Immunomodulation by low-dose methotrexate. I. Methotrexate selectively inhibits Lyt-2+ cells in murine acute graft-versus-host reactions.
We have studied the effect of methotrexate in murine acute graft vs host (GvH) disease at concentrations analogous to those used in human rheumatoid arthritis. The GvH reaction was induced by i.v. injection of parental spleen cells into a normal F1 recipient. The acute suppression of T cell function in GvH mice was prevented by methotrexate given orally for 10 days at 1.0 or 0.5 mg/kg but not at 0.25 mg/kg. T cell mitogen response and IL-2 secretion that were inhibited in GvH mice were restored by methotrexate. Protection from immunosuppression in drug-treated GvH mice lasted at least 3 wk after drug dosing was stopped. The mechanism of the protective effect appears to be a preferential inhibition of donor and host Lyt-2+ Ts cell proliferation. In mixing experiments we found that methotrexate inhibited Ts function in GvH mice. By dual fluorescence labeling we showed that the engraftment of donor Lyt-2+ cells was prevented by drug treatment. This was not true of donor L3T4+ cells which were clearly present in the spleens of GvH mice after methotrexate treatment. These donor L3T4 cells were functional in that they induced the production of anti-DNA autoantibodies in the methotrexate-treated GvH mice.


Interpretive monitoring in the caudate nucleus.
In a dynamic environment an organism has to constantly adjust ongoing behavior to adapt to a given context. This process requires continuous monitoring of ongoing behavior to provide its meaningful interpretation. The caudate nucleus is known to have a role in behavioral monitoring, but the nature of these signals during dynamic behavior is still unclear. We recorded neuronal activity in the caudate nucleus in monkeys during categorization behavior that changed rapidly across contexts. We found that neuronal activity maintained representation of the identity and context of a recently categorized stimulus, as well as interpreted the behavioral meaningfulness of the maintained trace. The accuracy of this cognitive monitoring signal was highest for behavior for which subjects were prone to make errors. Thus, the caudate nucleus provides interpretive monitoring of ongoing behavior, which is necessary for contextually specific decisions to adapt to rapidly changing conditions.


In-fiber quasi-Michelson interferometer with a core-cladding-mode fiber end-face mirror.
An in-fiber quasi-Michelson interferometer working on reflection is proposed and experimentally demonstrated. The device consists of a short section of multimode fiber (MMF) followed by a single-mode fiber (SMF) whose end face is terminated by a thick silver film. The MMF excites cladding modes into downstream SMF via the mismatched-core splicing interface. The core-cladding modes are reflected back by the silver film and recoupled to the core of lead-in SMF through the MMF. A well-defined interference pattern is obtained as the result of core-cladding mode interference. A configuration with a 40 mm pigtail SMF at a wavelength of 1528 nm exhibits a water level sensitivity of -49.8 pm/mm and a liquid refractive index sensitivity of -574.6 (pm/mm)/RIU (refractive index unit). In addition, the selected dip provides a considered temperature sensitivity of -61.26 pm/°C and a high displacement sensitivity of -1018.6 pm/mm.


Changes in size, morphology and weight of human anterior teeth during the fetal period.
The changes in size and weight of the calcified portions of the crowns of deciduous anterior teeth (maxillary and mandibular central and lateral incisors and canines) in human fetuses aged 5-10 months were studied. Relating the weight and size of each tooth to fetal age provided quantitative information on the rate of crown development in each of these teeth. There is a good correlation between crown height and fetal age. At the corresponding ages the length of the maxillary central incisor is greater than that of the maxillary lateral incisor which is greater than that of the maxillary canine. A similar pattern is found in the mandibular teeth. Generally, with the exception of a few mandibular central incisors, no type of anterior tooth crown has reached its final length before birth.


