Isolated Diastolic Hypertension in the UK Biobank: Comparison of ACC/AHA and ESC/NICE Guideline Definitions.
The 2017 American College of Cardiology/American Heart Association guideline defines hypertension as a blood pressure ≥130/80 mm Hg, whereas the 2018 European Society of Cardiology (ESC) and 2019 National Institute for Health and Care Excellence (NICE) guidelines use a ≥140/90 mm Hg threshold. Our objective was to study the associations between isolated diastolic hypertension (IDH), diagnosed using these 2 blood pressure thresholds, and cardiovascular disease (CVD) in a large cohort of UK adults. We analyzed data from UK Biobank, which enrolled participants between 2006 and 2010 with follow-up through March 2019. We excluded persons with systolic hypertension or baseline CVD. We defined incident CVD as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. We used Cox regression to quantify associations between IDH and CVD, as well as the individual outcomes included in the composite outcome. We studied 151 831 participants with normal systolic blood pressure (mean age 54 years, 40% male). Overall, 24.5% had IDH by the American College of Cardiology/American Heart Association definition compared with 6% by the ESC/NICE definition. Compared with normal diastolic blood pressure, IDH by the American College of Cardiology/American Heart Association definition was not significantly associated with CVD risk (hazard ratio, 1.08 [95% CI, 0.98-1.18]) whereas IDH by the ESC/NICE definition was significantly associated with a modest increase in CVD (hazard ratio, 1.15 [95% CI, 1.04-1.29]). Similar results were found by sex and among participants not taking baseline antihypertensives. Furthermore, neither IDH definition was associated with the individual outcomes of nonfatal myocardial infarction or stroke. In conclusion, the proportion of UK Biobank participants with IDH was significantly higher by the American College of Cardiology/American Heart Association definition compared with the ESC/NICE definitions; however, only the ESC/NICE definition was statistically associated with increased CVD risk.


Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas.
Prohormone convertases (PCs) are proteinases that cleave inactive prohormones to biologically active peptides. Seven PCs have been identified; two of them, PC1/3 and PC2, have only been localized in neuroendocrine (NE) tissues; a third, furin, in both endocrine and exocrine tissues. We have studied the immunoreactivity of PC1/3, PC2 and furin in the four major NE cell types of the human pancreas by using double immunofluorescence techniques. The study also included the expression of NE secretory protein 7B2 (secretogranin V), a member of the granin family, which influences the function of PC2. The results showed that the three PCs and 7B2 were expressed only in endocrine pancreas, furin also in exocrine cells. Insulin (B) cells harboured PC1/3 and PC2, but not furin. Glucagon (A) cells were immunoreactive to all three PCs; all glucagon cells expressed PC2, but one subpopulation showed PC1/3 immunoreactivity and another furin. Only a few somatostatin (D) cells contained PC2, but no other proconvertase. Pancreatic polypeptide (PP) cells were non-reactive to all three PCs. 7B2 occurred only in insulin and glucagon cells. A varying co-localization pattern was observed between PCs and between PCs and 7B2, with the exception of PC1/3 and furin which were not co-localized. In conclusion, our study shows that PCs are localized in insulin and glucagon cells and do seem to be important in these cell types for processing of hormone and other protein precursors, especially chromogranins, but for the two other major cell types probably other enzymes are of importance.


The mechanism of tail-anchored protein insertion into the ER membrane.
Tail-anchored (TA) proteins access the secretory pathway via posttranslational insertion of their C-terminal transmembrane domain into the endoplasmic reticulum (ER). Get3 is an ATPase that delivers TA proteins to the ER by interacting with the Get1-Get2 transmembrane complex, but how Get3's nucleotide cycle drives TA protein insertion remains unclear. Here, we establish that nucleotide binding to Get3 promotes Get3-TA protein complex formation by recruiting Get3 to a chaperone that hands over TA proteins to Get3. Biochemical reconstitution and mutagenesis reveal that the Get1-Get2 complex comprises the minimal TA protein insertion machinery with functionally critical cytosolic regions. By engineering a soluble heterodimer of Get1-Get2 cytosolic domains, we uncover the mechanism of TA protein release from Get3: Get2 tethers Get3-TA protein complexes into proximity with the ATPase-dependent, substrate-releasing activity of Get1. Lastly, we show that ATP enhances Get3 dissociation from the membrane, thus freeing Get1-Get2 for new rounds of substrate insertion.


Effect of ferrihydrite on 2,4,6-trinitrotoluene biotransformation by an aerobic yeast.
This study investigated the impact of ferrihydrite on the pathway and rate of 2,4,6-trinitrotoluene (TNT) transformation by Yarrowia lipolytica AN-L15. The presence of ferrihydrite in the culture medium decreased the rate of TNT biotransformation but resulted in the accumulation of the same TNT metabolites as in the absence of ferrihydrite, albeit at slightly different concentrations. Transformation products observed included aromatic ring reduction products, such as hydride-Meisenheimer complexes, and nitro group reduction products, such as hydroxylamino- and amino-dinitrotoluenes. Independently of the presence of ferrihydrite the subsequent degradation of the hydride complex(es) resulted in the release of nitrite followed by its conversion to nitrate and nitric oxide at the low pH values observed during yeast cultivation. Nitric oxide generation was ascertained by electron spin resonance spectroscopy. In addition, increased Fe(3+)-reduction was observed in the presence of TNT and Y. lipolytica. This study demonstrates that in the presence of yeast cells, TNT-hydride complexes were formed at approximately the same level as in the presence of ferrihydrite, opening up the possibility of aromatic ring cleavage, instead of promoting the production of potentially toxic nitro group reduction products in the presence of iron minerals.


Plastic Teabags Release Billions of Microparticles and Nanoparticles into Tea.
The increasing presence of micro- and nano-sized plastics in the environment and food chain is of growing concern. Although mindful consumers are promoting the reduction of single-use plastics, some manufacturers are creating new plastic packaging to replace traditional paper uses, such as plastic teabags. The objective of this study was to determine whether plastic teabags could release microplastics and/or nanoplastics during a typical steeping process. We show that steeping a single plastic teabag at brewing temperature (95 °C) releases approximately 11.6 billion microplastics and 3.1 billion nanoplastics into a single cup of the beverage. The composition of the released particles is matched to the original teabags (nylon and polyethylene terephthalate) using Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The levels of nylon and polyethylene terephthalate particles released from the teabag packaging are several orders of magnitude higher than plastic loads previously reported in other foods. An initial acute invertebrate toxicity assessment shows that exposure to only the particles released from the teabags caused dose-dependent behavioral and developmental effects.


Importin alpha binding and nuclear localization of PARP-2 is dependent on lysine 36, which is located within a predicted classical NLS.
The enzymes responsible for the synthesis of poly-ADP-ribose are named poly-ADP-ribose polymerases (PARP). PARP-2 is a nuclear protein, which regulates a variety of cellular functions that are mainly controlled by protein-protein interactions. A previously described non-conventional bipartite nuclear localization sequence (NLS) lies in the amino-terminal DNA binding domain of PARP-2 between amino acids 1-69; however, this targeting sequence has not been experimentally examined or validated. Using a site-directed mutagenesis approach, we found that lysines 19 and 20, located within a previously described bipartite NLS, are not required for nuclear localization of PARP-2. In contrast, lysine 36, which is located within a predicted classical monopartite NLS, was required for PARP-2 nuclear localization. While wild type PARP-2 interacted with importin alpha3 and to a very weak extent with importin alpha1 and importin alpha5, the mutant PARP-2 (K36R) did not interact with importin alpha3, providing a molecular explanation why PARP-2 (K36R) is not targeted to the nucleus. Our results provide strong evidence that lysine 36 of PARP-2 is a critical residue for proper nuclear targeting of PARP-2 and consequently for the execution of its biological functions.


Supramolecular Assembly of Peptide Amphiphiles.
Peptide amphiphiles (PAs) are small molecules that contain hydrophobic components covalently conjugated to peptides. In this Account, we describe recent advances involving PAs that consist of a short peptide sequence linked to an aliphatic tail. The peptide sequence can be designed to form β-sheets among the amino acids near the alkyl tail, while the residues farthest from the tail are charged to promote solubility and in some cases contain a bioactive sequence. In water, β-sheet formation and hydrophobic collapse of the aliphatic tails induce assembly of the molecules into supramolecular one-dimensional nanostructures, commonly high-aspect-ratio cylindrical or ribbonlike nanofibers. These nanostructures hold significant promise for biomedical functions due to their ability to display a high density of biological signals on their surface for targeting or to activate pathways, as well as for biocompatibility and biodegradable nature. Recent studies have shown that supramolecular systems, such as PAs, often become kinetically trapped in local minima along their self-assembly reaction coordinate, not unlike the pathways associated with protein folding. Furthermore, the assembly pathway can influence the shape, internal structure, and dimension of nanostructures and thereby affect their bioactivity. We discuss methods to map the energy landscape of a PA structure as a function of thermal energy and ionic strength and vary these parameters to convert between kinetically trapped and thermodynamically favorable states. We also demonstrate that the pathway-dependent morphology of the PA assembly can determine biological cell adhesion and survival rates. The dynamics associated with the nanostructures are also critical to their function, and techniques are now available to probe the internal dynamics of these nanostructures. For example, by conjugating radical electron spin labels to PAs, electron paramagnetic resonance spectroscopy can be used to study the rotational diffusion rates within the fiber, showing a liquidlike to solidlike transition through the cross section of the nanofiber. PAs can also be labeled with fluorescent dyes, allowing the use of super-resolution microscopy techniques to study the molecular exchange dynamics between PA fibers. For a weak hydrogen-bonding PA, individual PA molecules or clusters exchange between fibers in time scales as short as minutes. The amount of hydrogen bonding within PAs that dictates the dynamics also plays an important role in biological function. In one case, weak hydrogen bonding within a PA resulted in cell death through disruption of lipid membranes, while in another example reduced hydrogen bonding enhanced growth factor signaling by increasing lipid raft mobility. PAs are a promising platform for designing advanced hybrid materials. We discuss a covalent polymer with a rigid aromatic imine backbone and alkylated peptide side chains that simultaneously polymerizes and interacts with a supramolecular PA structure with identical chemistry to that of the side chains. The covalent polymerization can be "catalyzed" by noncovalent polymerization of supramolecular monomers, taking advantage of the dynamic nature of supramolecular assemblies. These novel hybrid structures have potential in self-repairing materials and as reusable scaffolds for delivery of drugs or other chemicals. Finally, we highlight recent biomedical applications of PAs and related structures, ranging from bone regeneration to decreasing blood loss during internal bleeding.


