Clinical outcomes of kidney transplantation in older end-stage renal disease patients: A nationwide cohort study.
The aim of the present study was to investigate the clinical outcomes of kidney transplantation (KT) in elderly recipients compared with those in young recipients. We compared the incidence of biopsy-proven acute rejection, death-censored allograft survival and all-cause mortality, and also compared the impact of high sensitization or desensitization on the clinical outcomes of elderly and young recipients. A total of 4966 KT recipients from the Korean Organ Transplantation Registry were included. The definition of elderly recipients was based on age >60 years (n = 356), and recipients aged <60 years were defined as young recipients (n = 4610). The incidence of biopsy-proven acute rejection did not differ between the two groups irrespective of the donor type; however, the impact of high sensitization was significant only in young recipients. Being an elderly recipient was an independent risk factor for death-censored allograft failure in terms of overall and living donor KT, but not with deceased donor KT. In regard to patient death, being an elderly recipient was a significant predictor in general and in the two subgroups, and desensitization showed a significant interaction with death in the elderly recipients in the living donor KT group. In conclusion, KT in elderly recipients might be associated with poor allograft or patient survival in general, and especially, desensitization therapy carried out in these patients might increase the risk of patient mortality. Geriatr Gerontol Int 2019; 19: 392-398.


Discordance in fetal biometry and Doppler are independent predictors of the risk of perinatal loss in twin pregnancies.
Impaired fetal growth might be better evaluated in twin pregnancies by assessing the intertwin discordance rather than the individual fetal size. The aim of this study was to investigate the prediction of perinatal loss in twin pregnancy using discordance in fetal biometry and Doppler. This was a retrospective cohort study in a tertiary referral center. The estimated fetal weight (EFW), umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR), and their discordance recorded at the last ultrasound assessment before delivery or demise of one or both fetuses were converted into centiles or multiples of the median (MoM). The discordance was calculated as the larger value-smaller value/larger value. A logistic regression analysis was performed to identify, and adjust for, potential confounders. The predictive accuracy was assessed using receiver-operating characteristic curve analysis. The analysis included 620 (464 dichorionic diamniotic and 156 monochorionic diamniotic) twin pregnancies (1240 fetuses). Perinatal loss of one or both fetuses complicated 16 pregnancies (2.6%). The combination of EFW discordance and CPR discordance had the best predictive performance (area under the curve, 0.96; 95% confidence interval, 0.92-1.00) for perinatal mortality. The detection rate, false-positive rate, positive likelihood ratio, and negative likelihood ratio were 87.5%, 6.7%, 13.08, and 0.13, respectively. The EFW centile, EFW below the 10th centile (small for gestational age), UA PI discordance, MCA PI discordance, and MCA PI MoM were significantly associated with the risk of perinatal loss on univariate analysis, but these associations became nonsignificant after adjusting for other confounders (P = .097, P = .090, P = .687, P = .360, and P = .074, respectively). The UA PI MoM, CPR MoM, EFW discordance, and CPR discordance were all independent predictors of the risk of perinatal loss, even after adjusting for potential confounders (P = .022, P = .002, P < .001, and P = .010, respectively). EFW discordance and CPR discordance are independent predictors of the risk of perinatal loss in twin pregnancies. Their combination could identify the majority of twin pregnancies at risk of perinatal loss. These findings highlight the importance of discordance in Doppler indices of fetal hypoxia, as well as fetal size, in assessing the risk of perinatal mortality.


Hairy polyp, a clinicopathologic study of four cases.
Hairy polyps (HPs), dermoids or teratoid tumors are rare tumors of naso-oropharyngeal region which commonly present at or shortly after birth. The etiology and classification of these tumors is still debatable and categorized by different authors differently. HPs have female predominance and usually present with respiratory and feeding problems. Microscopically, the polyp is covered by skin with underlying mesenchymal core. The aim of this study is to describe the clinicopathological features of Hairy polyps on a cohort of cases. We reviewed the surgical pathology database of our institution for last 10 years and retrieved four cases of hairy polyps. The age of patients ranged from 1 month to 18 years (mean = 12 years), with a female to male ratio of 1:3. Two of our cases presented at birth and two cases in late teens. Two of the HPs were located in nasopharynx, one on soft and hard palate and one on lower lip. One case was associated with bifurcation of tongue. Size of the polyps ranged from 2.3 to 4.5 cm (mean = 3 cm). Histologically, all HPs were lined by skin and the underlying core consisted of adnexal structures, adipocytes, skeletal muscle, smooth muscle and seromucinous glands. Lymphoid aggregates, cartilage and bone were seen in one case each. Our series highlights the diverse nature of this entity in terms of age of presentation and location. HP at lower lip and associated bifurcation of tongue has not been previously reported. We observed a male predominance in contrast to the published literature. However, number of cases is too few to read a definite conclusion on this point. The etiology is still controversial and includes congenital malformation and activation of pluripotent stem cells.


Health care coverage among long-distance truckers in India: an evaluation based on the Tanahashi model.
Long-distance truckers (LDTDs) are vulnerable to human immunodeficiency virus infection and other sexually transmitted infections due to the nature of their work, working environment, and frequent mobility. This paper examines and comments on the health care coverage provisioned under "Kavach" Project. Data from the Integrated Behavioural and Biological Survey, National Highway gathered from 2,066 LDTDs in Round 1 and 2,085 LDTDs in Round 2, who traveled in four extreme road corridors travelled by LDTDs in India, were used for analysis. Analysis reveals that service capacity in terms of socially marketed condoms per thousand LDTDs has increased from Round 1 to Round 2 (4,430 to 6,876, respectively). Accessibility coverage in terms of knowledge about the Khushi clinic has significantly decreased between Rounds 1 and 2 (60.9% to 54.6%; P<0.001). Acceptability coverage has increased between the two rounds (13.8% to 50.6%; P<0.001). Contact coverage has also increased between the rounds (12.7% to 22.3%; P<0.001). Effectiveness coverage for preventive and curative care has also increased significantly. This paper comments on the gaps in accessibility and acceptability of health care coverage and emphasizes the need for further studies to assess the contextual factors that influence the effectiveness and efficiency of interventions designed to address access barriers and to identify what combination of interventions may generate the best possible outcome.


Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.
To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro. Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.


Optical pumps for organic dye lasers.
Several types of low energy, ultrafast flashlamps systems have been investigated as optical pumps for lasers using fast decaying fluorescent materials, in particular, organic dyes. Of the various systems examined, the coaxial lamp with a spark gap switch proved to be the most useful for pumping the organic dyes. Parameters optimized were gas type, gas pressure, discharge volume, and electrical circuitry. At optimum operation, the annular volume of the coaxial lamp is completely filled with the discharge and the current rise time is determined mainly by the external circuit inductance. The rapidity and uniformity of the discharge is attributed to photoionization of the gas fill. Current rise times are typically 140 nsec for energies up to 100 J. Because of the photoionization process, these coaxial lamps are considered to be a different class of flashlamps from the standard capillary discharge lamp, the sliding spark lamp, and the ablating wall lamp. Less useful systems that were investigated are described, and the reason for their deficiencies are analyzed.


Modelling the genetic aetiology of complex disease: human-mouse conservation of noncoding features and disease-associated loci.
Understanding the genetic aetiology of loci associated with a disease is crucial for developing preventative measures and effective treatments. Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, the utility of mouse models is limited in part by evolutionary divergence in transcription regulation for pathways of interest. Here, we summarize the alignment of genomic (exonic and multi-cell regulatory) annotations alongside Mendelian and complex disease-associated variant sites between humans and mice. Our results highlight the importance of understanding evolutionary divergence in transcription regulation when interpreting functional studies using mice as models for human disease variants.


Diverse psychotomimetics act through a common signaling pathway.
Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated.


Angiotensin II responsiveness after preeclampsia: translational data from an experimental rat model and early-onset human preeclampsia.
Formerly preeclamptic women have an increased risk for cardiovascular and renal disease later in life. It is unknown which mechanisms contribute to this increased risk and whether this is induced by preeclampsia or by prepregnancy factors. We hypothesized that the increased risk for cardiovascular disease is partly due to an increased angiotensin II (ang II) responsiveness postpartum and that preeclampsia itself is involved in inducing this increased ang II responsiveness. In never-pregnant, formerly healthy pregnant rats and rats with former experimental preeclampsia [experimental preeclampsia model induced by low-dose endotoxin infusion on day 14 of pregnancy; endotoxin-infused pregnant rats (EP-rats)], ang II responsiveness was studied by measuring changes in blood pressure (BP) and proteinuria after chronic ang II infusion with osmotic minipumps (200 ng/kg per min). In addition, we measured BP and responses to ang II (0.3, 1.0 and 3.0 ng/kg per min) in 18 formerly early-onset preeclamptic, without comorbidities, and 18 formerly healthy pregnant women (controls). In rats, a significantly higher systolic BP at termination was observed in formerly EP-rats vs. never-pregnant rats after ang II infusion (159.5 ± 29.5 vs. 136.7 ± 16.8; P = 0.049). In response to ang II, there was a significant increase in proteinuria in formerly EP-rats vs. healthy pregnant and never-pregnant rats (P < 0.01 for both). In humans, 1.0 ng/kg per min ang II showed a trend towards an increased mean arterial BP response in formerly preeclamptic women vs. controls (P = 0.057). Our data show an increased ang II responsiveness following (experimental) preeclampsia and support a role for preeclampsia itself in altered ang II responsiveness postpartum.