Educating on professional habits: attitudes of medical students towards diverse strategies for promoting influenza vaccination and factors associated with the intention to get vaccinated.
Influenza vaccination coverage in medical students is usually low. Unlike health care workers, there is little information on the attitudes to and predictors of vaccination among medical students, and their attitudes towards institutional strategies for improving rates are unknown. This cross-sectional study evaluated the effect of three influenza vaccination promotional strategies (Web page, video and tri-fold brochure) on medical students' intention to get vaccinated and associated factors. A total of 538 medical students were asked to answer an anonymous questionnaire assessing the intention to get vaccinated after exposure to any of the promotional strategies. Sociodemographic data collected included: sex, age, university year, influenza risk group and cohabiting with member of a risk group. Four hundred twenty-one students answered the questionnaire, of whom 312 (74.1%) were female, 113 (26.8%) had done clinical rotations, and 111 (26.6%) reported intention to get the flu shot. Logistic regression showed the web group had a greater intention to get vaccinated than the reference group (OR: 2.42 95% CI: 1.16-5.03). Having done clinical rotations (OR: 2.55 95% CI: 1.36-4.38) and having received the shot in previous flu seasons (OR: 13.69 95% CI: 7.86-23.96) were independently associated with the intention to get vaccinated. Given that previous vaccination is a factor associated with the intention to get vaccinated, education on vaccination of health care workers should begin while they are students, thereby potentiating the habit. In addition, the intention to get vaccinated was greater during the clinical phase of the university career, suggesting this is a good time to introduce promotion strategies. Online promotional campaigns, such as a thematic Web to promote vaccination of health workers, could improve the intention to get vaccinated.


Accuracy of dynamic patient surface monitoring using a time-of-flight camera and B-spline modeling for respiratory motion characterization.
Time-of-flight (ToF) camera technology provides a real-time depth map of a scene with adequate frequency for the monitoring of physiological patient motion. However, dynamic surface motion estimation using a ToF camera is limited by issues such as the raw measurement accuracy and the absence of fixed anatomical landmarks. In this work we propose to overcome these limitations using surface modeling through B-splines. This approach was assessed in terms of both motion estimation accuracy and associated variability improvements using acquisitions of an anthropomorphic surface phantom for a range of observation distances (0.6-1.4 m). In addition, feasibility was demonstrated on patient acquisitions. Using the proposed B-spline modeling, the mean motion estimation error and associated repeatability with respect to the raw measurements decreased by a factor of 3. Significant correlation was found between patients' surfaces motion extracted using the proposed B-spline approach applied to the ToF data and the one extracted from synchronized 4D-CT acquisitions as the ground truth. ToF cameras represent a promising alternative for contact-less patient surface monitoring for respiratory motion synchronization or modeling in imaging and/or radiotherapy applications.


Comparison of Extracellular Matrix Patch and Standard Patch Material in the Pulmonary Arteries.
After pulmonary artery (PA) patch augmentation, surgical or catheterization reintervention to address PA stenosis is not uncommon. Multiple patch materials are available and the need for reintervention may be related to characteristics of the patch material. In this retrospective chart review of patients who underwent PA augmentation from 2004 through 2013, we compare outcomes after PA augmentation with standard patch (SP) material and extracellular matrix (ECM) patch material. The primary outcome was reintervention-free survival (surgery or catheterization) using Kaplan-Meier survival analysis with the log-rank test. Risk factors for reintervention were assessed with Cox proportional hazard analyses. Baseline characteristics between groups were similar, except single-ventricle (SV) patients were more likely to have SP, and duration of follow-up was longer in the SP group. Median time to reintervention for all patients was 1099 days (95 % CI 646-1552 days). There was no difference in reintervention-free survival between the patch groups (p = 0.12); however, in multivariable analysis controlling for surgeon and patch, longer reintervention-free survival was associated with SV physiology (HR 0.57 95 % CI 0.34-0.95, p = 0.03) and aortic cross-clamp (XC) use (HR 0.52, 95 % CI 0.32-0.84, p = 0.008). Since there is no difference in median time to reintervention following PA augmentation with SP or ECM, patch choice should be determined by other factors, such as surgeon preference and cost. Longer reintervention-free survival in SV patients may be related to the set schedule of staged palliation. XC use may allow more extensive PA augmentation, thus protecting against the need for reintervention.