Sex-ratio meiotic drive in Drosophila simulans: cellular mechanism, candidate genes and evolution.
The sex-ratio trait, reported in a dozen Drosophila species, is a type of naturally occurring meiotic drive in which the driving elements are located on the X chromosome. Typically, as the result of a shortage of Y-bearing spermatozoa, males carrying a sex-ratio X chromosome produce a large excess of female offspring. The presence of sex-ratio chromosomes in a species can have considerable evolutionary consequences, because they can affect individual fitness and trigger extended intragenomic conflict. Here, I present the main results of the study performed in Drosophila simulans. In this species, the loss of Y-bearing spermatozoa is related to the inability of the Y chromosome sister-chromatids to separate properly during meiosis II. Fine genetic mapping has shown that the primary sex-ratio locus on the X chromosome contains two distorter elements acting synergistically, both of which are required for drive expression. One element has been genetically mapped to a tandem duplication. To infer the natural history of the trait, the pattern of DNA sequence polymorphism in the surrounding chromosomal region is being analysed in natural populations of D. simulans harbouring sex-ratio X chromosomes. Initial results have revealed the recent spread of a distorter allele.


Functional interaction of yeast pre-mRNA 3' end processing factors with RNA polymerase II.
The RNA polymerase II CTD is essential for 3' end cleavage of metazoan pre-mRNAs and binds 3' end processing factors in vitro. We show genetic and biochemical interactions between the CTD and the Pcf11 subunit of the yeast cleavage/polyadenylation factor, CFIA. In vitro binding to Pcf11 required phosphorylation of the CTD on Ser2 in the YSPTSPS heptad repeats. Deletion of the yeast CTD reduced the efficiency of cleavage at poly(A) sites, and the length of poly(A) tails suggesting that it helps couple 3' end formation with transcription. Consistent with this model, the 3' end processing factors CFIA, CFIB, and PFI were recruited to genes progressively, starting at the 5' end, in a process that required ongoing transcription.


Implementing low-dose computed tomography screening for lung cancer in Canada: implications of alternative at-risk populations, screening frequency, and duration.
Low-dose computed tomography (ldct) screening has been shown to reduce mortality from lung cancer; however, the optimal screening duration and "at risk" population are not known. The Cancer Risk Management Model developed by Statistics Canada for the Canadian Partnership Against Cancer includes a lung screening module based on data from the U.S. National Lung Screening Trial (nlst). The base-case scenario reproduces nlst outcomes with high fidelity. The impact in Canada of annual screening on the number of incident cases and life-years gained, with a wider range of age and smoking history eligibility criteria and varied participation rates, was modelled to show the magnitude of clinical benefit nationally and by province. Life-years gained, costs (discounted and undiscounted), and resource requirements were also estimated. In 2014, 1.4 million Canadians were eligible for screening according to nlst criteria. Over 10 years, screening would detect 12,500 more lung cancers than the expected 268,300 and would gain 9200 life-years. The computed tomography imaging requirement of 24,000-30,000 at program initiation would rise to between 87,000 and 113,000 by the 5th year of an annual nlst-like screening program. Costs would increase from approximately $75 million to $128 million at 10 years, and the cumulative cost nationally over 10 years would approach $1 billion, partially offset by a reduction in the costs of managing advanced lung cancer. Modelling various ways in which ldct might be implemented provides decision-makers with estimates of the effect on clinical benefit and on resource needs that clinical trial results are unable to provide.


Asthma Medication Regimens in Pregnancy: Longitudinal Changes in Asthma Status.
This study aimed to assess the impact of common asthma medication regimens on asthma symptoms, exacerbations, lung function, and inflammation during pregnancy. A total of 311 women with asthma were enrolled in a prospective pregnancy cohort. Asthma medication regimen was categorized into short-acting β agonist (SABA) alone, SABA + inhaled corticosteroid (ICS), SABA + ICS + long-acting β agonist (LABA), and no asthma medications (reference). We evaluated asthma control at enrollment (< 15 weeks' gestation) and its change into trimesters 2 and 3, including per cent predicted forced expiratory volume in 1 second (%FEV1) and peak expiratory flow (%PEF), pulse oximetry, fractional exhaled nitric oxide (FeNO), asthma symptoms (asthma attacks/month, night symptoms/week), and severe exacerbations. Linear mixed models adjusted for site, age, race, annual income, gestational age, body mass index, and smoking, and propensity scores accounted for asthma control status at baseline. Women taking SABA + ICS and SABA + ICS + LABA had better first trimester %PEF (83.5% [75.7-91.3] and 84.6% [76.9-92.3], respectively) compared with women taking no asthma medications (72.7% [66.0-79.3]). Women taking SABA + ICS + LABA also experienced improvements in %FEV1 (+11.1%, p < 0.01) in the third trimester and FeNO in the second (-12.3 parts per billion [ppb], p < 0.01) and third (-11.0 ppb, p < 0.01) trimesters as compared with the trajectory of women taking no medications. SABA + ICS use was associated with increased odds of severe exacerbations in the first (odds ratio [OR]: 2.22 [1.10-4.46]) and second (OR: 3.15 [1.11-8.96]) trimesters, and SABA + ICS + LABA use in the second trimester (OR: 7.89 [2.75-21.47]). Women taking SABA alone were similar to those taking no medication. Pregnant women taking SABA + ICS and SABA + ICS + LABA had better lung function in the first trimester. SABA + ICS + LABA was associated with improvements in lung function and inflammation across gestation. However, both the SABA + ICS and SABA + ICS + LABA groups had a higher risk of severe exacerbation during early to mid-pregnancy. · Medication regimens may affect perinatal asthma control.. · Intensive regimens improved lung function/inflammation.. · Women on intensive regimens had more acute asthma events..


Superselective vesical artery embolization in the management of intractable hematuria secondary to hemorrhagic cystitis.
To evaluate the efficacy and outcome of superselective vesical arterial embolization in the management of severe intractable hematuria secondary to hemorrhagic cystitis. We retrospectively reviewed the medical records of nine patients with severe intractable hematuria treated with superselective vesical artery embolization at our institution between March 2003 and February 2015. There were six males and three females with a mean age of 56.1 years. Seven patients had transitional cell carcinoma (TCC) of urinary bladder and had undergone transurethral resection of bladder tumor and pelvic radiotherapy. One patient had synchronous renal pelvis and bladder TCC. One patient had aortoarteritis and was receiving cyclophosphamide therapy and another patient had carcinoma cervix post-pelvic radiotherapy. Following the failure of conservative management, superselective vesical artery catheterization and embolization was performed with 300-500-μ PVA particles in all patients. Coil embolization of inferior gluteal artery followed by particle embolization of vesical arteries was done in one patient in whom superior, inferior vesical and inferior gluteal arteries were arising as a trifurcation. The technical success rate was 100% with complete cessation of hematuria within 48 h in all patients. No significant complications were noted, except for post-embolization syndrome in one patient, which improved on symptomatic treatment. During a mean follow-up period of 14.45 months (ranging from 3-28 months), one patient had mild recurrent hematuria (at 2 months) which resolved spontaneously. Superselective vesical artery embolization is a safe and effective procedure in controlling intractable life-threatening hematuria in a select group of patients who have failed conventional treatment protocols. This procedure may be considered as the treatment of choice since it usually obviates the need for emergency surgery in these severely ill patients.


Effect of Force Field Parameters on Sodium and Potassium Ion Binding to Dipalmitoyl Phosphatidylcholine Bilayers.
The behavior of electrolytes in molecular dynamics simulations of zwitterionic phospholipid bilayers is very sensitive to the force field parameters used. Here, several 200 ns molecular dynamics of simulations of dipalmitoyl phosphotidylcholine (PC) bilayers in 0.2 M sodium or potassium chloride using various common force field parameters for the cations are presented. All employed parameter sets give a larger number of Na(+) ions than K(+) ions that bind to the lipid heads, but depending on the parameter choice quite different results are seen. A wide range of coordination numbers for the Na(+) and K(+) ions is also observed. These findings have been analyzed and compared to published experimental data. Some simulations produce aggregates of potassium chloride, indicating (in accordance with published simulations) that these force fields do not reproduce the delicate balance between salt and solvated ions. The differences between the force fields can be characterized by one single parameter, the electrostatic radius of the ion, which is correlated to σMO (M represents Na(+)/K(+)), the Lennard-Jones radius. When this parameter exceeds a certain threshold, binding to the lipid heads is no longer observed. One would, however, need more accurate experimental data to judge or rank the different force fields precisely. Still, reasons for the poor performance of some of the parameter sets are clearly demonstrated, and a quality control procedure is provided.