Population-specific polymorphisms of the human FMO3 gene: significance for detoxication.
Flavin-containing monooxygenase form 3 (FMO3) is one of the major enzyme systems that protect humans from the potentially toxic properties of drugs and chemicals. FMO3 converts nucleophilic heteroatom-containing chemicals and endogenous materials to polar metabolites, which facilitates their elimination. For example, the tertiary amine trimethylamine is N-oxygenated by human FMO3 to trimethylamine N-oxide, and trimethylamine N-oxide is excreted in a detoxication and deoderation process. In normal humans, virtually all trimethylamine is metabolized to trimethylamine N-oxide. In a few humans, trimethylamine is not efficiently metabolized to trimethylamine N-oxide, and those individuals suffer from trimethylaminuria, or fishlike odor syndrome. Previously, we identified mutations of the FMO3 gene that cause trimethylaminuria. We now report two prevalent polymorphisms of this gene (K158E and V257M) that modulate the activity of human FMO3. These polymorphisms are widely distributed in Canadian and Australian white populations. In vitro analysis of wild-type and variant human FMO3 proteins expressed from the cDNA for the two naturally occurring polymorphisms showed differences in substrate affinities for nitrogen-containing substrates. Thus, for polymorphic forms of human FMO3, lower k(cat)/K(m) values for N-oxygenation of 10-(N, N-dimethylaminopentyl)-2-(trifluoromethyl) phenothiazine, trimethylamine, and tyramine were observed. On the basis of in vitro kinetic parameters, human FMO1 does not significantly contribute to human metabolism of trimethylamine or tyramine. The results imply that prevalent polymorphisms of the human FMO3 gene may contribute to low penetrance predispositions to diseases associated with adverse environmental exposures to heteroatom-containing chemicals, drugs, and endogenous amines.


Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia.
Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. During hypoglycemia, ventromedial hypothalamus (VMH) production of nitric oxide (NO) and activation of its receptor soluble guanylyl cyclase (sGC) are critical for the CRR. Hypoglycemia also increases brain reactive oxygen species (ROS) production. NO production in the presence of ROS causes protein S-nitrosylation. S-nitrosylation of sGC impairs its function and induces desensitization to NO. We hypothesized that during hypoglycemia, the interaction between NO and ROS increases VMH sGC S-nitrosylation levels and impairs the CRR to subsequent episodes of hypoglycemia. VMH ROS production and S-nitrosylation were quantified following three consecutive daily episodes of insulin-hypoglycemia (RH model). The CRR was evaluated in rats in response to acute insulin-induced hypoglycemia or via hypoglycemic-hyperinsulinemic clamps. Pretreatment with the anti-oxidant N-acetyl-cysteine (NAC) was used to prevent increased VMH S-nitrosylation. Acute insulin-hypoglycemia increased VMH ROS levels by 49±6.3%. RH increased VMH sGC S-nitrosylation. Increasing VMH S-nitrosylation with intracerebroventricular injection of the nitrosylating agent S-nitroso-L-cysteine (CSNO) was associated with decreased glucagon secretion during hypoglycemic clamp. Finally, in RH rats pre-treated with NAC (0.5% in drinking water for 9 days) hypoglycemia-induced VMH ROS production was prevented and glucagon and epinephrine production was not blunted in response to subsequent insulin-hypoglycemia. These data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.


Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer.
Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001). We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.


Unraveling the binding mechanism of asiatic acid with human serum albumin and its biological implications.
Asiatic acid (AsA), a naturally occurring pentacyclictriterpenoid found in Centella asiatica, plays a major role in neuroprotection, anticancer, antioxidant, and hepatoprotective activities. Human serum albumin (HSA), a blood plasma protein, participates in the regulation of plasma osmotic pressure and transports endogenous and exogenous substances. The study undertaken to analyze the drug-binding mechanisms of HSA is crucial in understanding the bioavailability of drugs. In this study, we analyzed the cytotoxic activity of AsA on HepG2 (human hepatocellular carcinoma) cell lines and its binding, conformational, docking, molecular simulation studies with HSA under physiological pH 7.2. These studies revealed a clear decrease in the viability of HepG2 cells upon exposure to AsA in a dose-dependent manner with an IC50 of 45 μM. Further studies showed the quenching of intrinsic fluorescence of HSA by AsA with a binding constant of KAsA = 3.86 ± 0.01 × 10(4) M(-1), which corresponds to the free energy of (ΔG) -6.3 kcal M(-1) at 25 °C. Circular dichroism (CD) studies revealed that there is a clear decrease in the α-helical content from 57.50 ± 2.4 to 50% ± 2.3 and an increase in the β-turns from 25 ± 0.65 to 29% ± 0.91 and random coils from 17.5% ± 0.95 to 21% ± 1.2, suggesting partial unfolding of HSA. Autodock studies revealed that the AsA is bound to the subdomain IIA with hydrophobic and hydrophilic interactions. From molecular dynamics, simulation data (RMSD, Rg and RMSF) emphasized the local conformational changes and rigidity of the residues of both HSA and HSA-AsA complexes.


MPS1 and MPS2: novel yeast genes defining distinct steps of spindle pole body duplication.
It is crucial to the eucaryotic cell cycle that the centrosome undergo precise duplication to generate the two poles of the mitotic spindle. In the budding yeast Saccharomyces cerevisiae, centrosomal functions are provided by the spindle pole body (SPB), which is duplicated at the time of bud emergence in G1 of the cell cycle. Genetic control of this process has previously been revealed by the characterization of mutants in CDC31 and KAR1, which prevent SPB duplication and lead to formation of a monopolar spindle. Newly isolated mutations described here (mps1 and mps2, for monopolar spindle) similarly cause monopolar mitosis but their underlying effects on SPB duplication are unique. The MPS1 gene is found by electron microscopy to be essential for proper formation of the site at which the new SPB normally arises adjacent to the existing one. By contrast, a mutation in MPS2 permits duplication to proceed, but the newly formed SPB is structurally defective and unable to serve as a functional spindle pole. Distinct temporal requirements for the CDC31, MPS1, and MPS2 gene functions during the SPB duplication cycle further demonstrate the individual roles of these genes in the morphogenetic pathway.


Absorption mechanism of the second pulse in double-pulse femtosecond laser glass microwelding.
The absorption mechanism of the second pulse is experimentally and theoretically investigated for high-efficiency microwelding of photosensitive glass by double-pulse irradiation using a femtosecond laser. The transient absorption change during the second pulse irradiation for various energies induced by the first pulse is measured at different delay times. The resulting effects depend on whether the delay time is 0-30 ps (time domain I) or 30- several ns (domain II). By solving rate equations for the proposed electronic processes, the excitation and relaxation times of free electrons in time domain I are estimated to be 0.98 and 20.4 ps, respectively, whereas the relaxation times from the conduction band to a localized state and from the localized state to the valence band in domain II are 104.2 and 714.3 ps, respectively. Single-photon absorption of the second pulse by free electrons dominates in domain I, resulting in high bonding strength. In time domain II, about 46% of the second pulse is absorbed by a single photon due to the localized state, which is responsible for higher bonding strength compared with that prepared by single-pulse irradiation.


Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma.
Consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) is the standard of care for transplantation-eligible patients with multiple myeloma, based on randomized trials showing improved progression-free survival with autologous transplantation after combination chemotherapy induction. These trials were performed before novel agents were introduced; subsequently, combinations of immunomodulatory drugs and proteasome inhibitors as induction therapy have significantly improved rates and depth of response. Ongoing randomized trials are testing whether conventional autologous transplantation continues to improve responses after novel agent induction. Although these results are awaited, it is important to review strategies for improving outcomes after ASCT. Conditioning before ASCT with higher doses of melphalan and combinations of melphalan with other agents, including radiopharmaceuticals, has been explored. Tandem ASCT, consolidation, and maintenance therapy after ASCT have been investigated in phase III trials. Experimental cellular therapies using ex vivo-primed dendritic cells, ex vivo-expanded autologous lymphocytes, Killer Immunoglobulin Receptor (KIR)-mismatched allogeneic natural killer cells, and genetically modified T cells to augment ASCT are also in phase I trials. This review summarizes these strategies and highlights the importance of exploring strategies to augment ASCT, even in the era of novel agent induction.