Sericin improves heart and liver mitochondrial architecture in hypercholesterolaemic rats and maintains pancreatic and adrenal cell biosynthesis.
Hypercholesterolaemia is well known to be associated with mitochondrial dysfunction, subsequently leading to multiple organ failure. Similar to other natural products, sericin is a candidate for adjunctive therapy in hyperlipidaemic conditions. However, the cholesterol-lowering mechanisms of sericin are multifactorial and controversial. Here, a high-cholesterol-fed rat model with or without sericin treatment was established using a dosage of 1000mg/kg/day for 30 days. Blood lipid profiles, oxidative stress markers (superoxide dismutase, SOD; malondialdehyde, MDA; nuclear factor erythroid 2-related factor, Nrf-2), dysmorphic mitochondria in relation to fission (dynamin-related protein-1; Drp-1) and fusion (guanosine triphosphatase mutated in dominant optic atrophy; OPA-1) markers and biosynthetic markers (aquaporin, AQP-1; tubulin-4β, Tb4B) in the pancreas and adrenal gland were evaluated. The results showed that sericin reduced blood cholesterol and increased high-density lipoprotein (HDL) by acting against oxidative stress. Hypocholesterolaemic and antioxidant conditions further preserved heart and liver mitochondrial architecture; however, this protection was not exhibited in the kidney, where a high level of renal mitophagy, indicating by LC-3 up-regulation, was presented. The steps of ultrastructural alteration of mitochondria from degenerative changes to necrosis were also demonstrated. Sericin also conserved AQP-1 and Tb4B levels in the exocrine pancreatic acinar cells and zona glomerulosa cells, which were positively correlated with serum lipase, HDL, antioxidative markers and mitochondrial integrity. The present study revealed that sericin not only has antioxidant capacity but also balances pancreatic and adrenal cell biosynthesis, especially lipase activity, which may have played an important role in improving lipid dysregulation in the hypercholesterolaemic rat model, leading to the reduction of dysmorphic mitochondria, particularly in the heart and liver.


Facial and prosodic emotion recognition in social anxiety disorder.
Patients with social anxiety disorder (SAD) have a cognitive preference to negatively evaluate emotional information. In particular, the preferential biases in prosodic emotion recognition in SAD have been much less explored. The present study aims to investigate whether SAD patients retain negative evaluation biases across visual and auditory modalities when given sufficient response time to recognise emotions. Thirty-one SAD patients and 31 age- and gender-matched healthy participants completed a culturally suitable non-verbal emotion recognition task and received clinical assessments for social anxiety and depressive symptoms. A repeated measures analysis of variance was conducted to examine group differences in emotion recognition. Compared to healthy participants, SAD patients were significantly less accurate at recognising facial and prosodic emotions, and spent more time on emotion recognition. The differences were mainly driven by the lower accuracy and longer reaction times for recognising fearful emotions in SAD patients. Within the SAD patients, lower accuracy of sad face recognition was associated with higher severity of depressive and social anxiety symptoms, particularly with avoidance symptoms. These findings may represent a cross-modality pattern of avoidance in the later stage of identifying negative emotions in SAD. This pattern may be linked to clinical symptom severity.