Refresh my memory: Episodic memory reinstatements intrude on working memory maintenance.
A fundamental question in memory research is how different forms of memory interact. Previous research has shown that people rely on working memory (WM) in short-term recognition tasks; a common view is that episodic memory (EM) only influences performance on these tasks when WM maintenance is disrupted. However, retrieval of memories from EM has been widely observed during brief periods of quiescence, raising the possibility that EM retrievals during maintenance-critically, before a response can be prepared-might affect short-term recognition memory performance even in the absence of distraction. We hypothesized that this influence would be mediated by the lingering presence of reactivated EM content in WM. We obtained support for this hypothesis in three experiments, showing that delay-period EM reactivation introduces incidentally associated information (context) into WM, and that these retrieved associations negatively impact subsequent recognition, leading to substitution errors (Experiment 1) and slowing of accurate responses (Experiment 2). FMRI pattern analysis showed that slowing is mediated by the content of EM reinstatement (Experiment 3). These results expose a previously hidden influence of EM on WM, raising new questions about the adaptive nature of their interaction.


Diagnosis of bladder cancer recurrence based on urinary levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 hypermethylation.
Non muscle invasive bladder cancer (NMIBC) has the highest recurrence rate of any malignancy and as many as 70% of patients experience relapse. Aberrant DNA methylation is present in all bladder tumors and can be detected in urine specimens. Previous studies have identified DNA methylation markers that showed significant diagnostic value. We evaluated the significance of the biomarkers for early detection of tumor recurrence in urine. The methylation levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 in urine specimens were measured by real-time PCR (MethyLight). We analyzed 390 urine sediments from 184 patients diagnosed with NMIBC. Urine from 35 age-matched control individuals was used to determine the methylation baseline levels. Recurrence was diagnosed by cystoscopy and verified by histology. Initially, we compared urine from bladder cancer patients and healthy individuals and detected significant hypermethylation of all six markers (P<0.0001) achieving sensitivity in the range 82%-89% and specificity in the range 94%-100%. Following, we validated the urinary hypermethylation for use in recurrence surveillance and found sensitivities of 88-94% and specificities of 43-67%. EOMES, POU4F2, VIM and ZNF154 were more frequently methylated in urine from patients with higher grade tumors (P ≤ 0.08). Univariate Cox regression analysis showed that five markers were significantly associated with disease recurrence; HOXA9 (HR=7.8, P=0.006), POU4F2 (HR=8.5, P=0.001), TWIST1 (HR=12.0, P=0.015), VIM (HR=8.0, P=0.001), and ZNF154 (HR=13.9, P<0.001). Interestingly, for one group of patients (n=15) we found that hypermethylation was consistently present in the urine samples despite the lack of tumor recurrences, indicating the presence of a field defect. Methylation levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 in urine specimens are promising diagnostic biomarkers for bladder cancer recurrence surveillance.


Clinicians' caseload management behaviours as explanatory factors in patients' length of time on caseloads: a predictive multilevel study in paediatric community occupational therapy.
Long waiting times and large caseloads are a challenge to children's therapy services internationally. Research in hospital-based healthcare indicates that waiting times are a function of throughput, and that length of care episode is related to clinicians' caseload management behaviour (i.e. actions at assessment, treatment, post-treatment, and discharge). There have been few attempts to study this in community health services. The present study investigated whether community occupational therapists' behaviour predicts children's length of time (LoT) on caseloads. Retrospective survey of case notes of children recently discharged from occupational therapy services. Using cluster random sampling, case notes were drawn from therapy records in six NHSScotland Health Boards. Data about therapists' behaviours of assessing, treating, reviewing and discharging, together with child characteristics, were used to construct regression models of factors related to LoT. Twenty-six therapists [median(IQR) time in paediatrics 8(6-13) years] and 154 of their cases [mean(SD) age 7(3) years; median(IQR) LoT 10(3-21)] were included. A multi-level model, adjusting for clustering, for therapists' actions of communicating assessment outcomes to parents, providing treatment, and placing the child on review, and for a diagnosis of cerebral palsy, explained 44% of variation in LoT. Occupational therapists' caseload management behaviours are associated with children's LoT on caseloads. Further research is required to investigate the direction of relationships between therapists' behaviours and LoT; and the relationships between contextual factors, therapists' caseload management behaviours and LoT. Further exploration of therapists' beliefs about caseload management could also be useful in identifying possible factors contributing to variation between therapists.


T cells produce TRF in response to Con A and factors in T cell hybridoma supernatants.
In recent experiments, a soluble factor (TRF) that mediates the differentiation of anti-immunoglobulin (Ig)-activated B cells to Ig-secreting cells has been identified. TRF works in concert with a growth factor, probably IL 2, in the induction of activated B cells. In previous studies, TRF was identified in culture supernatants of activated T cells and accessory cells, and thus the cellular source (T cell or accessory cell) of the factor was not determined. In the present studies, we succeeded in inducing the production of TRF by T cell populations from which accessory cells had been vigorously depleted. Lymph node cells were depleted of accessory cells by nylon wool adherence and anti-Ia and complement treatment; these cells were activated with Con A and a T cell hybridoma supernatant that contains IL 2. Supernatants from these activated T cell cultures supported the differentiation of anti-Ig-activated B cells to Ig secreting cells. These results show that T cells produce the differentiation factor, and further that they do so in response to ligand (Con A) plus a T cell-derived factor.


The importance of active learning and practice on the students' mastery of pharmacokinetic calculations for the intermittent intravenous infusion dosing of antibiotics.
Estimation of pharmacokinetic parameters after intermittent intravenous infusion (III) of antibiotics, such as aminoglycosides or vancomycin, has traditionally been a difficult subject for students in clinical pharmacology or pharmacokinetic courses. Additionally, samples taken at different intervals during repeated dose therapy require manipulation of sampling times before accurate calculation of the patient-specific pharmacokinetic parameters. The main goal of this study was to evaluate the effectiveness of active learning tools and practice opportunities on the ability of students to estimate pharmacokinetic parameters from the plasma samples obtained at different intervals following intermittent intravenous infusion. An extensive reading note, with examples, and a problem case, based on a patient's chart data, were created and made available to students before the class session. Students were required to work through the case before attending the class. The class session was devoted to the discussion of the case requiring active participation of the students using a random participation program. After the class, students were given additional opportunities to practice the calculations, using online modules developed by the instructor, before submitting an online assignment. The performance of students significantly (P < 0.001) improved from a baseline of 11.3% (pretest) to 60.3% (posttest) after the class discussion. The grades of students further improved (P < 0.001) to 89.3% on the take-home assignment after they had a chance to study on their own and work on the online practices. Finally, students scored 82.6% in a formal mid-term examination, suggesting significant retention of the materials. Despite being a difficult subject, students achieve mastery of pharmacokinetic calculations for the topic of intermittent intravenous infusion when appropriate active learning strategies and practice opportunities are employed.


Sepsis mediators.
During sepsis, the plasma levels of numerous inflammatory markers are enhanced. Some of these markers are the mediators responsible for the syndromes observed during sepsis as well as for organ dysfunction and eventually death. Their role has been demonstrated in experimental models that employed either transgenic and gene-targeted animals or the use of neutralizing agents. Accordingly, anaphylatoxins generated after complement system activation, factors of coagulation and fibrinolysis, proinflammatory cytokines, chemokines, proteases, lipid mediators, nitric oxide, and cell markers of stress (eg, high mobility group box-1) have been shown to contribute to the deleterious events observed during sepsis. On the other hand, the counter-regulation of the inflammatory process, which involves mediators such as anti-inflammatory cytokines and some neuromediators, can jeopardize the immune status of the host and render the patients more sensitive to nosocomial infections.


Circulating tumor cell detection using a parallel flow micro-aperture chip system.
We report on-chip isolation and detection of circulating tumor cells (CTCs) from blood samples using a system that integrates a microchip with immunomagnetics, high-throughput fluidics and size-based filtration. CTCs in a sample are targeted via their surface antigens using magnetic beads functionalized with antibodies. The mixture is then run through a fluidic chamber that contains a micro-fabricated chip with arrays of 8 μm diameter apertures. The fluid runs parallel to the microchip while a magnetic field is generated underneath to draw the beads and cells bound to them toward the chip surface for detection of CTCs that are larger than the apertures and clear out free beads and other smaller particles bound to them. The parallel flow configuration allows high volumetric flow rates, which reduces nonspecific binding to the chip surface and enables multiple circulations of the sample fluid through the system in a short period of time. In this study we first present models of the magnetic and fluidic forces in the system using a finite element method. We then verify the simulation results experimentally to determine an optimal flow rate. Next, we characterize the system by detecting cancer cell lines spiked into healthy human blood and show that on average 89% of the spiked MCF-7 breast cancer cells were detected. We finally demonstrate detection of CTCs in 49 out of 50 blood samples obtained from non-small cell lung cancer (NSCLC) patients and pancreatic cancer (PANC) patients. The number of CTCs detected ranges from 2 to 122 per 8 mL s of blood. We also demonstrate a statistically significant difference between the CTC counts of NSCLC patients who have received therapy and those who have not.