Validation of a Machine Learning Algorithm to Predict 180-Day Mortality for Outpatients With Cancer.
Machine learning (ML) algorithms can identify patients with cancer at risk of short-term mortality to inform treatment and advance care planning. However, no ML mortality risk prediction algorithm has been prospectively validated in oncology or compared with routinely used prognostic indices. To validate an electronic health record-embedded ML algorithm that generated real-time predictions of 180-day mortality risk in a general oncology cohort. This prognostic study comprised a prospective cohort of patients with outpatient oncology encounters between March 1, 2019, and April 30, 2019. An ML algorithm, trained on retrospective data from a subset of practices, predicted 180-day mortality risk between 4 and 8 days before a patient's encounter. Patient encounters took place in 18 medical or gynecologic oncology practices, including 1 tertiary practice and 17 general oncology practices, within a large US academic health care system. Patients aged 18 years or older with outpatient oncology or hematology and oncology encounters were included in the analysis. Patients were excluded if their appointment was scheduled after weekly predictions were generated and if they were only evaluated in benign hematology, palliative care, or rehabilitation practices. Gradient-boosting ML binary classifier. The primary outcome was the patients' 180-day mortality from the index encounter. The primary performance metric was the area under the receiver operating characteristic curve (AUC). Among 24 582 patients, 1022 (4.2%) died within 180 days of their index encounter. Their median (interquartile range) age was 64.6 (53.6-73.2) years, 15 319 (62.3%) were women, 18 015 (76.0%) were White, and 10 658 (43.4%) were seen in the tertiary practice. The AUC was 0.89 (95% CI, 0.88-0.90) for the full cohort. The AUC varied across disease-specific groups within the tertiary practice (AUC ranging from 0.74 to 0.96) but was similar between the tertiary and general oncology practices. At a prespecified 40% mortality risk threshold used to differentiate high- vs low-risk patients, observed 180-day mortality was 45.2% (95% CI, 41.3%-49.1%) in the high-risk group vs 3.1% (95% CI, 2.9%-3.3%) in the low-risk group. Integrating the algorithm into the Eastern Cooperative Oncology Group and Elixhauser comorbidity index-based classifiers resulted in favorable reclassification (net reclassification index, 0.09 [95% CI, 0.04-0.14] and 0.23 [95% CI, 0.20-0.27], respectively). In this prognostic study, an ML algorithm was feasibly integrated into the electronic health record to generate real-time, accurate predictions of short-term mortality for patients with cancer and outperformed routinely used prognostic indices. This algorithm may be used to inform behavioral interventions and prompt earlier conversations about goals of care and end-of-life preferences among patients with cancer.


Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: Rationale and design of the ticagrelor in patients with ST elevation myocardial infarction treated with thrombolysis (TREAT) trial.
The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.


Surgeons expect patients to buy-in to postoperative life support preoperatively: results of a national survey.
Evidence suggests that surgeons implicitly negotiate with their patients preoperatively about the use of life supporting treatments postoperatively as a condition for performing surgery. We sought to examine whether this surgical buy-in behavior is present among a large, nationally representative sample of surgeons who routinely perform high-risk operations. Using findings from a qualitative study, we designed a survey to determine the prevalence of surgical buy-in and its consequences. Respondents were asked to consider their response to a patient at moderate risk for prolonged mechanical ventilation or dialysis who has a preoperative request to limit postoperative life- supporting treatment. We used bivariate and multivariate analysis to identify surgeon characteristics associated with 1) preoperatively creating an informal contract with the patient defining agreed upon limitations of postoperative life support and 2) declining to operate on such patients. U.S. mail-based survey of 2,100 cardiothoracic, vascular, and neurosurgeons. None. The adjusted response rate was 56%. Nearly two thirds of respondents (62%) reported they would create an informal contract with the patient describing agreed upon limitations of aggressive therapy and a similar number (60%) endorsed sometimes or always refusing to operate on a patient with preferences to limit life support. After adjusting for potentially confounding covariates, the odds of preoperatively contracting about life-supporting treatment were more than two-fold greater among surgeons who felt it was acceptable to withdraw life support on postoperative day 14 compared with those who believed it was not acceptable to withdraw life support on postoperative day 14 (odds ratio 2.1, 95% confidence intervals 1.3-3.2). Many surgeons will report contracting informally with patients preoperatively about the use of postoperative life support. Recognition of this process and its limitations may help to inform postoperative decision making.


Waveguide holographic elements recorded by guided modes.
Recording holographic optical elements in planar waveguides with both interfering beams being guided modes has certain advantages. We show that such holograms can be efficiently recorded when only a small fraction of the guided modes penetrates the recording material that is deposited outside the main guiding region. An integrated optic wavelength-division demultiplexer is analyzed and implemented as a specific example. In this example the holographic grating also acts as a focusing element; thus no additional collimating or focusing lenses are required.


PARP-1 deficiency increases the severity of disease in a mouse model of multiple sclerosis.
Poly(ADP-ribose) polymerase-1 (PARP-1) has been implicated in the pathogenesis of several central nervous system (CNS) disorders. However, the role of PARP-1 in autoimmune CNS injury remains poorly understood. Therefore, we studied experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis in mice with a targeted deletion of PARP-1. We identified inherent physiological abnormalities in the circulating and splenic immune composition between PARP-1(-/-) and wild type (WT) mice. Upon EAE induction, PARP-1(-/-) mice had an earlier onset and developed a more severe EAE compared with WT cohorts. Splenic response was significantly higher in PARP-1(-/-) mice largely because of B cell expansion. Although formation of Th1 and Th17 effector T lymphocytes was unaffected, PARP-1(-/-) mice had significantly earlier CD4+ T lymphocyte and macrophage infiltration into the CNS during EAE. However, we did not detect significant differences in cytokine profiles between PARP-1(-/-) and WT spinal cords at the peak of EAE. Expression analysis of different PARP isozymes in EAE spinal cords showed that PARP-1 was down-regulated in WT mice and that PARP-3 but not PARP-2 was dramatically up-regulated in both PARP-1(-/-) and WT mice, suggesting that these PARP isozymes could have distinct roles in different CNS pathologies. Together, our results indicate that PARP-1 plays an important role in regulating the physiological immune composition and in immune modulation during EAE; our finding identifies a new aspect of immune regulation by PARPs in autoimmune CNS pathology.


Optical Actuation of Inorganic/Organic Interfaces: Comparing Peptide-Azobenzene Ligand Reconfiguration on Gold and Silver Nanoparticles.
Photoresponsive molecules that incorporate peptides capable of material-specific recognition provide a basis for biomolecule-mediated control of the nucleation, growth, organization, and activation of hybrid inorganic/organic nanostructures. These hybrid molecules interact with the inorganic surface through multiple noncovalent interactions which allow reconfiguration in response to optical stimuli. Here, we quantify the binding of azobenzene-peptide conjugates that exhibit optically triggered cis-trans isomerization on Ag surfaces and compare to their behavior on Au. These results demonstrate differences in binding and switching behavior between the Au and Ag surfaces. These molecules can also produce and stabilize Au and Ag nanoparticles in aqueous media where the biointerface can be reproducibly and reversibly switched by optically triggered azobenzene isomerization. Comparisons of switching rates and reversibility on the nanoparticles reveal differences that depend upon whether the azobenzene is attached at the peptide N- or C-terminus, its isomerization state, and the nanoparticle composition. Our integrated experimental and computational investigation shows that the number of ligand anchor sites strongly influences the nanoparticle size. As predicted by our molecular simulations, weaker contact between the hybrid biomolecules and the Ag surface, with fewer anchor residues compared with Au, gives rise to differences in switching kinetics on Ag versus Au. Our findings provide a pathway toward achieving new remotely actuatable nanomaterials for multiple applications from a single system, which remains difficult to achieve using conventional approaches.


Cardiopulmonary Impairments Caused by a Large Hiatal Hernia with Organoaxial Gastric Volvulus Showing Upside-Down Stomach: A Case Report.
BACKGROUND Upside-down stomach (UDS) is the rarest type of hiatal hernia (HH), with organoaxial gastric volvulus. A large HH sometimes causes cardiopulmonary impairments owing to multiple factors. CASE REPORT We herein report a case of a large HH with UDS that had induced weight loss and severe cardiopulmonary dysfunction in a 74-year-old female patient who presented with shortness of breath, chest pain, severe anorexia, and weight loss of 5 kg over the 3 previous months. Chest X-ray and CT examination revealed that her heart was retracted on the right side, and the hernia contents had induced physical compression of the left lung on the cranial side. Spirometry revealed that the patient's vital capacity (VC), percentage VC, and percentage forced expiratory volume (% FEV) at 1 s were 1.32 L, 60.2%, and 67.5%, respectively. A barium swallow test confirmed a diagnosis of HH with UDS. On the basis of these findings, we performed a laparoscopic Nissen procedure, which resulted in the patient's dramatic recovery. Postoperative examinations showed that the stomach and heart were once again normally located, and the left lung had re-inflated. Postoperative spirometry dramatically improved. CONCLUSIONS A large HH causes cardiac and pulmonary compression due to mass effects and leads to cardiopulmonary dysfunction. For cases that have both a complicated HH and cardiopulmonary dysfunction owing to the mass effects of hernia contents, laparoscopic HH repair can be a good alternative procedure.


Executive functions, categorization of probabilities, and learning from feedback: what does really matter for decision making under explicit risk conditions?
In two experiments with healthy subjects, we used the Game of Dice Task (GDT), the Probability-Associated Gambling (PAG) task, the Iowa Gambling Task (IGT), and executive-function and logical thinking tasks to shed light on the underlying processes of decision making under risk. Results indicate that handling probabilities, as in the PAG task, is an important ingredient of GDT performance. Executive functions and logical thinking also play major roles in deciding in the GDT. Implicit feedback learning, as measured by the IGT, has little impact. Results suggest that good probability handling may compensate for the effects of weak executive functions in decisions under risk.