Comparative pre-emptive analgesic efficacy study of novel antiepileptic agents gabapentin, lamotrigine and topiramate in patients undergoing major surgeries at a tertiary care hospital: a randomized double blind clinical trial.
Surgical injury leads to postoperative pain hypersensitivity preceded by central nervous sensitization, due to lowered pain threshold in peripheral nociceptors and increased excitability of the spinal neurons. Pre-emptive analgesia is intended to decrease pain perception and overall analgesic need by use of drug regimen seizing central nervous system sensitization before exposure to painful stimuli. Earlier, few studies support pre-emptive analgesic efficacy of novel antiepileptic agent gabapentin. But topiramate and lamotrigine though proven analgesic in animal models of chronic pain and clinical studies of gabapentin resistant neuropathic pain; literature search revealed scarce data on its pre-emptive analgesic efficacy. The present study is designed to study and compare the pre-emptive analgesic efficacy of lamotrigine, topiramate and gabapentin (as control) in postoperative pain control. This randomized clinical trial included 90 patients of either sex, between 18 and 70 years undergoing major surgeries. Patients were randomly allocated into control and test groups and received respective treatment 30 min before induction of anesthesia. Aldrete's score and pain score were recorded using visual analogue scale and facial and behavioral rating scales at awakening and at 1, 2, 4, 6 and 24 h. Postoperative rescue analgesic consumption for 24 h was recorded. Data were analyzed using OpenEpi and SciStatCalc statistical softwares. Significantly higher pain scores were observed in the topiramate group postoperatively for 2 h on all pain scales (p<0.05). Lamotrigine-treated patients were more comfortable throughout the study with significantly less (p<0.05) postoperative analgesic requirement comparable to gabapentin. Study results are strongly suggestive of pre-emptive analgesic efficacy of single oral dose lamotrigine comparable to gabapentin and superior to topiramate in postoperative pain control.


Agreed definitions and a shared vision for new standards in stroke recovery research: The Stroke Recovery and Rehabilitation Roundtable taskforce.
The first Stroke Recovery and Rehabilitation Roundtable established a game changing set of new standards for stroke recovery research. Common language and definitions were required to develop an agreed framework spanning the four working groups: translation of basic science, biomarkers of stroke recovery, measurement in clinical trials and intervention development and reporting. This paper outlines the working definitions established by our group and an agreed vision for accelerating progress in stroke recovery research.


Intramolecular photoassisted cycloadditions of azaxylylenes and postphotochemical capstone modifications via Suzuki coupling provide access to complex polyheterocyclic biaryls.
Modular preassembly of azaxylylene photoprecursors, halogen-substituted in the aromatic ring, their intramolecular [4 + 4] or [4 + 2] cycloadditions to tethered unsaturated pendants, and subsequent postphotochemical capstone modification of the primary photoproducts via Suzuki coupling provides rapid access to diverse biaryls of unprecedented topology. This synthetic sequence allows for rapid growth of molecular complexity and is well aligned with methodology of Diversity-Oriented Synthesis.


Serotonin syndrome from combination hydrocodone and cyclobenzaprine in a patient with cerebral palsy.
Aim: Serotonin syndrome (SS) is a life-threatening syndrome that occurs with the use of serotonergic drugs, most commonly due to two or more agents. Cerebral palsy is associated with mood disorders, and more commonly pain, with a prevalence of up to 50-80%. Case presentation: A 58-year-old female with cerebral palsy, metastatic malignancy and mood disorder who presented to the emergency department with acute-on-chronic pain, and signs of SS. She was initiated on iv. dilaudid, titrated off oral medications and scheduled for a left-sided sacroiliac joint injection. Results: It was suspected that due to additional doses of hydrocodone and cyclobenzaprine, she developed moderate-SS. Conclusion: Physicians need to be cognizant of comorbidities and uncommon pain medications that can predispose patients to SS.


Cyclic hydrostatic pressure stimulates enhanced bone development in the foetal chick femur in vitro.
Mechanical loading of bone and cartilage in vivo results in the generation of cyclic hydrostatic forces as bone compression is transduced to fluid pressure in the canalicular network and the joint synovium. It has therefore been suggested that hydrostatic pressure is an important stimulus by which osteochondral cells and their progenitors sense and respond to mechanical loading in vivo. In this study, hydrostatic pressure regimes of 0-279kPa at 0.005-2Hz were applied to organotypically cultured ex vivo chick foetal femurs (e11) for 1hour per day in a custom designed bioreactor for 14days and bone formation assessed by X-ray microtomography and qualified by histology. We found that the mineralised portion of the developing femur cultured under any cyclic hydrostatic pressure regime was significantly larger and/or denser than unstimulated controls but that constant (non-cycling) hydrostatic pressure had no effect on bone growth. Further experiments showed that the increase in bone formation was directly proportional to stimulation frequency (R(2)=0.917), but independent of the magnitude of the pressure applied, whilst even very low frequencies of stimulation (0.005Hz) had significant effects on bone growth. Expression of Type-II collagen in both epiphyses and diaphysis was significantly upregulated (1.48-fold and 1.95-fold respectively), together with osteogenic genes (osteonectin and osteopontin) and the osteocyte maturation marker CD44. This work demonstrates that cyclic hydrostatic pressure promotes bone growth and mineralisation in a developmental model and supports the hypothesis that hydrostatic forces play an important role in regulating bone growth and remodelling in vivo.