PRISM: Priority Symptom Management Project phase I: assessment.
To provide an overview of the process, goals, and outcome recommendations from the assessment phase of the Oncology Nursing Society's Priority Symptom Management (PRISM) project and to provide the foundation for a series of evidence-based practice and qualitative systematic review articles generated from the first phase of PRISM. Published articles, abstracts, and books; computerized databases; nonpublished research; personal communications; and proceedings of the PRISM summit meeting. Symptom management is a key component in quality cancer care. The assessment phase of PRISM yielded systematic reviews with an evidence-based framework to evaluate key symptoms, developed a framework for teaching and evaluating other symptoms, and recommended future ONS initiatives. Outcome recommendations from the PRISM summit targeted practice; professional and public education; research; and health policy. These activities provide background for subsequent evidence-based practice and qualitative systematic review articles that will focus on cancer symptom management.


Dehydroepiandrosterone (DHEA) reduces neuronal injury in a rat model of global cerebral ischemia.
Many studies report an inverse correlation between levels of DHEA and neurological diseases. Exogenous DHEA protects hippocampal neurons against excitatory amino acid induced neurotoxicity. The purpose of this experiment is to evaluate the effect of DHEA in an animal model of transient but severe forebrain ischemia. At thirteen days prior to induction of ischemia, male Wistar rats were implanted with various doses of DHEA-placebo, 25 mg, 50 mg or 100 mg. Forebrain ischemia was induced for 10 min using a modified four-vessel occlusion technique, with hippocampal neuronal injury assessed at 7 days post-ischemically and expressed as a percentage of total cells. Both normal and necrotic hippocampal CA(1) cells were counted. Percentages of hippocampal injury observed were 88+/-13% in animals treated with placebo, 84+/-8% in the 25 mg DHEA group, and 60+/-7% in the 50 mg DHEA group. Animals treated with 100 mg DHEA displayed a significant (P<0.05) reduction of hippocampal CA(1) cell injury at 60+/-7% Treatment with a high dose, but not a low or moderate dose, of DHEA implantation reduces hippocampal CA(1) neuronal injury following severe but transient forebrain ischemia.


Neutralization of colony-stimulating factor 1 receptor prevents sickness behavior syndrome by reprogramming inflammatory monocytes to produce IL-10.
Sickness behavior syndrome (SBS) as characterized by fatigue and depression impairs quality of life in patients with inflammatory diseases caused by infections and autoimmunity. Systemic engagement of CD40 in mice leads to an inflammatory syndrome with acute hepatitis, lymphadenopathy and development of SBS as evidenced by induction of sleep and weight loss. In the study presented here we show that the elimination of resident tissue macrophages in mice by antibody-mediated neutralization of colony-stimulating factor-1 receptor (CSF1R) did not prevent CD40 induced hepatitis, but conferred resistance to the development of SBS. The protective effect of CSF1R mAb on weight loss and behavior changes induced by CD40 activation coincided with the transformation of pro-inflammatory monocytes to IL-10 producing myeloid cells. In IL-10 knockout mice CSF1R neutralization failed to exert protection from the occurrence of SBS. This study establishes the unexpected key role of CSF1R in the polarization of inflammatory monocytes and thereby SBS in inflammatory liver diseases.


Ethics and etiquette in neonatal intensive care.
When parents voice their dissatisfaction with the neonatal intensive care unit (NICU), it is often not because they think their baby has not received good medical care. Instead, it is often because their needs have not been addressed. Policy statements and pedagogy alike urge professionals to be empathetic, compassionate, honest, and caring. However, these theoretical concepts are generally endorsed without practical suggestions on how to achieve these goals. Negative encounters for parents are generally not about the caregivers' technical expertise or knowledge and often reflect a failure in a different domain. Simple rules of etiquette are not always applied in a busy NICU or in the hospital at large. The investigators of the POST (Parents from the Other Side of Treatment) group are health care professionals who regularly communicate with parents of sick children and who were also "NICU parents." We have developed an etiquette-based systematic approach to communication with families in the NICU. These specific and practical recommendations may help parents feel well treated and respected as they go through a challenging NICU stay.


Evidence of eelgrass (Zostera marina) seed dispersal by northern diamondback terrapin (Malaclemys terrapin terrapin) in lower Chesapeake Bay.
The initial discovery in May 2009 of eelgrass (Zostera marina) seeds in fecal samples of wild-caught northern diamondback terrapins (Malaclemys terrapin terrapin) was the first field evidence of eelgrass seed ingestion in this species. This finding suggested the potential of terrapins as seed dispersers in eelgrass beds, which we sampled for two additional years (2010 and 2011). Seeds were only found in feces of terrapins captured prior to June 8 in all three years, coinciding with eelgrass seed maturation and release. Numbers of seeds in terrapin feces varied annually and decreased greatly in 2011 after an eelgrass die off in late 2010. The condition of seeds in terrapin feces was viable-mature, germinated, damaged, or immature. Of terrapins captured during time of seed release, 97% were males and juvenile females, both of which had head widths <30 mm. The fraction of individuals with ingested seeds was 33% for males, 35% for small females, and only 6% for large (mature) females. Probability of seed ingestion decreased exponentially with increasing terrapin head width; only males and small females (head width <30 mm) were likely to be vectors of seed dispersal. The characteristic that diamondback terrapins have well-defined home ranges allowed us to estimate the number of terrapins potentially dispersing eelgrass seeds annually. In seagrass beds of the Goodwin Islands region (lower York River, Virginia), there were 559 to 799 terrapins, which could disperse between 1,341 and 1,677 eelgrass seeds annually. These would represent a small proportion of total seed production within a single seagrass bed. However, based on probable home range distances, terrapins can easily traverse eelgrass meadow boundaries, thereby dispersing seeds beyond the bed of origin. Given the relatively short dispersion distance of eelgrass seeds, the diamondback terrapin may be a major source of inter-bed seed dispersal and genetic diversity.


The In Vitro Antimicrobial Effects of Lavandula angustifolia Essential Oil in Combination with Conventional Antimicrobial Agents.
The paper focuses on the in vitro antimicrobial activity of Lavandula angustifolia Mill. (lavender) essential oil in combination with four commercial antimicrobial agents. Stock solutions of chloramphenicol, ciprofloxacin, nystatin, and fusidic acid were tested in combination with L. angustifolia essential oil. The antimicrobial activities of the combinations were investigated against the Gram-positive bacterial strain Staphylococcus aureus (ATCC 6538) and Gram-negative Pseudomonas aeruginosa (ATCC 27858) and Candida albicans (ATCC 10231) was selected to represent the yeasts. The antimicrobial effect was performed using the minimum inhibitory concentration (MIC) microdilution assay. Isobolograms were constructed for varying ratios. The most prominent interaction was noted when L. angustifolia essential oil was combined with chloramphenicol and tested against the pathogen P. aeruginosa (ΣFIC of 0.29). Lavendula angustifolia essential oil was shown in most cases to interact synergistically with conventional antimicrobials when combined in ratios where higher volumes of L. angustifolia essential oil were incorporated into the combination.


Improved survival with preoperative radiotherapy in resectable rectal cancer.
Adjuvant radiotherapy for rectal cancer has been extensively studied, but no trial has unequivocally demonstrated improved overall survival with radiotherapy, despite a reduction in the rate of local recurrence. Between March 1987 and February 1990, we randomly assigned 1168 patients younger than 80 years of age who had resectable rectal cancer to undergo preoperative irradiation (25 Gy delivered in five fractions in one week) followed by surgery within one week or to have surgery alone. The irradiation did not increase postoperative mortality. After five years of follow-up, the rate of local recurrence was 11 percent (63 of 553 patients) in the group that received radiotherapy before surgery and 27 percent (150 of 557) in the group treated with surgery alone (P<0.001). This difference was found in all subgroups defined according to Dukes' stage. The overall five-year survival rate was 58 percent in the radiotherapy-plus-surgery group and 48 percent in the surgery-alone group (P=0.004). The cancer-specific survival rates at nine years among patients treated with curative resection were 74 percent and 65 percent, respectively (P=0.002). A short-term regimen of high-dose preoperative radiotherapy reduces rates of local recurrence and improves survival among patients with resectable rectal cancer.


Reconstruction of cyclooxygenase evolution in animals suggests variable, lineage-specific duplications, and homologs with low sequence identity.
Cyclooxygenase (COX) enzymatically converts arachidonic acid into prostaglandin G/H in animals and has importance during pregnancy, digestion, and other physiological functions in mammals. COX genes have mainly been described from vertebrates, where gene duplications are common, but few studies have examined COX in invertebrates. Given the increasing ease in generating genomic data, as well as recent, although incomplete descriptions of potential COX sequences in Mollusca, Crustacea, and Insecta, assessing COX evolution across Metazoa is now possible. Here, we recover 40 putative COX orthologs by searching publicly available genomic resources as well as ~250 novel invertebrate transcriptomic datasets. Results suggest the common ancestor of Cnidaria and Bilateria possessed a COX homolog similar to those of vertebrates, although such homologs were not found in poriferan and ctenophore genomes. COX was found in most crustaceans and the majority of molluscs examined, but only specific taxa/lineages within Cnidaria and Annelida. For example, all octocorallians appear to have COX, while no COX homologs were found in hexacorallian datasets. Most species examined had a single homolog, although species-specific COX duplications were found in members of Annelida, Mollusca, and Cnidaria. Additionally, COX genes were not found in Hemichordata, Echinodermata, or Platyhelminthes, and the few previously described COX genes in Insecta lacked appreciable sequence homology (although structural analyses suggest these may still be functional COX enzymes). This analysis provides a benchmark for identifying COX homologs in future genomic and transcriptomic datasets, and identifies lineages for future studies of COX.