On the flexibility of metal-organic frameworks.
Occasional, large amplitude flexibility in metal-organic frameworks (MOFs) is one of the most intriguing recent discoveries in chemistry and material science. Yet, there is at present no theoretical framework that permits the identification of flexible structures in the rapidly expanding universe of MOFs. Here, we propose a simple method to predict whether a MOF is flexible, based on treating it as a system of rigid elements, connected by hinges. This proposition is correct in application to MOFs based on rigid carboxylate linkers. We validate the method by correctly classifying known experimental MOFs into rigid and flexible groups. Applied to hypothetical MOFs, the method reveals an abundance of flexibility phenomena, and this seems to be at odds with the proportion of flexible structures among experimentally known MOFs. We speculate that the flexibility of a MOF may constitute an intrinsic impediment on its experimental realization. This highlights the importance of systematic prediction of large amplitude flexibility regimes in MOFs.


Simplified and improved string method for computing the minimum energy paths in barrier-crossing events.
We present a simplified and improved version of the string method, originally proposed by E et al. [Phys. Rev. B 66, 052301 (2002)] for identifying the minimum energy paths in barrier-crossing events. In this new version, the step of projecting the potential force to the direction normal to the string is eliminated and the full potential force is used in the evolution of the string. This not only simplifies the numerical procedure, but also makes the method more stable and accurate. We discuss the algorithmic details of the improved string method, analyze its stability, accuracy and efficiency, and illustrate it via numerical examples. We also show how the string method can be combined with the climbing image technique for the accurate calculation of saddle points and we present another algorithm for the accurate calculation of the unstable directions at the saddle points.


The effect of caffeine consumption and nausea on the risk of miscarriage.
Evidence for a harmful effect of caffeine intake on risk of miscarriage (spontaneous abortion) is inconsistent and nausea during pregnancy has been claimed to explain any association seen. The objective of this analysis was to determine whether caffeine consumption both before and during pregnancy influenced the risk of miscarriage in a group of pregnant women in the UK. We examined the association with maternal caffeine intake in a case-control study of 474 nulliparous women. Participants were recruited during the years 1987-89 from the Royal Berkshire Hospital in Reading and from a large group practice situated within the hospital's catchment area. Cases were 160 women with a clinically diagnosed miscarriage and controls were 314 pregnant women attending for antenatal care. Information on coffee/tea/cola consumption and potential confounders was collected by interview and caffeine content was assigned to individual drinks according to published data on caffeine content of beverages. Compared with a maternal caffeine intake of < 151 mg/day, we found evidence that caffeine consumption > 300 mg/day doubled the risk of miscarriage. Adjusted odds ratios were 1.94 [95% CI 1.04, 3.63] for 301-500 mg/day and 2.18 [95% CI 1.08, 4.40] for > 500 mg/day. This effect could not be explained by nausea in pregnancy. Nausea appeared to be strongly independently associated with a reduced risk of miscarriage (test for trend P < 0.0001). There was no evidence that prepregnancy caffeine consumption affected the risk. Our results indicate that high caffeine consumption during pregnancy (>300 mg/day), in particular coffee consumption, is an independent risk factor for increased risk and nausea is an independent protective factor for a lower risk of miscarriage.


Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks.
An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)cyclobutanone. Dissociation constants (p Ka) and log P values for 2,2-difluorocyclobutaneamine and 2,2-difluorocyclobutanecarboxylic acid or their derivatives were measured and compared with the values obtained for the corresponding 3,3-difluorocyclobutane derivatives and nonfluorinated counterparts. Three-dimensional structures of 2,2- and 3,3-difluorocyclobutanamines were compared using exit vector plot analysis of X-ray crystallographic data.


The predictive role of atherogenic dyslipidemia in subjects with non-coronary atherosclerosis.
Recent findings have suggested that subjects with non-coronary atherosclerosis may show elevated prevalence of atherogenic dyslipidemia, including higher triglyceride levels, reduced HDL-cholesterol concentrations and increased levels of small, dense low-density lipoproteins (LDL). These three lipid abnormalities constitute the so-called "atherogenic-lipoprotein-phenotype" (ALP) but its predictive role in these patients still remains to be established. We performed a 2-year follow-up study to assess clinical and biochemical predictors of cardiovascular events in 44 male patients (64+/-5 years, BMI: 27+/-3), 26 with peripheral arterial disease and 18 with abdominal aortic aneurysm. Beyond traditional cardiovascular risk factors, we measured LDL size and subclasses by gradient gel electrophoresis. Clinical events were registered in the 43% of patients. At univariate analysis we found that patients with events had increased prevalence of hypertension (p=.0098), diabetes (p=.0089), family history of cardiovascular diseases (p=.0089), of elevated small, dense LDL (p=.0222) and ALP (p=.0224). At multivariate analysis (including all clinical and laboratory variables) we found the following independent predictors of events: hypertension (OR 8.9, p=.0347), diabetes (OR 9.4, p=.0270), elevated small, dense LDL (OR 6.9, p=.0488) and ALP (OR 8.7, p=.0497). This is the first study that evaluated the predictive role of ALP beyond traditional cardiovascular risk factors in patients with peripheral arterial disease or abdominal aortic aneurysm. We confirmed that hypertension and diabetes are strong predictors of cardiovascular events in these subjects but ALP seems to be an independent predictor too. Yet, the therapeutical consequences of these findings need to be tested by future studies.


Decision-making tree for women considering hysterectomy.
This paper reports on a study carried out to establish a decision tree model to describe how women in Taiwan make the decision whether or not to have a hysterectomy. In addition, we examined the predictability of the decision-tree model. Hysterectomy is the second most common surgical procedure performed worldwide. Medical professionals believe that the operation can relieve pain and prevent cervical cancer, thus improving a woman's quality of life. While most physicians advise hysterectomy even for benign uterine conditions, feminists decry the belief that the uterus has no purpose, believing that it is an important symbol of womanhood. The study was conducted in two phases. Phase I, the model development phase, was carried out to generalize data from a qualitative study of 14 women and to establish a tree model outlining their decision to proceed with hysterectomy. The second phase was the model prediction phase that applied inductive and deductive methods to data analysis and development of the decision-tree model. The model tree was then tested with 18 women who were deciding whether or not to undergo hysterectomy. Using the decision-making tree, we studied the women's thought processes and analysed their primary concerns. The study was carried out in 1999-2001. The study determined 13 criteria that Taiwanese women use when deciding about having a hysterectomy. Developed in accordance with Gladwin's methodology, the model tree successfully predicted 90% of decisions whether or not to have a hysterectomy. Nurses working in gynaecological services should understand how women decide to undergo hysterectomy so that the proper counselling and follow-up can be provided. With further testing, our decision tree may help in this process.


Eccentric placentae have reduced surface area and are associated with lower birth weight in babies small for gestational age.
Placental structure and function determine birth outcomes. Placental mass does not always correlate with fetal birth weight (BW) in uncomplicated pregnancies which raises the possibility of other variables such as placental shape and cord insertion being the determinants of placental efficiency. In total, 160 women with singleton pregnancy, recruited into a pregnancy cohort were studied. Placental weight (PW) was measured and other data were obtained from clinical records. Birth outcomes were classified as small for gestational age (SGA) and appropriate for gestational age (AGA) based on fetal gender, gestational age (GA) and BW. High-resolution images of the chorionic plate were recorded. The shape of the placenta and the insertion of the cord were measured using eccentricity index (EI) and cord centrality index (CCI). Only placentae with eccentrically inserted cords (n=136) were included. The mean BW and PW were 2942 (±435) g and 414 (±82) g with average GA of 38.6 weeks. The mean CCI and EI was 0.483 (±0.17) and 0.482 (±0.16). Neither of these correlated with placental efficiency. However, EI showed negative correlation with placental surface area and breadth. Upon sub-grouping the cohort into SGA (n=32) and AGA (n=104), the SGA babies with the highest EI (third tertile) had significantly lower BW than those with the least eccentric placentae (first tertile). Although eccentric-shaped placentae were present in both SGA and AGA groups, the effect on BW was observed only in the SGA group.