Mechanism of enhanced hematopoietic response by soluble beta-glucan SCG in cyclophosphamide-treated mice.
SCG is a major 6-branched 1,3-beta-D-glucan in Sparassis crispa Fr. SCG shows antitumor activity and also enhances the hematopoietic response in cyclophosphamide (CY)-treated mice. In the present study, the molecular mechanism of the enhancement of the hematopoietic response was investigated. The levels of interferon-(IFN-)gamma, tumor necrosis factor-(TNF-)alpha, granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin-(IL-) 6 and IL-12p70 were significantly increased by SCG in CY-treated mice. GM-CSF production in the splenocytes from the CY-treated mice was higher than that in normal mice regardless of SCG stimulation. Neutralizing GM-CSF significantly inhibited the induction of IFN-gamma, TNF-alpha and IL-12p70 by SCG. The level of cytokine induction by SCG was regulated by the amount of endogenous GM-CSF produced in response to CY treatment in a dose-dependent manner. The expression of beta-glucan receptors, such as CR3 and dectin-1, was up-regulated by CY treatment. Blocking dectin-1 significantly inhibited the induction of TNF-alpha and IL-12p70 production by SCG. Taken together, these results suggest that the key factors in the cytokine induction in CY-treated mice were the enhanced levels of both endogenous GM-CSF production and dectin-1 expression.


Venous thromboembolism among HIV-positive patients and anticoagulation clinic outcomes integrated within the HIV primary care setting.
The purpose of this study was to explore factors associated with venous thromboembolism (VTE) among a cohort of HIV-infected patients and to describe early outcomes of warfarin anticoagulation therapy treated in a pharmacist-based anticoagulation clinic (ACC). A nested case-control study was conducted using the University of Alabama at Birmingham 1917 HIV Clinic Cohort. Conditional logistic regression was used to estimate factors associated with VTE. Among HIV-infected VTE cases, ACC-managed patients were compared to primary care provider (PCP)-managed patients to determine Time within Therapeutic INR Range (TTR). CD4 < 200 cells/µl (OR = 4.50; 95% CI = 1.52, 13.37; p = 0.007) and prior surgical procedures (13.20; 1.56; 111.4; p = 0.018) demonstrated positive associations with VTE, whereas longer HIV duration demonstrated a negative association (0.87; 0.78, 0.98; p = 0.019). TTR was 56.2% among ACC-managed patients compared to 30.5% of PCP-managed patients (p = 0.174). Overall, prior surgical procedures and low CD4 count were associated with an increased risk of VTE among HIV-infected patients. Despite small sample size, patients managed in ACC tend to achieve greater proportion of TTR compared to those managed by PCPs, suggesting that this model of therapy may provide additional benefits to HIV-infected patients.


Management of fever in patients with central vein catheters.
We have evaluated a standardized prospective system for managing episodes of fever in pediatric patients with indwelling central vein catheters being used primarily for delivery of parenteral nutrients. Over an 18-month period 72 such patients, accounting for 4347 "catheter days," were followed. Thirty-two patients experienced a total of 88 episodes of fever. An infection unrelated to the presence of the catheter (e.g. otitis media, pneumonia, urinary tract infection) was found to be the cause of fever in 27 episodes (31.7%); in all the infection responded to appropriate antibiotic therapy. Ten of the episodes of fever (11.4%) lasted for less than 2 hours and were not evaluated further. Two episodes occurred in patients who no longer required the catheter; these resolved with elective catheter removal. The cause of the remaining 49 episodes of fever was assumed to be catheter-related sepsis; these were treated empirically with an intravenous antibiotic regimen of vancomycin (40 mg/kg/day) and gentamicin (7.5 mg/kg/day). In 16 of these cases blood cultures were negative and the antibiotic regimen was either stopped or continued for other indications. The remaining 33 episodes of fever were associated with positive blood cultures, i.e. documented episodes of catheter-related sepsis. In 10 of these the catheters were removed. The remaining 23 episodes of catheter-related sepsis were treated for 14 days with antibiotics given through the central vein catheter. In 5 of these episodes blood cultures remained positive after 48 hours of specific antibiotic therapy at which time the catheter was removed.(ABSTRACT TRUNCATED AT 250 WORDS)