Below the disappearing marshes of an urban estuary: historic nitrogen trends and soil structure.
Marshes in the urban Jamaica Bay Estuary, New York, USA are disappearing at an average rate of 13 ha/yr, and multiple stressors (e.g., wastewater inputs, dredging activities, groundwater removal, and global warming) may be contributing to marsh losses. Among these stressors, wastewater nutrients are suspected to be an important contributing cause of marsh deterioration. We used census data, radiometric dating, stable nitrogen isotopes, and soil surveys to examine the temporal relationships between human population growth and soil nitrogen; and we evaluated soil structure with computer-aided tomography, surface elevation and sediment accretion trends, carbon dioxide emissions, and soil shear strength to examine differences among disappearing (Black Bank and Big Egg) and stable marshes (JoCo). Radiometric dating and nitrogen isotope analyses suggested a rapid increase in human wastewater nutrients beginning in the late 1840s, and a tapering off beginning in the 1930s when wastewater treatment plants (WWTPs) were first installed. Current WWTPs nutrient loads to Jamaica Bay are approximately 13 995 kg N/d and 2767 kg P/d. At Black Bank, the biomass and abundance of roots and rhizomes and percentage of organic matter on soil were significantly lower, rhizomes larger in diameter, carbon dioxide emission rates and peat particle density significantly greater, and soil strength significantly lower compared to the stable JoCo Marsh, suggesting Black Bank has elevated decomposition rates, more decomposed peat, and highly waterlogged peat. Despite these differences, the rates of accretion and surface elevation change were similar for both marshes, and the rates of elevation change approximated the long-term relative rate of sea level rise estimated from tide gauge data at nearby Sandy Hook, New Jersey. We hypothesize that Black Bank marsh kept pace with sea level rise by the accretion of material on the marsh surface, and the maintenance of soil volume through production of larger diameter rhizomes and swelling (dilation) of waterlogged peat. JoCo Marsh kept pace with sea-level rise through surface accretion and soil organic matter accumulation. Understanding the effects of multiple stressors, including nutrient enrichment, on soil structure, organic matter accumulation, and elevation change will better inform management decisions aimed at maintaining and restoring coastal marshes.


Assessment of the Quality of Life in Moroccan Patients Undergoing Orthognathic Surgery.
Dentofacial deformities can affect patient "quality of life" (QoL), and orthognathic surgery can improve this QoL. The aim of the present study is to assess changes in QoL in Moroccan adult patients with dentofacial deformities undergoing orthodontic surgical treatment. 32 patients (21 females and 11 males; mean age 27±5.96 years) completed a specific questionnaire of QoL once the surgical phase is completed. The questionnaire includes 22 questions marked on a 4-point scale depending on how much the question covered by the statement disturbs the respondent. The 22 questions contribute to four aspects: social aspects of dentofacial deformities, facial aesthetic, oral function, and awareness of dentofacial aesthetics. A significant difference in QoL was observed before surgery between men and women. On the other hand, 73.6% stated of patients said that they were uncomfortable by their dentofacial appearance before surgery, and almost half of the patients have made functional limitations before surgery. After surgery, 85.42% of patients reported a positive change in their QoL. Class III patients reported greater pre-surgical aesthetic and functional restrictions than Class II skeletal patients. In post-surgery, patients in both skeletal classes showed significant improvement in their QoL, so improving the aesthetics, oral functions and self-confidence are the main motivators to seek orthognathic treatment for our patients. Improving the aesthetics, oral functions and self-confidence are the main motivators to seek orthognathic treatment for Moroccan patients.


Characterization of late gene transcripts expressed during vegetative replication of human papillomavirus type 31b.
Human papillomaviruses (HPVs) are etiologic agents of anogenital cancers. The lack of an efficient in vitro system with which to study the differentiation-dependent viral life cycle has impeded most investigations of viral transcription and gene expression. The CIN-612 clone 9E cell line latently maintains episomal copies of HPV type 31b (HPV31b). The complete replicative life cycle of HPV31b can be studied by using the organotypic (raft) culture system. A number of spliced HPV31b early gene transcripts and two late gene transcripts have been described in studies using the raft system. An HPV31b early promoter, P97, and a differentiation-induced promoter, P742, have been characterized by using this system. In this study, we used the raft system to analyze the temporal expression patterns of HPV31b late gene transcripts during the viral life cycle. The expression of late RNAs peaked at day 12 after lifting to the air-liquid interface; the levels then declined dramatically by day 16. The peak of late RNA expression was coincident with the appearance of virus particles in the raft tissues. We characterized transcripts with the potential to encode late gene products, including 19 RNAs containing the L1 region and 4 RNAs containing the E5b and L2 open reading frames. We also found evidence for two novel promoters. Transcription of both L1- and L2-containing RNAs initiated at a region upstream of the early promoter. In addition, late gene RNAs were also transcribed by using a promoter in the E4 reading frame.


Frequency matters: comparison of drug resistance mutation detection by Sanger and next-generation sequencing in HIV-1.
Next-generation sequencing (NGS) is gradually replacing Sanger sequencing (SS) as the primary method for HIV genotypic resistance testing. However, there are limited systematic data on comparability of these methods in a clinical setting for the presence of low-abundance drug resistance mutations (DRMs) and their dependency on the variant-calling thresholds. To compare the HIV-DRMs detected by SS and NGS, we included participants enrolled in the Swiss HIV Cohort Study (SHCS) with SS and NGS sequences available with sample collection dates ≤7 days apart. We tested for the presence of HIV-DRMs and compared the agreement between SS and NGS at different variant-calling thresholds. We included 594 pairs of SS and NGS from 527 SHCS participants. Males accounted for 80.5% of the participants, 76.3% were ART naive at sample collection and 78.1% of the sequences were subtype B. Overall, we observed a good agreement (Cohen's kappa >0.80) for HIV-DRMs for variant-calling thresholds ≥5%. We observed an increase in low-abundance HIV-DRMs detected at lower thresholds [28/417 (6.7%) at 10%-25% to 293/812 (36.1%) at 1%-2% threshold]. However, such low-abundance HIV-DRMs were overrepresented in ART-naive participants and were in most cases not detected in previously sampled sequences suggesting high sequencing error for thresholds <3%. We found high concordance between SS and NGS but also a substantial number of low-abundance HIV-DRMs detected only by NGS at lower variant-calling thresholds. Our findings suggest that a substantial fraction of the low-abundance HIV-DRMs detected at thresholds <3% may represent sequencing errors and hence should not be overinterpreted in clinical practice.


SAMStat: monitoring biases in next generation sequencing data.
The sequence alignment/map format (SAM) is a commonly used format to store the alignments between millions of short reads and a reference genome. Often certain positions within the reads are inherently more likely to contain errors due to the protocols used to prepare the samples. Such biases can have adverse effects on both mapping rate and accuracy. To understand the relationship between potential protocol biases and poor mapping we wrote SAMstat, a simple C program plotting nucleotide overrepresentation and other statistics in mapped and unmapped reads in a concise html page. Collecting such statistics also makes it easy to highlight problems in the data processing and enables non-experts to track data quality over time. We demonstrate that studying sequence features in mapped data can be used to identify biases particular to one sequencing protocol. Once identified, such biases can be considered in the downstream analysis or even be removed by read trimming or filtering techniques. SAMStat is open source and freely available as a C program running on all Unix-compatible platforms. The source code is available from http://samstat.sourceforge.net. email@example.com.


Cystic fibrosis: newborn screening in America.
Cystic fibrosis is the most common lethal genetic disease in Caucasians, manifesting as progressive lung dysfunction, pancreatic insufficiency, and intestinal disease. CF was traditionally diagnosed clinically, either because of a family history or occurrence of meconium ileus, or as a result of intestinal malabsorption and chronic pulmonary disease. In 1979, it was discovered that immunoreactive trypsinogen was increased in neonatal dried-blood specimens on Guthrie cards, making it possible to screen neonates. During the past decades, survival rates of patients with CF have improved significantly (see Figure 5). To continue this progress, universal newborn screening has been implemented in many states as an addition to the arsenal of therapies and strategies to improve survival. National newborn-screening programs to identify CF patients after birth have been adopted for a number of years in Europe, Australia, and Canada. As expected, many benefits have been seen due to the early identification of CF patients, including improved survival, better lung function and growth with less intensive therapy, and reduced cost of therapy. To date, 37 states in the United States have adopted similar programs, in the hopes of improving CF outcomes. This welcome trend should help improve the lives of CF patients living in America.