Financial and Economic Costs of the Elimination and Eradication of Onchocerciasis (River Blindness) in Africa.
Onchocerciasis (river blindness) is a parasitic disease transmitted by blackflies. Symptoms include severe itching, skin lesions, and vision impairment including blindness. More than 99% of all cases are concentrated in sub-Saharan Africa. Fortunately, vector control and community-directed treatment with ivermectin have significantly decreased morbidity, and the treatment goal is shifting from control to elimination in Africa. We estimated financial resources and societal opportunity costs associated with scaling up community-directed treatment with ivermectin and implementing surveillance and response systems in endemic African regions for alternative treatment goals--control, elimination, and eradication. We used a micro-costing approach that allows adjustment for time-variant resource utilization and for the heterogeneity in the demographic, epidemiological, and political situation. The elimination and eradication scenarios, which include scaling up treatments to hypo-endemic and operationally challenging areas at the latest by 2021 and implementing intensive surveillance, would allow savings of $1.5 billion and $1.6 billion over 2013-2045 as compared to the control scenario. Although the elimination and eradication scenarios would require higher surveillance costs ($215 million and $242 million) than the control scenario ($47 million), intensive surveillance would enable treatments to be safely stopped earlier, thereby saving unnecessary costs for prolonged treatments as in the control scenario lacking such surveillance and response systems. The elimination and eradication of onchocerciasis are predicted to allow substantial cost-savings in the long run. To realize cost-savings, policymakers should keep empowering community volunteers, and pharmaceutical companies would need to continue drug donation. To sustain high surveillance costs required for elimination and eradication, endemic countries would need to enhance their domestic funding capacity. Societal and political will would be critical to sustaining all of these efforts in the long term.


A case of pituitary apoplexy following posterior lumbar fusion surgery.
Pituitary adenoma is a common primary brain neoplasm. Pituitary apoplexy (PA) is a rare complication of pituitary adenoma and occurs as the result of sudden tumor growth and following different comorbidities. The authors describe the first case of PA following posterior lumbar fusion surgery performed while the patient was prone. In patients with a preexisting pituitary adenoma, thorough clinical and laboratory investigations should be conducted using an interdisciplinary approach before any planned surgery. In unknown cases of pituitary adenoma, PA should be kept in mind for the differential diagnosis in a case with headache, nausea, vomiting, ophthalmoplegia, visual loss, and electrolyte imbalance concurrent with an ongoing disease state.


Violence and PTSD in Mexico: gender and regional differences.
We examined the lifetime prevalence of violence in Mexico and how different characteristics of the violent event effect the probability of meeting criteria for lifetime post-traumatic stress disorder (PTSD). We interviewed a probability sample of 2,509 adults from 4 cities in Mexico (Oaxaca, Guadalajara, Hermosillo, Mérida) using the Composite International Diagnostic Interview (CIDI). Lifetime prevalence of violence was 34%. Men reported more single-experience, recurrent, physical, adolescent, adulthood, and stranger violence; women more sexual, childhood, family, and intimate partner violence. Prevalence was generally higher in Guadalajara, though the impact was greater in Oaxaca compared to other cities. Of those exposed, 11.5% met DSM-IV criteria for PTSD. Probabilities were highest after sexual and intimate partner violence, higher for women than men, and higher in Oaxaca than other cities. It is important to consider the characteristics and the context of violence in order to develop effective prevention and intervention programs to reduce the exposure to and impact of violence.


Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine.
Evidence exists for the pathogenic role of the enteric flora in inflammatory bowel disease. Probiotics contain living microorganisms which exert health effects on the host. We compared the efficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and established therapy with mesalazine in patients with ulcerative colitis. In total, 327 patients were recruited and assigned to a double blind, double dummy trial to receive either the probiotic drug 200 mg once daily (n = 162) or mesalazine 500 mg three times daily (n = 165). The study lasted for 12 months and patients were assessed by clinical and endoscopic activity indices (Rachmilewitz) as well as by histology. The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses. The per protocol analysis revealed relapses in 40/110 (36.4%) patients in the E coli Nissle 1917 group and 38/112 (33.9%) in the mesalazine group (significant equivalence p = 0.003). Subgroup analyses showed no differences between the treatment groups in terms of duration and localisation of disease or pretrial treatment. Safety profile and tolerability were very good for both groups and were not different. The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic treatment further underlines the pathogenetic significance of the enteric flora.


Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease.
Recent studies indicate that there is a marked reduction in trkA-containing nucleus basalis neurons in end-stage Alzheimer's disease (AD). We used unbiased stereological counting procedures to determine whether these changes extend to individuals with mild cognitive impairment (MCI) without dementia from a cohort of people enrolled in the Religious Orders Study. Thirty people (average age 84.7 years) came to autopsy. All individuals were cognitively tested within 12 months of death (average MMSE 24.2). Clinically, 9 had no cognitive impairment (NCI), 12 were categorized with MCI, and 9 had probable AD The average number of trkA-immunoreactive neurons in persons with NCI was 196, 632 +/- 12,093 (n = 9), for those with MCI it was 106,110 +/- 14,565, and for those with AD it was 86,978 +/- 12,141. Multiple comparisons showed that both those with MCI and those with AD had significant loss in the number of trkA-containing neurons compared to those with NCI (46% decrease for MCI, 56% for AD). An analysis of variance revealed that the total number of neurons containing trkA immunoreactivity was related to diagnostic classification (P < 0.001), with a significant reduction in AD and MCI compared to NCI but without a significant difference between MCI and AD. Cell density was similarly related to diagnostic classification (P < 0.001). There was a significant correlation with the Boston Naming Test and with a global score measure of cognitive function. The number of trkA-immunoreactive neurons was not correlated with MMSE, age at death, education, apolipoprotein E allele status, gender, or Braak score. These data indicate that alterations in the number of nucleus basalis neurons containing trkA immunoreactivity occurs early and are not accelerated from the transition from MCI to mild AD.


Developing strategies for predicting hyperkalemia in potassium-increasing drug-drug interactions.
To compare different strategies predicting hyperkalemia (serum potassium level ≥5.5 mEq/l) in hospitalized patients for whom medications triggering potassium-increasing drug-drug interactions (DDIs) were ordered. We investigated 5 strategies that combined prediction triggered at onset of DDI versus continuous monitoring and taking into account an increasing number of patient parameters. The considered patient parameters were identified using generalized additive models, and the thresholds of the prediction strategies were calculated by applying Youden's J statistic to receiver operation characteristic curves. Half of the data served as the calibration set, half as the validation set. We identified 132 incidences of hyperkalemia induced by 8413 potentially severe potassium-increasing DDIs among 76 467 patients. The positive predictive value (PPV) of those strategies predicting hyperkalemia at the onset of DDI ranged from 1.79% (undifferentiated anticipation of hyperkalemia due to the DDI) to 3.02% (additionally considering the baseline serum potassium) and 3.10% (including further patient parameters). Continuous monitoring significantly increased the PPV to 8.25% (considering the current serum potassium) and 9.34% (additional patient parameters). Continuous monitoring of the risk for hyperkalemia based on current potassium level shows a better predictive power than predictions triggered at the onset of DDI. This contrasts with efforts to improve DDI alerts by taking into account more patient parameters at the time of ordering.


Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice.
Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1-positive (Sca-1-positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.


Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism.
Camphor is a naturally occurring compound that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite its long history of common medical use, the underlying molecular mechanism of camphor action is not understood. Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, respectively. Camphor has recently been shown to activate TRPV3, and here we show that camphor also activates heterologously expressed TRPV1, requiring higher concentrations than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were observed in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. We found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. We also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.


Computational reconstruction of atomistic protein structures from coarse-grained models.
Three-dimensional protein structures, whether determined experimentally or theoretically, are often too low resolution. In this mini-review, we outline the computational methods for protein structure reconstruction from incomplete coarse-grained to all atomistic models. Typical reconstruction schemes can be divided into four major steps. Usually, the first step is reconstruction of the protein backbone chain starting from the C-alpha trace. This is followed by side-chains rebuilding based on protein backbone geometry. Subsequently, hydrogen atoms can be reconstructed. Finally, the resulting all-atom models may require structure optimization. Many methods are available to perform each of these tasks. We discuss the available tools and their potential applications in integrative modeling pipelines that can transfer coarse-grained information from computational predictions, or experiment, to all atomistic structures.


Microbiological risks of recycling urban stormwater via aquifers.
With the release of the Australian Guidelines for Water Recycling: Managed Aquifer Recharge (MAR), aquifers are now being included as a treatment barrier when assessing risk of recycled water systems. A MAR research site recharging urban stormwater in a confined aquifer was used in conjunction with a Quantitative Microbial Risk Assessment to assess the microbial pathogen risk in the recovered water for different end uses. The assessment involved undertaking a detailed assessment of the treatment steps and exposure controls, including the aquifer, to achieve the microbial health-based targets.


Sequestration and segregation of receptor kinases in epithelial cells: implications for ErbB2 oncogenesis.
Cell behaviors are regulated by signaling pathways triggered by the activation of cell surface receptors. A key aspect of receptor signaling is the location of these receptors relative to their ligands and to other receptors, particularly in epithelia, whose cells are polarized by tight junction barriers into apical and basolateral membrane regions. In polarized epithelia, the co-receptor ErbB2 is often localized to the apical surface by its intramembrane ligand Muc4, thus segregating it from its partner ErbB3, which is sequestered at the lateral surface, co-localized with cadherin junctions. The ErbB2-ErbB3 receptor heterodimer, when activated, is a potent stimulator of cell proliferation; thus, the segregation mechanism helps maintain these cells in a differentiated state. Similarly, epidermal growth factor, the ligand for ErbB1, which is present in the apical fluid of some epithelia, is segregated from its receptor by the tight junction barrier. Loss of cell polarity and the tight junction barrier facilitates the interaction of ErbB2 with the hemidesmosome integrin alpha(6)beta(4). This integrin acts as a docking site for signaling pathways to promote cell proliferation and further disruption of cell junctions. The ultimate dissolution of tight junctions may result from activation of transforming growth factor-beta receptors, one subunit of which is directly associated with the junction. This activation triggers degradation of critical tight junction components. These sequestration and segregation phenomena provide a model by which overexpression of the ErbB2 receptor kinase may trigger oncogenesis by initiating junction breakdown. Equally important, these mechanisms may act as a sensor for epithelial damage that can activate repair mechanisms.


