAR, 29.3%), smoking (PAR, 25.6%), nonuse of alcohol (PAR, 14.8%), caffeine intake (PAR, 12.8%), physical inactivity (PAR, 9.6%), and poor diet (PAR, 6.0%) were the most important MI risk factors. Subjects in the favorable categories of the above 6 risk factors showed a lower risk of MI (odds ratio, 0.09; 95% CI, 0.03 to 0.33) than those in the unfavorable categories. Compared with women, men were more likely to smoke (31% versus 10%) but less likely to have waist circumferences greater than Adult Treatment Panel III cutoffs (9% versus 35%). Many subjects did not meet the American Heart Association or World Health Organization/Food and Agriculture Organization dietary guidelines. For instance, 95% obtained > or = 7% of energy from saturated fat, 25% had < or = 5% of energy from polyunsaturated fat, 63% had > or = 1% energy from trans fat, and 53% had low fiber intake (< 25 g/d). These findings confirm the benefit of a healthy diet, physical activity, moderate alcohol, and cessation of smoking as approaches for the primary prevention of MI. Obesity and smoking were the 2 most important risk factors for nonfatal MI in Costa Rica.


Rewiring cell signaling: the logic and plasticity of eukaryotic protein circuitry.
Living cells rival computers in their ability to process external information and make complex behavioral decisions. Many of these decisions are made by networks of interacting signaling proteins. Ongoing structural, biochemical and cell-based studies have begun to reveal several common principles by which protein components are used to specifically transmit and process information. Recent engineering studies demonstrate that these relatively simple principles can be used to rewire signaling behavior in a process that mimics the evolution of new phenotypic responses.


Apoptosis and cytokine release induced by ionizing or ultraviolet B radiation in primary and immortalized human keratinocytes.
We have compared the induction of apoptosis and cytokine release by UVB and gamma-radiation in primary (untransformed) and in two immortalized human epithelial/keratinocyte cell lines, HaCaT and KB (KB is now known to be a subline of the ubiquitous keratin-forming tumour cell line HeLa and we therefore designate it HeLa-KB). In both the primary and the immortalized cell lines apoptosis and release of the inflammatory cytokine interleukin-6 are induced rapidly following UVB irradiation. In contrast, only the immortalized cells undergo apoptosis and release interleukin-6 after gamma-irradiation and here the onset of apoptosis and cytokine release are delayed. The same distinction between primary and immortalized cells was observed when double-strand breaks were induced with the anticancer drug mitoxantrone, which stabilizes topoisomerase II-cleavable complexes. We suggest that immortalization may sensitize keratinocytes to the apoptogenic effect of ionizing radiation or mitoxantrone by deregulating normal cell cycle checkpoints. In both human keratinocytes and fibroblasts, cell killing, as assayed by loss of colony-forming ability, is not coupled to apoptosis. Immortalization increases resistance to gamma-radiation killing but sensitizes to apoptosis. In contrast, although immortalization also sensitizes to UVB-induced apoptosis, it does not affect UVB-induced cell killing. Apoptosis unambiguously indicates death at the single cell level but clonal cell survival integrates all the cellular and genetic processes which prevent or permit a scorable clone to develop.


Training self-assessment and task-selection skills to foster self-regulated learning: Do trained skills transfer across domains?
Students' ability to accurately self-assess their performance and select a suitable subsequent learning task in response is imperative for effective self-regulated learning. Video modeling examples have proven effective for training self-assessment and task-selection skills, and-importantly-such training fostered self-regulated learning outcomes. It is unclear, however, whether trained skills would transfer across domains. We investigated whether skills acquired from training with either a specific, algorithmic task-selection rule or a more general heuristic task-selection rule in biology would transfer to self-regulated learning in math. A manipulation check performed after the training confirmed that both algorithmic and heuristic training improved task-selection skills on the biology problems compared with the control condition. However, we found no evidence that students subsequently applied the acquired skills during self-regulated learning in math. Future research should investigate how to support transfer of task-selection skills across domains.


Tractography gone wild: probabilistic fibre tracking using the wild bootstrap with diffusion tensor MRI.
Diffusion tensor magnetic resonance imaging (DT-MRI) permits the noninvasive assessment of tissue microstructure and, with fibre-tracking algorithms, allows for the 3-D trajectories of white matter fasciculi to be reconstructed noninvasively. Probabilistic algorithms allow one to assign a "confidence" to a given reconstructed pathway--but often rely on a priori assumptions about sources of uncertainty in the data. Bootstrap methods have been proposed as a way of circumventing this problem, deriving the uncertainty from the data themselves--but acquisition times for data amenable to precise and robust bootstrapping are clinically prohibitive. By combining the wild bootstrap, recently introduced to the DT-MRI literature, with tractography, we show how confidence can be assigned to reconstructed trajectories using data collected in a fraction of the time required for regular bootstrapping. We compare in vivo wild bootstrap tracking results with regular tracking results and show that results are comparable. This approach therefore allows users who have collected data sets for use with deterministic tracking algorithms, rather than those specifically designed for bootstrapping, to be able to apply bootstrap analyses and retrospectively assign confidence to their reconstructed trajectories with minimum additional effort.