Gender differences in osteoporosis and fractures.
Osteoporosis is generally thought of as a "woman's disease" because the prevalence of osteoporosis and the rate of fractures are much higher in postmenopausal women than in older men. However, the absolute number of men affected by osteoporosis and fractures is large, as at least 2.8 million men in the United States are thought to have osteoporosis. The purposes of this review are to (1) highlight gender differences in osteoporosis and fracture risk, (2) describe disparities in treatment and outcomes after fractures between men and women, and (3) propose solutions to reducing disparities in treatment and prevention. A literature survey was conducted using MEDLINE with a variety of search terms and using references from the author's personal collection of articles. A formal search strategy and exclusion criteria were not employed and the review is therefore selective. WHERE ARE WE NOW?: Postmenopausal women have a higher prevalence of osteoporosis and greater incidence of fracture than older men. Despite the higher fracture risk in postmenopausal women, older men tend to have worse outcomes after fracture and poorer treatment rates, although less is known about the disease course in men. Multifaceted interventions to improve the screening and treatment for osteoporosis were recently developed. WHERE DO WE NEED TO GO?: Improvement in treatment rates of those at risk, regardless of gender, is an important goal in osteoporosis management. HOW DO WE GET THERE?: Further development and evaluation of cost-effective, multifaceted interventions for screening and treatment of osteoporosis and fractures are needed; such interventions will likely improve the primary prevention of fractures.


Influence of group size on the success of wolves hunting bison.
An intriguing aspect of social foraging behaviour is that large groups are often no better at capturing prey than are small groups, a pattern that has been attributed to diminished cooperation (i.e., free riding) in large groups. Although this suggests the formation of large groups is unrelated to prey capture, little is known about cooperation in large groups that hunt hard-to-catch prey. Here, we used direct observations of Yellowstone wolves (Canis lupus) hunting their most formidable prey, bison (Bison bison), to test the hypothesis that large groups are more cooperative when hunting difficult prey. We quantified the relationship between capture success and wolf group size, and compared it to previously reported results for Yellowstone wolves hunting elk (Cervus elaphus), a prey that was, on average, 3 times easier to capture than bison. Whereas improvement in elk capture success levelled off at 2-6 wolves, bison capture success levelled off at 9-13 wolves with evidence that it continued to increase beyond 13 wolves. These results are consistent with the hypothesis that hunters in large groups are more cooperative when hunting more formidable prey. Improved ability to capture formidable prey could therefore promote the formation and maintenance of large predator groups, particularly among predators that specialize on such prey.


Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation.
A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.


Effects of mannuronic acid (M2000) on gene expression profile of signal transducer and activator of transcription proteins (STATs) in rheumatoid arthritis patients.
Rheumatoid arthritis (RA), a form of inflammatory arthritis, is a chronic joint disease characterized by pain and inflammation that affects 0.5% to 1% of the population worldwide. The safety, efficacy, tolerability, and potency of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property has been reported by several in vitro studies, experimental models and clinical trials phase I/II and III in ankylosing spondylitis and rheumatoid arthritis (RA) patients This research is designed to study the therapeutic efficacy of oral administration of mannuronic acid in RA patients who had inadequate response to conventional drugs and to assess the effect of this drug on gene expression of the signal transducer and activator of transcription (STATs) protein (STAT1, STAT3, STAT4, and STAT6). The study has included 15 RA patients who had an insufficient response to the conventional therapy. The oral dose of mannuronic acid was 1000mg divided into two 500 mg doses per day for 3 months as an addition to conventional therapy. There were 15 healthy volunteer in the control group. Blood samples were collected from both groups, once from healthy controls and twice from RA patients before and after treatment by M2000. The peripheral blood mononuclear cells (PBMCs) were isolated to assess the gene expression level of STAT1, STAT3, STAT4, and STAT6 using the real-time PCR method. Results obtained in this study demonstrated a significant difference in the gene expression level of STAT1 between healthy controls and patients before treatment as well as a significant reduction in RA patients after treatment compared with the level before treatment. In addition, the gene expression level of STAT3 and STAT4 showed a significant reduction in RA patients after treatment compared to patients before treatment, while there was no significant difference between RA patients before treatment and the healthy control group for both molecules. On the other hand, there was no change in the gene expression level of STAT6 among all groups. The outcomes of this study confirmed that β-D-mannuronic acid (M2000) has the ability to control the levels of STAT1, STAT3 and STAT4 in RA patients, and might be beneficial in the management and therapy of RA.


The effects of phenylephrine on pupil diameter and accommodation in rhesus monkeys.
Phenylephrine is used to dilate the iris through alpha-adrenergic stimulation of the iris dilator muscle. Sympathetic stimulation of the ciliary muscle is believed to be inhibitory, decreasing accommodative amplitude. Investigations in humans have suggested some loss of functional accommodation after phenylephrine. It is unclear whether this loss is due to direct action of phenylephrine on the ciliary muscle or to secondary optical factors associated with mydriasis. The purpose of this study was to determine whether phenylephrine affects Edinger-Westphal (EW)-stimulated accommodation in rhesus monkeys. The time course for maximum mydriasis was determined by videographic pupillography after phenylephrine instillation in 10 normal rhesus monkeys. Static and dynamic EW-stimulated accommodative responses were studied in five iridectomized rhesus monkeys before and after phenylephrine instillation. Accommodative amplitude was measured with a Hartinger coincidence refractometer. Dynamic accommodative responses were measured with infrared photorefraction, and functions were fitted to the data to determine peak velocity versus accommodative response relationships. The maximum dilated pupil diameter of 8.39 +/- 0.23 mm occurred 15 minutes after administration of phenylephrine. In iridectomized monkeys, postphenylephrine accommodative amplitudes were similar to prephenylephrine amplitudes. Dynamic analysis of the accommodative responses showed linear peak velocity versus accommodative amplitude relationships that were not statistically different before and after phenylephrine. alpha-Adrenergic stimulation causes a strong pupil dilation in noniridectomized monkey eyes but does not affect EW-stimulated accommodative amplitude or dynamics in anesthetized, iridectomized rhesus monkeys.


The tao of hematopoietic stem cells: toward a unified theory of tissue regeneration.
Hematopoietic stem cells (HSCs) are the best studied of the tissue-specific stem cells. By definition, HSCs have long been regarded as restricted to formation of blood cells of both the lymphoid and myeloid lineages. HSCs residing in the bone marrow microenvironment have self-renewal capacity and can repopulate the hematopoietic system of irradiated transplant recipients for the lifetime of the individual. Therefore, HSCs are extremely important targets for gene therapy applications aimed toward the treatment of inherited and acquired blood disorders. However, recent studies have suggested that a subpopulation of HSCs may have the ability to contribute to diverse cell types such as hepatocytes, myocytes, and neuronal cells, especially following induced tissue damage. Preclinical amelioration of liver disease and myocardial infarcts by HSC-enriched bone marrow cell populations raises the possibility that HSC transplants have the potential to provide therapeutic benefit for a wide variety of diseases. These surprising findings contradict the dogma that adult stem cells are developmentally restricted. Extrapolation of these findings to the clinic will be facilitated by prospective identification of the stem cells that possess this developmental plasticity. Furthermore, characterization of the signaling pathways and molecular determinants regulating the remarkable transdifferentiation capacity of these stem cells may provide insight into novel approaches for modulating frequency of differentiative potential.


An exploratory study of the need for curriculum review of Master of Public Health Degree at a Rural-based University in South Africa.
Master of Public Health (MPH) training programmes were developed worldwide in response to the crisis in human resources for health. To determine whether the MPH programme at the selected rural-based university in South Africa enabled students to achieve the MPH core competencies relevant for Lower Middle Income Countries. The study was carried out at a rural-based University in South Africa. The target population was the 2011 first-year cohort of MPH students who by the beginning of 2014 had just completed their coursework. A quantitative cross-sectional descriptive research design was adapted. Eighty-five students were randomly selected to participate in the study. A structured questionnaire comprising seven competency clusters was developed. The selected students completed a self-administered questionnaire. Only those students who signed consent forms participated in this study. The questionnaire was tested for construct validity and reliability using 10 students with similar characteristics to those sampled for the study. Microsoft Excel software was used to analyse the data descriptively in terms of frequency and percentages. The students were confident of their competencies regarding public health science skills. Amongst these were analytical assessment, communication, community and intersectorial competencies as well as ethics. However, the students lacked confidence in contextsensitive issues, planning and management, research and development, and leadership competencies. Yet the latter is the backbone of public health practice. There is a need for revamping public health curricula. In this respect, a follow-up study that builds a deeper understanding of the subject is needed.