Characterization of the biomedical query mediation process.
To most medical researchers, databases are obscure black boxes. Query analysts are often indispensable guides aiding researchers to perform mediated data queries. However, this approach does not scale up and is time-consuming and expensive. We analyzed query mediation dialogues to inform future designs of intelligent query mediation systems. Thirty-one mediated query sessions for 22 research projects were recorded and transcribed. We analyzed 10 of these to develop an annotation schema for dialogue acts through iterative refinement. Three coders independently annotated all 3160 dialogue acts. We assessed the inter-rater agreement and resolved disagreement by group consensus. This study contributes early knowledge of the query negotiation space for medical research. We conclude that research data query formulation is not a straightforward translation from researcher data needs to database queries, but rather iterative, process-oriented needs assessment and refinement.


Oncology nurses awareness of drug interactions.
The aim of this study was to determine oncology nurses awareness of drug interactions. This descriptive study was conducted with nurses working in the oncology clinics who are a member of Oncology Nursing Association of Turkey. A total of 115 nurses (response rate %20) were responded to the online survey that consists of 28 questions. The mean age of the nurses was 33 ± 6.8. The majority of nurses work in university hospital (60%) as a clinical nurse (62.6%) and have a Bachelor Degree in Nursing (63.5%). The mean working years in oncology was 4 years. Half of them stated receiving information on drug interactions mostly through in-service education and courses/congresses in last 5 years. The majority of them (84.3%) indicated that they are considering the possibility of drug interactions when they are scheduling the medication administration time. More than half of the responders (59.1%) encountered drug interactions; however, few explored drug interactions with food, drinks, and nutritional supplements. Their practices to assess possibility of drug interactions were reviewing the drug prospectus (78.3%); consulting with their colleagues (58.3%) and searching on the available website (42.6%) and looking at the drug interaction (39.1%). More than half (65.2%) stated lack of any system to identify drug interactions in their workplace. Nearly half of them indicated to including the drug interaction into patient education mostly for food-drug (73.9%) and drug-drug (63.5%) interactions. Almost all indicated the needs for further education on drug interactions and suggested to have guideline/packet guide.


The zinc finger region of simian virus 40 large T antigen is needed for hexamer assembly and origin melting.
Simian virus 40 large T antigen contains a single sequence element with an arrangement of cysteines and histidines that is characteristic of a zinc finger motif. The finger region maps from amino acids 302 through 320 and has the sequence C-302 L K C-305 I K K E Q P S H Y K Y H-317 E K H-320. Previous genetic analysis has shown that the cysteine and histidine sequences and the contiguous S H Y K Y region in the finger are important for DNA replication in vivo. We show here that representative mutations in either of these elements of the finger prevent the assembly of large T antigen into stable hexamers in vitro. These same mutations have a characteristic effect on the interaction of T antigen with the simian virus 40 core origin of replication. The mutant T antigens bind to the central pentanucleotide domain of the core origin but fail to melt the adjacent inverted repeat domain and to untwist the adenine-thymine domain. These defects would prevent the formation of a replication bubble and the initiation of DNA replication. Finger mutations have lesser effects on the helicase function of T antigen and no observable effect on binding of T antigen to the mouse p53 protein. We propose that the zinc finger region contributes to protein-protein interactions essential for the assembly of stable T-antigen hexamers at the origin of replication and that hexamers are needed for subsequent alterations in the structure of origin DNA. We cannot exclude the possibility that the zinc finger region also makes specific contacts with components of origin DNA.


Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms.
A nef gene is present in all primate lentiviral genomes and is important for high viral loads and progression to AIDS in human or experimental macaque hosts of HIV or SIV, respectively. In these hosts, infection of the thymus results in a decreased output of naive T cells that may contribute to the development of immunodeficiency. We have previously shown that HIV-1 subtype B Nef proteins can block human T-cell development. However, the underlying mechanism(s) and the conservation of this Nef function between different groups of HIV and SIV remained to be determined. We investigated whether reduction of thymic output is a conserved function of highly divergent lentiviral Nef proteins including those from both types of human immunodeficiency viruses (HIV-1 and HIV-2), their direct simian counterparts (SIVcpz, SIVgor and SIVsmm, respectively), and some additional SIV strains. We found that expression of most of these nef alleles in thymocyte progenitors impaired T-cell development and reduced thymic output. For HIV-1 Nef, binding to active p21 protein (Cdc42/Rac)-activated kinase (PAK2) was a major determinant of this function. In contrast, selective disruption of PAK2 binding did not eliminate the effect on T-cell development of SIVmac239 Nef, as was shown by expressing mutants in a newly discovered PAK2 activating structural motif (PASM) constituted by residues I117, H121, T218 and Y221, as well as previously described mutants. Rather, down-modulation of cell surface CD3 was sufficient for reduced thymic output by SIVmac Nef, while other functions of SIV Nefs contributed. Our results indicate that primate lentiviral Nef proteins impair development of thymocyte precursors into T cells in multiple ways. The interaction of HIV-1 Nef with active PAK2 by HIV-1 seem to be most detrimental, and downregulation of CD3 by HIV-2 and most SIV Nef proteins sufficient for reduced thymic output. Since the reduction of thymic output by Nef is a conserved property of divergent lentiviruses, it is likely to be relevant for peripheral T-cell depletion in poorly adapted primate lentiviral infections.


Relation of Intravascular Volume Profiles to Heart Failure Progression and Clinical Outcomes.
Heart failure (HF) commonly progresses over time and identifying differences in volume profiles may help stratify risk and guide therapy. The aim of this study was to assess the pathophysiologic and prognostic roles of volume profiles for HF progression in stable ambulatory and hospitalized patients. HF patients who had undergone quantitative intravascular volume analysis (185 outpatients and 139 inpatients) were retrospectively assessed for the combined end point of HF-related hospital admissions (outpatients), HF-readmissions (inpatients), and overall all-cause mortality. After multivariate Cox regression analysis, greater total blood volume expansion was associated with higher risk of HF-admission in previously stable outpatients (HR: 1.023, CI 1.005 to 1.043; p = 0.013) while in more advanced HF (inpatients) total blood volume expansion was associated with lower risk for HF-readmission and mortality (HR: 0.982, CI 0.967 to 0.997; p = 0.017). Secondary analysis suggests that subclinical plasma volume expansion was a driving factor for the detrimental association in outpatients (HR: 1.018, CI 0.997 to 1.036; p = 0.054), while an increase in red blood cell mass was central to the beneficial association in advanced HF (HR: 0.979, CI 0.968 to 0.991; p <0.001). In conclusion, understanding differences in plasma volume and red blood cell mass profiles can provide insight into the pathophysiology and progression of HF.


Connectome-Based Propagation Model in Amyotrophic Lateral Sclerosis.
Clinical trials in amyotrophic lateral sclerosis (ALS) continue to rely on survival or functional scales as endpoints, despite the emergence of quantitative biomarkers. Neuroimaging-based biomarkers in ALS have been shown to detect ALS-associated pathology in vivo, although anatomical patterns of disease spread are poorly characterized. The objective of this study is to simulate disease propagation using network analyses of cerebral magnetic resonance imaging (MRI) data to predict disease progression. Using brain networks of ALS patients (n = 208) and matched controls across longitudinal time points, network-based statistics unraveled progressive network degeneration originating from the motor cortex and expanding in a spatiotemporal manner. We applied a computational model to the MRI scan of patients to simulate this progressive network degeneration. Simulated aggregation levels at the group and individual level were validated with empirical impairment observed at later time points of white matter and clinical decline using both internal and external datasets. We observe that computer-simulated aggregation levels mimic true disease patterns in ALS patients. Simulated patterns of involvement across cortical areas show significant overlap with the patterns of empirically impaired brain regions on later scans, at both group and individual levels. These findings are validated using an external longitudinal dataset of 30 patients. Our results are in accordance with established pathological staging systems and may have implications for patient stratification in future clinical trials. Our results demonstrate the utility of computational models in ALS to predict disease progression and underscore their potential as a prognostic biomarker. ANN NEUROL 2020;87:725-738.


Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor.
The initiation of DNA replication in Saccharomyces cerevisiae requires the action of a multisubunit complex of six proteins known as the origin recognition complex (ORC). The identification of higher eukaryotic homologs of several ORC components suggests a universal role for this complex in DNA replication. We now demonstrate that the expression of one of these homologs is regulated by cell proliferation. Expression of the human Orc1 gene (HsOrc1) is low in quiescent cells, and it is then dramatically induced upon stimulation of cell growth. In contrast, expression of the HsOrc2 gene does not appear to be similarly regulated. We have isolated the promoter that regulates HsOrc1 transcription, and we show that the promoter confers cell growth-dependent expression. We also demonstrate that the cell growth control is largely the consequence of E2F-dependent negative transcription control in quiescent cells. Activation of HsOrc1 transcription following growth stimulation requires G1 cyclin-dependent kinase activity, and forced E2F1 expression can bypass this requirement. These results thus provide a direct link between the initiation of DNA replication and the cell growth regulatory pathway involving G1 cyclin-dependent kinases, the Rb tumor suppressor, and E2F.


Comparison of endocardial activation times at effective and ineffective ablation sites within the pulmonary veins.
Recent studies demonstrated that atrial arrhythmias may be generated within pulmonary veins. The purpose of this study was to compare the endocardial activation times at effective and ineffective ablation sites during radiofrequency catheter ablation of arrhythmias initiated or generated within pulmonary veins. Twenty-one of 28 patients without structural heart disease underwent successful ablation of 23 arrhythmogenic foci within a pulmonary vein. Electrograms were recorded at 75 pulmonary venous sites and categorized into three groups: 23 successful ablation sites; 28 unsuccessful target sites within an arrhythmogenic pulmonary vein; and 24 sites within nonarrhythmogenic pulmonary veins. The endocardial activation time of premature depolarizations arising at successful target sites was significantly earlier than at other sites. During premature depolarizations, an endocardial activation time of -75 msec or earlier had a sensitivity of 83% and a specificity of 79% for identification of a successful ablation site. Endocardial activation times earlier than -100 msec were recorded only at successful ablation sites, and endocardial activation times later than -30 msec were recorded only at sites within nonarrhythmogenic pulmonary veins. The presence of a split potential during sinus rhythm or premature depolarizations was not a specific indicator of a successful ablation site. The endocardial activation times of premature depolarizations that arise within pulmonary veins and initiate atrial tachycardia/fibrillation are useful in identifying successful ablation sites.


Social imitation versus strategic choice, or consensus versus cooperation, in the networked Prisoner's Dilemma.
The interplay of social and strategic motivations in human interactions is a largely unexplored topic in collective social phenomena. Whether individuals' decisions are taken in a purely strategic basis or due to social pressure without a rational background crucially influences the model outcome. Here we study a networked Prisoner's Dilemma in which decisions are made either based on the replication of the most successful neighbor's strategy (unconditional imitation) or by pure social imitation following an update rule inspired by the voter model. The main effects of the voter dynamics are an enhancement of the final consensus, i.e., asymptotic states are generally uniform, and a promotion of cooperation in certain regions of the parameter space as compared to the outcome of purely strategic updates. Thus, voter dynamics acts as an interface noise and has a similar effect as a pure random noise; furthermore, its influence is mostly independent of the network heterogeneity. When strategic decisions are made following other update rules such as the replicator or Moran processes, the dynamic mixed state found under unconditional imitation for some parameters disappears, but an increase of cooperation in certain parameter regions is still observed. Comparing our results with recent experiments on the Prisoner's Dilemma, we conclude that such a mixed dynamics may explain moody conditional cooperation among the agents.


Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression.
The antidepressant effect of a compound formed by co-ultramicronized palmitoylethanolamide (PEA) and luteolin (PEA+luteolin) was investigated in a mouse model of anxiety/depressive-like behavior. 129Sv/Ev mice were subjected to 6 weeks of corticosterone administration, and then behavior, neurogenesis, neuroplasticity, neurotrophic and apoptotic proteins expression were evaluated. The effect of PEA+luteolin compound treatment (1mg/kg, i.p.), on depression-like behaviour was assessed using different paradigms such as open field, novelty suppressed feeding, forced swim test and elevated plus maze. In particular in the open field, novelty suppressed feeding and elevated plus maze the time spent in the open arm was employed as an indicator of anxiety; forced swim test was used to evaluate the antidepressant capacity of PEA+luteolin on immobility time as an indicator of depression. Adult hippocampal neurogenesis and neuroplasticity were evaluated by immunohistochemical techniques; brain-derived neurotrophic factor and apoptotic protein (Bax and Bcl2) expression were studied by immunostaining and Western blot analysis. For the first time we demonstrated that PEA+luteolin compound exerts a significant antidepressant effect a low dose and may be considered as a novel therapeutic strategy in depression.


Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake.
Effects of genetic selection for high wheel-running activity (17th generation) and access to running wheels on skeletal muscle glucose uptake were studied in mice with the following treatments for 8 wk: 1) access to unlocked wheels; 2) same as 1, but wheels locked 48 h before glucose uptake measurement; or 3) wheels always locked. Selected mice ran more than random-bred (nonselected) mice (8-wk mean +/- SE = 8,243 +/- 711 vs. 3,719 +/- 233 revolutions/day). Body weight was 5-13% lower for selected vs. nonselected groups. Fat pad/body weight was ~40% lower for selected vs. nonselected and unlocked vs. locked groups. Insulin-stimulated glucose uptake and fat pad/body weight were inversely correlated for isolated soleus (r = -0.333; P < 0.005) but not extensor digitorum longus (EDL) or epitrochlearis muscles. Insulin-stimulated glucose uptake was higher in EDL (P < 0.02) for selected vs. nonselected mice. Glucose uptake did not differ by wheel group, and amount of running did not correlate with glucose uptake for any muscle. Wheel running by mice did not enhance subsequent glucose uptake by isolated muscles.


Risk assessment, genetic testing, and management of Lynch syndrome.
Of the estimated 150,000 colorectal cancer (CRC) cases diagnosed annually, approximately 30% have a familial basis and 3% to 5% are from high-penetrance inherited cancer syndromes. Lynch syndrome, or hereditary nonpolyposis colorectal cancer, caused by inherited germline mutations in mismatch repair (MMR) genes, is the most commonly inherited CRC syndrome. It is characterized by young-onset CRC and an increased risk for extracolonic tumors, including gynecologic, urinary tract, and other gastrointestinal cancers. Commercial testing is available for mutations in the MMR genes, but testing all patients with CRC would be economically prohibitive. Therefore, a comprehensive evaluation of a multigenerational family cancer history is essential for the identification of at-risk individuals. The presence of tumors diagnosed at a young age, multiple first- and second-degree relatives with cancer, or 2 or more primary cancers may be indicative of an inherited cancer syndrome and these individuals should undergo genetic evaluation. Genetic test results, when conclusive, can guide management for patients and their families. However, indeterminate test results may provide false reassurance to patients who should be managed as being at higher-than-average risk. Online risk assessment tools and commercial genetic testing offer the potential to identify a greater number of at-risk individuals at an earlier age. However, for these measures to improve outcomes, patients must receive screening recommendations and counseling appropriate for their cancer risk.


Characterization of tungiasis infection and morbidity using thermography in Kenya revealed higher disease burden during COVID-19 school closures.
Tungiasis is a neglected tropical skin disease caused by the sand flea Tunga penetrans. Female fleas penetrate the skin, particularly at the feet, and cause severe inflammation. This study aimed to characterize disease burden in two highly affected regions in Kenya, to test the use of thermography to detect tungiasis-associated inflammation and to create a new two-level classification of disease severity suitable for mapping, targeting, and monitoring interventions. From February 2020 to April 2021, 3532 pupils age 8-14 years were quasi-randomly selected in 35 public primary schools and examined for tungiasis and associated symptoms. Of the infected pupils, 266 were quasi-randomly selected and their households visited, where an additional 1138 family members were examined. Inflammation was assessed using infra-red thermography. A Clinical score was created combining the number of locations on the feet with acute and chronic symptoms and infra-red hotspots. The overall prevalence of tungiasis among all the school pupils who were randomly selected during survey rounds 1 and 3 was 9.3% [95% confidence interval (CI): 8.4-10.3]. Based on mixed effects logistic models, the odds of infection with tungiasis among school pupils was three times higher in Kwale (coastal Kenya) than in Siaya [western Kenya; adjusted odds ratio (aOR) = 0.36, 95% CI: 0.18-0.74]; three times higher in males than in females (aOR = 3.0, 95% CI: 2.32-3.91) and three times lower among pupils sleeping in a house with a concrete floor (aOR = 0.32, 95% CI: 0.24-0.44). The odds of finding an infected person among the household population during surveys before the COVID-19 pandemic was a third (aOR = 0.32, 95% CI: 0.19-0.53) of that when schools were closed due to COVID-19 restrictions and approximately half (aOR = 0.44, 95% CI: 0.29-0.68) in surveys done after school re-opening (round 3). Infection intensity was positively correlated with inflammation as measured by thermography (Spearman's rho = 0.68, P < 0.001) and with the clinical score (rho = 0.86, P < 0.001). Based on the two-level classification, severe cases were associated with a threefold higher level of pain (OR = 2.99, 95% CI: 2.02-4.43) and itching (OR = 3.31, 95% CI: 2.24-4.89) than mild cases. Thermography was a valuable addition for assessing morbidity and the proposed two-level classification of disease severity clearly separated patients with mild and severe impacts. The burden of tungiasis was considerably higher in households surveyed during COVID-19 restrictions suggesting underlying risks are found in the home environment more than in school.


METTL3 regulates heterochromatin in mouse embryonic stem cells.
METTL3 (methyltransferase-like 3) mediates the N6-methyladenosine (m6A) methylation of mRNA, which affects the stability of mRNA and its translation into protein1. METTL3 also binds chromatin2-4, but the role of METTL3 and m6A methylation in chromatin is not fully understood. Here we show that METTL3 regulates mouse embryonic stem-cell heterochromatin, the integrity of which is critical for silencing retroviral elements and for mammalian development5. METTL3 predominantly localizes to the intracisternal A particle (IAP)-type family of endogenous retroviruses. Knockout of Mettl3 impairs the deposition of multiple heterochromatin marks onto METTL3-targeted IAPs, and upregulates IAP transcription, suggesting that METTL3 is important for the integrity of IAP heterochromatin. We provide further evidence that RNA transcripts derived from METTL3-bound IAPs are associated with chromatin and are m6A-methylated. These m6A-marked transcripts are bound by the m6A reader YTHDC1, which interacts with METTL3 and in turn promotes the association of METTL3 with chromatin. METTL3 also interacts physically with the histone 3 lysine 9 (H3K9) tri-methyltransferase SETDB1 and its cofactor TRIM28, and is important for their localization to IAPs. Our findings demonstrate that METTL3-catalysed m6A modification of RNA is important for the integrity of IAP heterochromatin in mouse embryonic stem cells, revealing a mechanism of heterochromatin regulation in mammals.


The human vertebral column at the end of the embryonic period proper. 2. The occipitocervical region.
The present investigation of the cervical region of the vertebral column at eight post-ovulatory weeks is the first such study based on precise reconstructions of staged embryos. At the end of the embryonic period proper, a typical vertebra is a U-shaped piece of cartilage characterized by spina bifida occulta. The notochord ascends through the centra and leaves the dens to enter the basal plate of the skull. The median column of the axis comprises three parts (designated X, Y, Z) which persist well into the fetal period. They are related to the first, second and third cervical nerves, respectively. Part X may project into the foramen magnum and form an occipito-axial joint. Part Z appears to be the centrum of the axis. The articular columns of the cervical vertebrae are twofold, as in the adult: an anterior (atlanto-occipital and atlanto-axial) and a posterior (from the lower aspect of the axis downwards). Alar and transverse ligaments are present. Cavitation is not found in the embryonic period in either the atlanto-occipital or zygapophysial joints, and is generally not present in the median atlanto-axial joint either. Most of the transverse processes exhibit anterior and posterior tubercles. An 'intertubercular lamella' may or may not be present, i.e. the foramina transversaria are being formed around the vertebral artery. The spinal ganglia are generally partly in the vertebral canal and partly on the neural arches, medial to the articular processes. During the fetal period, the articular processes shift to a coronal position and this alteration appears to be associated with a corresponding change in the location of the spinal ganglia.


Outbreak of staphylococcal food poisoning among children and staff at a Swiss boarding school due to soft cheese made from raw milk.
On October 1, 2014, children and staff members at a Swiss boarding school consumed Tomme, a soft cheese produced from raw cow milk. Within the following 7h, all 14 persons who ingested the cheese fell ill, including 10 children and 4 staff members. Symptoms included abdominal pain and violent vomiting, followed by severe diarrhea and fever. We aim to present this food poisoning outbreak and characterize the causative agent. The duration of the incubation period was dependent of the age of the patient: 2.5h in children under 10 yr of age, 3.5h in older children and teenagers, and 7h in adults. The soft cheese exhibited low levels of staphylococcal enterotoxin (SE) A (>6ng of SEA/g of cheese) and high levels of staphylococcal enterotoxin D (>200ng of SED/g of cheese). Counts of 10(7) cfu of coagulase-positive staphylococci per gram of cheese were detected, with 3 different Staphylococcus aureus strains being present at levels >10(6) cfu/g. The 3 strains were characterized using spa typing and a DNA microarray. An enterotoxin-producing strain exhibiting sea and sed was identified as the source of the outbreak. The strain was assigned to spa type tbl 3555 and clonal complex 8, and it exhibited genetic criteria consistent with the characteristics of a genotype B strain. This genotype comprises bovine Staph. aureus strains exclusively associated with very high within-herd prevalence of mastitis and has been described as a major contaminant in Swiss raw milk cheese. It is therefore highly likely that the raw milk used for Tomme production was heavily contaminated with Staph. aureus and that levels further increased due to growth of the organism and physical concentration effects during the cheese-making process. Only a few staphylococcal food poisoning outbreaks involving raw milk products have been described. Still, in view of this outbreak and the possible occurrence of other foodborne pathogens in bovine milk, consumption of raw milk and soft cheese produced from raw milk constitutes a health risk, particularly when young children or other members of sensitive populations are involved.


The experience of Greek-Cypriot individuals living with mental illness: preliminary results of a phenomenological study.
Research evidence shows that healthcare professionals do not fully comprehend the difficulty involved in problems faced by people living with severe mental illness (SMI). As a result, mental health service consumers do not show confidence in the healthcare system and healthcare professionals, a problem related to the phenomenon of adherence to therapy. Moreover, the issue of unmet needs in treating individuals living with SMI is relared to their quality of life in a negative way. A qualitative methodological approach based on the methodology of van Manen phenomenology was employed through a purposive sampling of ten people living with SMI. The aim was to explore their perceptions and interpretations regarding: a) their illness, b) their self-image throughout the illness, c) the social implications following their illness, and d) the quality of the therapeutic relationship with mental health nurses. Participants were recruited from a community mental health service in a Greek-Cypriot urban city. Data were collected through personal, semi-structured interviews. Several main themes were identified through the narratives of all ten participants. Main themes included: a) The meaning of mental illness, b) The different phases of the illness in time, c) The perception of the self during the illness, d) Perceptions about the effectiveness of pharmacotherapy, e) Social and personal consequences for participants following the diagnosis of mental illness, f) Participants' perceptions regarding mental health professionals and services and g) The therapeutic effect of the research interview on the participants. The present study provides data for the enhancement of the empathic understanding of healthcare professionals regarding the concerns and particular needs of individuals living with SMI, as well as the formation of targeted psychosocial interventions based on these needs. Overall, the present data illuminate the necessity for the reconstruction of the provided mental healthcare in Cyprus into a more recovery- oriented approach in order to address personal identity and self-determination issues and the way these are related to management of pharmacotherapy. Qualitative studies aiming to further explore issues of self-identity during ill health and its association with adherence to therapy, resilience and self-determination, are also proposed.


Optically anisotropic microlens array film directly formed on a single substrate.
An optically anisotropic microlens array film directly formed on a single substrate is demonstrated. UV curable diacrylate monomers are coated as a film on the substrate. Under the action of fringing field, not only the film surface is flattened by the generated dielectric force but also the monomers are reoriented to form a gradient refractive index (GRIN) distribution in the film. Via UV exposure, the GRIN distribution is fixed and the polymeric film behaves as a microlens array. The fabrication process is simple and the film offers a switchable focus through controlling the polarization direction of the incident light. Integrating with a 90° twisted-nematic liquid crystal cell, our polymeric microlens array film shows great potential for switchable 2D/3D autostereoscopic displays.


Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients.
To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 (MEN 1) and Zollinger-Ellison syndrome (ZES) underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors (NETs) between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test (SASI test) with secretin or calcium solution was performed as well as somatostatin receptor scintigraphy (SRS) and other imaging methods such as computed tomography (CT) or magnetic resonance imaging (MRI). The modus of surgery for gastrinoma has been changed over time, searching for the optimal surgery: pancreaticoduodenectomy (PD) was first performed guided by localization with the SAST test, then local resection of duodenal gastrinomas with dissection of regional lymph nodes (LR), and recently pancreas-preserving total duodenectomy (PPTD) has been performed for multiple duodenal gastrinomas. Among various types of preoperative localizing methods for gastrinoma, the SASI test was the most useful method. Imaging methods such as SRS or CT made it essentially impossible to differentiate functioning gastrinoma among various kinds of NETs. However, recent imaging methods including SRS or CT were useful for detecting both distant metastases and ectopic NETs; therefore they are indispensable for staging of NETs. Biochemical cure of gastrinoma was achieved in 14 of 16 patients (87.5%); that is, 100% in 3 patients who underwent PD, 100% in 6 patients who underwent LR (although in 2 patients (33.3%) second LR was performed for recurrence of duodenal gastrinoma), and 71.4% in 7 patients who underwent PPTD. Pancreatic NETs more than 1 cm in diameter were resected either by distal pancreatectomy or enucleations, and no hepatic metastases have developed postoperatively. Pathological study of the resected specimens revealed co-existence of pancreatic gastrinoma with duodenal gastrinoma in 2 of 16 patients (13%), and G cell hyperplasia and/or microgastrinoma in the duodenal Brunner's gland was revealed in all of 7 duodenal specimens after PPTD. Aggressive resection surgery based on accurate localization with the SASI test was useful for biochemical cure of gastrinoma in patients with MEN 1.