Heparin and the in-hospital management of deep venous thrombosis: cost considerations.
Numerous protocols for the treatment of deep venous thrombosis (DVT) with heparin have been recommended. In the past, physicians rarely considered costs in their decision to use a particular protocol; however, the recent introduction of the diagnosis-related groups (DRGs) and other cost-reduction measures has imposed financial limitations on the practice of medicine and surgery. To determine how the cost of treatment for DVT at the Mayo Clinic might be affected by the use of alternative heparin protocols, we conducted a two-stage study. In the first part, charts of 40 patients with uncomplicated DVT were analyzed retrospectively to determine an "average" Mayo Clinic heparin protocol for DVT. In the second part, this "average" protocol was compared with four other currently advocated protocols, and the cost of using each protocol at the Mayo Clinic was estimated. These protocols differed from the Mayo Clinic protocol with respect to method and route of heparin administration, frequency of monitoring anticoagulation, and duration of heparin treatment. This analysis revealed that the average charges resulting from treatment of DVT at the Mayo Clinic exceeded the corresponding DRG payment and that the cost of treatment varied substantially with the protocol used (a difference of more than $2,000 between two of the protocols analyzed). A review of the literature provided little evidence to suggest that the alternative protocols were not equally effective. Therefore, we concluded that measures such as shortening the duration of heparin therapy, administration of heparin by the subcutaneous route, and minimal monitoring of anticoagulation (in patients with a low risk of bleeding) can substantially reduce the cost of treating DVT and may be no less effective than other protocols for heparinization.(ABSTRACT TRUNCATED AT 250 WORDS)


An exploration of person-centredness in practice.
Person-centredness' is a term that is becoming increasingly familiar within health and social care at a global level; it is being used to describe a standard of care that ensures the patient/client is at the centre of care delivery. In this article we explore the relevance of person-centredness in the context of nursing, taking account of the ongoing critical debate and dialogue regarding developments in this field. Person-centredness is recognised as a multidimensional concept. The complexity of the concept contributes to the challenge of articulating its shared meaning and describing how it can be applied in practice. The aim of this paper is to explore some of the issues pertaining to language and conceptual clarity, with a view to making connections and increasing our shared understanding of person-centred care in a way that can impact nursing practice. We begin by describing the development of the concept of person-centredness, after which we discuss the synergies with patient-centredness and other related terms, and consider how nurses can operationalise person-centredness in their practice.


Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers.
Carbon nanotubes (CNT) are intensively being developed for biomedical applications including drug and gene delivery. Although all possible clinical applications will require compatibility of CNT with the biological milieu, their in vivo capabilities and limitations have not yet been explored. In this work, water-soluble, single-walled CNT (SWNT) have been functionalized with the chelating molecule diethylentriaminepentaacetic (DTPA) and labeled with indium ((111)In) for imaging purposes. Intravenous (i.v.) administration of these functionalized SWNT (f-SWNT) followed by radioactivity tracing using gamma scintigraphy indicated that f-SWNT are not retained in any of the reticuloendothelial system organs (liver or spleen) and are rapidly cleared from systemic blood circulation through the renal excretion route. The observed rapid blood clearance and half-life (3 h) of f-SWNT has major implications for all potential clinical uses of CNT. Moreover, urine excretion studies using both f-SWNT and functionalized multiwalled CNT followed by electron microscopy analysis of urine samples revealed that both types of nanotubes were excreted as intact nanotubes. This work describes the pharmacokinetic parameters of i.v. administered functionalized CNT relevant for various therapeutic and diagnostic applications.


Mitochondria play a central role in estrogen-induced neuroprotection.
Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activity-relationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.


A recombinant fusion toxin based on enzymatic inactive C3bot1 selectively targets macrophages.
The C3bot1 protein (~23 kDa) from Clostridium botulinum ADP-ribosylates and thereby inactivates Rho. C3bot1 is selectively taken up into the cytosol of monocytes/macrophages but not of other cell types such as epithelial cells or fibroblasts. Most likely, the internalization occurs by a specific endocytotic pathway via acidified endosomes. Here, we tested whether enzymatic inactive C3bot1E174Q serves as a macrophage-selective transport system for delivery of enzymatic active proteins into the cytosol of such cells. Having confirmed that C3bot1E174Q does not induce macrophage activation, we used the actin ADP-ribosylating C2I (∼50 kDa) from Clostridium botulinum as a reporter enzyme for C3bot1E174Q-mediated delivery into macrophages. The recombinant C3bot1E174Q-C2I fusion toxin was cloned and expressed as GST-protein in Escherichia coli. Purified C3bot1E174Q-C2I was recognized by antibodies against C2I and C3bot and showed C2I-specific enzyme activity in vitro. When applied to cultured cells C3bot1E174Q-C2I ADP-ribosylated actin in the cytosol of macrophages including J774A.1 and RAW264.7 cell lines as well as primary cultured human macrophages but not of epithelial cells. Together with confocal fluorescence microscopy experiments, the biochemical data indicate the selective uptake of a recombinant C3-fusion toxin into the cytosol of macrophages. In summary, we demonstrated that C3bot1E174Q can be used as a delivery system for fast, selective and specific transport of enzymes into the cytosol of living macrophages. Therefore, C3-based fusion toxins can represent valuable molecular tools in experimental macrophage pharmacology and cell biology as well as attractive candidates to develop new therapeutic approaches against macrophage-associated diseases.


Cerebral blood flow imaged with ultrahigh-resolution optical coherence angiography and Doppler tomography.
Speckle contrast based optical coherence angiography (OCA) and optical coherence Doppler tomography (ODT) have been applied to image cerebral blood flow previously. However, the contrast mechanisms of these two methods are not fully studied. Here, we present both flow phantom and in vivo animal experiments using ultrahigh-resolution OCA (μOCA) and ODT (μODT) to investigate the flow sensitivity differences between these two methods. Our results show that the high sensitivity of μOCA for visualizing minute vasculature (e.g., slow capillary beds) is due to the enhancement by random Brownian motion of scatterers (e.g., red and white blood cells) within the vessels; whereas, μODT permits detection of directional flow below the Brownian motion regime (e.g., laser-induced microischemia) and is, therefore, more suitable for brain functional imaging.


Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer.
Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.


Global liver proteomics of rats exposed for 5 days to phenobarbital identifies changes associated with cancer and with CYP metabolism.
A global proteomics approach was applied to model the hepatic response elicited by the toxicologically well-characterized xenobiotic phenobarbital (PB), a prototypical inducer of hepatic xenobiotic metabolizing enzymes and a well-known nongenotoxic liver carcinogen in rats. Differential detergent fractionation two-dimensional liquid chromatography electrospray ionization tandem mass spectrometry and systems biology modeling were used to identify alterations in toxicologically relevant hepatic molecular functions and biological processes in the livers of rats following a 5-day exposure to PB at 80 mg/kg/day or a vehicle control. Of the 3342 proteins identified, expression of 121 (3.6% of the total proteins) was significantly increased and 127 (3.8%) significantly decreased in the PB group compared to controls. The greatest increase was seen for cytochrome P450 (CYP) 2B2 (167-fold). All proteins with statistically significant differences from control were then analyzed using both Gene Ontology (GO) and Ingenuity Pathways Analysis (IPA, 5.0 IPA-Tox) for cellular location, function, network connectivity, and possible disease processes, especially as they relate to CYP-mediated metabolism and nongenotoxic carcinogenesis mechanisms. The GO results suggested that PB's mechanism of nongenotoxic carcinogenesis involves both increased xenobiotic metabolism, especially induction of the 2B subfamily of CYP enzymes, and increased cell cycle activity. Apoptosis, however, also increased, perhaps, as an attempt to counter the rising cancer threat. Of the IPA-mapped proteins, 41 have functions which are procarcinogenic and 14 anticarcinogenic according to the hypothesized nongenotoxic mechanism of imbalance between apoptosis and cellular proliferation. Twenty-two additional IPA nodes can be classified as procarcinogenic by the competing theory of increased metabolism resulting in the formation of reactive oxygen species. Since the systems biology modeling corresponded well to PB effects previously elucidated via more traditional methods, the global proteomic approach is proposed as a new screening methodology that can be incorporated into future toxicological studies.


Will "Combined Prevention" Eliminate Racial/Ethnic Disparities in HIV Infection among Persons Who Inject Drugs in New York City?
It has not been determined whether implementation of combined prevention programming for persons who inject drugs reduce racial/ethnic disparities in HIV infection. We examine racial/ethnic disparities in New York City among persons who inject drugs after implementation of the New York City Condom Social Marketing Program in 2007. Quantitative interviews and HIV testing were conducted among persons who inject drugs entering Mount Sinai Beth Israel drug treatment (2007-2014). 703 persons who inject drugs who began injecting after implementation of large-scale syringe exchange were included in the analyses. Factors independently associated with being HIV seropositive were identified and a published model was used to estimate HIV infections due to sexual transmission. Overall HIV prevalence was 4%; Whites 1%, African-Americans 17%, and Hispanics 4%. Adjusted odds ratios were 21.0 (95% CI 5.7, 77.5) for African-Americans to Whites and 4.5 (95% CI 1.3, 16.3) for Hispanics to Whites. There was an overall significant trend towards reduced HIV prevalence over time (adjusted odd ratio = 0.7 per year, 95% confidence interval (0.6-0.8). An estimated 75% or more of the HIV infections were due to sexual transmission. Racial/ethnic disparities among persons who inject drugs were not significantly different from previous disparities. Reducing these persistent disparities may require new interventions (treatment as prevention, pre-exposure prophylaxis) for all racial/ethnic groups.


Demand for long-acting and permanent contraceptive methods among Kurdish women in Mahabad, Iran.
It is anticipated that the demand for contraceptives in Iran will increase in the near future as the number of women of reproductive age increases and with women wanting smaller families. The aim of this paper was to study the demand for long-acting and permanent contraceptive methods (LAPCMs), and its determinants, among Kurdish women in Mahabad city, Iran. Data were taken from the Mahabad Fertility Survey (MFS) conducted on a sample of over 700 households in April 2012. The results show that the demand for LAPCMs was 71.35% at the time of survey, although only 27.7% of women were using these methods. Thus, the number of unintended pregnancies is likely to increase in the future if this gap is not reduced. The multivariate analysis showed significant impacts on the dependent variables of the number of children ever born, perceived contraceptive costs and childbearing intentions. Moreover, women at the end of their reproductive lives and those with higher education were more likely to desire LAPCMs. It is concluded that despite a growing use of contraceptive methods in Iran in recent decades, the development of reproductive health services and promotion of the quality of family planning services remains a necessity.


Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia-reperfusion injury in rats.
The aim of the present study was to evaluate the protective effects of the NF-кB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia-reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-кB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p < 0.05). The TBARS levels were significantly decreased in group III compared with the group II (p < 0.05). CAT, SOD and GST activities were decreased in group II, but these enzymes levels were significantly increased in group III according to the group II (p < 0.05). Under microscopic evaluation NF-кB expression increased significantly in group II compared to the group I (p < 0.05) and then decreased in group III (p < 0.05). HSP60 and p53 expression in group II was increased significantly compared with group I. Under microscopic evaluation we detected that HSP60 and p53 expression was increased significantly in group II compared with group I. In group III PDTC administration was decreased the HSP60 and p53 expression, this difference was statistically significant (p < 0.05). The results of the present study have demonstrated that NF-кB inhibition with PDTC protects and provides beneficial effects on ischemia/reperfusion stress related bladder tissue destruction.


Two particle enhanced nano Raman microscopy and spectroscopy.
The distance- and polarization-dependent near-field enhancement of two coupling metal nanoparticles (MNPs) is analyzed by means of the novel scanning particle enhanced Raman spectroscopy (SPRM) technique. In contrast to single MNP Raman experiments, the near-field coupling between two dissimilar MNPs as followed here leads to a Raman hot spot yielding an extra enhancement factor of 17.6 and 20, as proven here both in experiment and in theory. Three-dimensional electric field calculations for our two-particle arrangements were performed using the semianalytical multiple-multipole method. An excellent agreement is found to our experiments, in which we inspect the interaction between a "scanning" 30 nm gold MNP (Au30) and a "fixed" 80 nm Au MNP (Au80). The Au80 MNP is attached to the apex of an optical fiber manipulator and exposed to the Gaussian focus of a high NA = 1.45 objective at lambda = 532 nm. A monolayer of 1-octanethiol molecules covering the Au80 MNP serves as the electric field prober when scanning the Au30 MNP through the optical focus. This constellation allows recording the Raman signatures from a very low number of well-confined molecules. Moreover, also the spectral and spatial dependence could be explored with a superb sensitivity and very low integration time.


Nuclear magnetic resonance spectroscopy-based metabolite profiling of transgenic tomato fruit engineered to accumulate spermidine and spermine reveals enhanced anabolic and nitrogen-carbon interactions.
Polyamines are ubiquitous aliphatic amines that have been implicated in myriad processes, but their precise biochemical roles are not fully understood. We have carried out metabolite profiling analyses of transgenic tomato (Solanum lycopersicum) fruit engineered to accumulate the higher polyamines spermidine (Spd) and spermine (Spm) to bring an insight into the metabolic processes that Spd/Spm regulate in plants. NMR spectroscopic analysis revealed distinct metabolite trends in the transgenic and wild-type/azygous fruits ripened off the vine. Distinct metabolites (glutamine, asparagine, choline, citrate, fumarate, malate, and an unidentified compound A) accumulated in the red transgenic fruit, while the levels of valine, aspartic acid, sucrose, and glucose were significantly lower as compared to the control (wild-type and azygous) red fruit. The levels of isoleucine, glucose, gamma-aminobutyrate, phenylalanine, and fructose remained similar in the nontransgenic and transgenic fruits. Statistical treatment of the metabolite variables distinguished the control fruits from the transgenic fruit and provided credence to the pronounced, differential metabolite profiles seen during ripening of the transgenic fruits. The pathways involved in the nitrogen sensing/signaling and carbon metabolism seem preferentially activated in the high Spd/Spm transgenics. The metabolite profiling analysis suggests that Spd and Spm are perceived as nitrogenous metabolites by the fruit cells, which in turn results in the stimulation of carbon sequestration. This is seen manifested in higher respiratory activity and up-regulation of phosphoenolpyruvate carboxylase and NADP-dependent isocitrate dehydrogenase transcripts in the transgenic fruit compared to controls, indicating high metabolic status of the transgenics even late in fruit ripening.


Insulin sensitivity does not differentiate by hirsutism in non-obese women with polycystic ovary syndrome.
Hirsutism is one of the component of polycystic ovary syndrome. According to the Rotterdam Consensus has concluded that principially obese women with polycystic ovary syndrome (PCOS) should be evaluated for the metabolic syndrome. The aim of the present study was to investigate the insulin sensitivity in PCOS women with and without hirsutism regardless of obesity. Clinical characteristics, sex hormones and fasting glucose and insulin levels of fifty-eight women with PCOS were analyzed. Hirsutism has been evaluated through the Ferriman-Gallwey (FG) map scoring system. Twenty-two women (38%) were hirsute. They were not any significant difference between hirsute and nonhirsute women for their sex steroids and insulin sensitivity (P>0.05). There were no correlation among sex steroids, WHR and insulin sensitivity in relation to FG score in the subgroup with hirsutism (P>0.05). Our study suggests that normal weight and overweight women with hirsutism can have normal insulin sensitivity and normal levels of circulating androgens in PCOS women.


Disengagement and social support moderate distress among women with a family history of breast cancer.
Using a cross-sectional, exploratory design, this pilot study analyzed the relationships between familial history of breast cancer and psychological distress in order to evaluate who is more distressed and to assess the possible need for intervention. Coping style, social support, and family relations were investigated as potential moderators of these relationships. Participants were 45 women with a familial history of breast cancer recruited from the Family Registry for Breast Cancer (FRBC) at the Northern California Cancer Center (NCCC). Contrary to previous reports of similar cohorts, the overall level of psychological distress in this cohort was comparable to normative samples. The number of relatives with breast cancer was related to distress as measured by the State-Trait Anxiety Inventory (STAI) scale, but there was no significant differentiation in distress associated with the number of first-degree as compared to second- and third-degree relatives with breast cancer. Having more relatives that had died from breast cancer was associated with greater distress on a number of measures. The number of first-degree relative deaths, including maternal death, was also associated with distress. Positive and network support, disengagement coping responses, and family cohesion were each significant moderators of the impact of family history on distress. This association between distress and disengagement is similar to that found in metastatic breast cancer patients themselves, and the findings suggest a subgroup that merits and might respond to more intensive intervention to provide support and facilitate emotional expression.


Hybridization promotes asexual reproduction in Caenorhabditis nematodes.
Although most unicellular organisms reproduce asexually, most multicellular eukaryotes are obligately sexual. This implies that there are strong barriers that prevent the origin or maintenance of asexuality arising from an obligately sexual ancestor. By studying rare asexual animal species we can gain a better understanding of the circumstances that facilitate their evolution from a sexual ancestor. Of the known asexual animal species, many originated by hybridization between two ancestral sexual species. The balance hypothesis predicts that genetic incompatibilities between the divergent genomes in hybrids can modify meiosis and facilitate asexual reproduction, but there are few instances where this has been shown. Here we report that hybridizing two sexual Caenorhabditis nematode species (C. nouraguensis females and C. becei males) alters the normal inheritance of the maternal and paternal genomes during the formation of hybrid zygotes. Most offspring of this interspecies cross die during embryogenesis, exhibiting inheritance of a diploid C. nouraguensis maternal genome and incomplete inheritance of C. becei paternal DNA. However, a small fraction of offspring develop into viable adults that can be either fertile or sterile. Fertile offspring are produced asexually by sperm-dependent parthenogenesis (also called gynogenesis or pseudogamy); these progeny inherit a diploid maternal genome but fail to inherit a paternal genome. Sterile offspring are hybrids that inherit both a diploid maternal genome and a haploid paternal genome. Whole-genome sequencing of individual viable worms shows that diploid maternal inheritance in both fertile and sterile offspring results from an altered meiosis in C. nouraguensis oocytes and the inheritance of two randomly selected homologous chromatids. We hypothesize that hybrid incompatibility between C. nouraguensis and C. becei modifies maternal and paternal genome inheritance and indirectly induces gynogenetic reproduction. This system can be used to dissect the molecular mechanisms by which hybrid incompatibilities can facilitate the emergence of asexual reproduction.


Beliefs about depression and depression treatment among depressed veterans.
Because of the misunderstanding and stigmatization of mental health disorders and treatment, health beliefs may be important in treatment seeking for depression. It is important to understand patients' beliefs about mental health disorders and mental health treatment to improve systems of care. We studied beliefs about depression and depression treatment among patients in a randomized trial of a chronic care intervention to improve depression treatment in the Veterans Administration healthcare system (n = 395). The Depression Beliefs Inventory was used to assess beliefs regarding: (1) perceived need for depression treatment, (2) the efficacy of depression treatment, and (3) treatment barriers, including stigma, at baseline and 6 months. We calculated descriptive statistics on patients' baseline beliefs, and used multiple regression to investigate the extent to which beliefs changed in intervention and treatment as usual patients between baseline and 6-month assessments. We used logistic regression to investigate the relationship between beliefs and antidepressant initiation, adherence and clinical response. At baseline, 73% of our sample believed that they had depression, and 66% believed that taking antidepressants would be helpful for their depression. However, the depression intervention had few effects on beliefs, and individual beliefs were generally not associated with taking medication or clinical response. However, a summary measure of beliefs was found to have predictive validity with respect to initiating and adhering to antidepressant treatment. Our results highlight the potential difficulty in modifying individuals' attitudes regarding depression and depression treatment in chronic care models for depression interventions.