Differential properties of enantiomers of commercially available racemates.
The existence of left- or right-handedness of a compound is referred to as chirality. Each form (left- or right-handed) of a chiral compound is called an 'enantiomer' or an 'isomer'. A collection containing only one enantiomeric form of a chiral molecule is called an optically pure, chirally pure, enantiomerically pure or unichiral compound while collection of equal amounts of the two enantiomeric forms (R and S) is called a racemate. Many of the drugs currently used in medical practice are racemates. However it is well documented that the two enantiomers of a racemate can differ in their pharmacokinetic/pharmacodynamic and efficacy/ safety profiles. Replacing existing racemates with unichiral drugs may result in improved safety and/or efficacy profile of various racemates. This article presents an overview of differential properties of enantiomers of some commercially available racemates.


Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability.
The eukaryotic Rad51 protein is a structural and functional homolog of Escherichia coli RecA with a role in DNA repair and genetic recombination. Five paralogs of Rad51 have been identified in vertebrates, Rad51B, Rad51C, Rad51D, Xrcc2 and Xrcc3, which are also implicated in recombination and genome stability. Here, we identify a mammalian cell mutant in Rad51C. We show that the Chinese hamster cell mutant, CL-V4B, has a defect in Rad51C. Sequencing of the hamster Rad51C cDNA revealed a 132 bp deletion corresponding to an alternatively spliced transcript with lack of exon 5. CL-V4B was hypersensitive to the interstrand cross-linking agents mitomycin C (MMC) and cisplatinum, the alkylating agent methyl methanesulfonate and the topoisomerase I inhibitor campthotecin and showed impaired Rad51 foci formation in response to DNA damage. The defect in Rad51C also resulted in an increase of spontaneous and MMC-induced chromosomal aberrations as well as a lack of induction of sister chromatid exchanges. However, centrosome formation was not affected. Intriguingly, a reduced level of sister chromatid cohesion was found in CL-V4B cells. These results reveal a role for Rad51C that is unique among the Rad51 paralogs.


Aging and performance on an everyday-based visual search task.
Research on aging and visual search often requires older people to search computer screens for target letters or numbers. The aim of this experiment was to investigate age-related differences using an everyday-based visual search task in a large participant sample (n=261) aged 20-88 years. Our results show that: (1) old-old adults have more difficulty with triple conjunction searches with one highly distinctive feature compared to young-old and younger adults; (2) age-related declines in conjunction searches emerge in middle age then progress throughout older age; (3) age-related declines are evident in feature searches on target absent trials, as older people seem to exhaustively and serially search the whole display to determine a target's absence. Together, these findings suggest that declines emerge in middle age then progress throughout older age in feature integration, guided search, perceptual grouping and/or spreading suppression processes. Discussed are implications for enhancing everyday functioning throughout adulthood.


Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.
There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.


Quantum Chemically Estimated Abraham Solute Parameters Using Multiple Solvent-Water Partition Coefficients and Molecular Polarizability.
Polyparameter Linear Free Energy Relationships (pp-LFERs), also called Linear Solvation Energy Relationships (LSERs), are used to predict many environmentally significant properties of chemicals. A method is presented for computing the necessary chemical parameters, the Abraham parameters (AP), used by many pp-LFERs. It employs quantum chemical calculations and uses only the chemical's molecular structure. The method computes the Abraham E parameter using density functional theory computed molecular polarizability and the Clausius-Mossotti equation relating the index refraction to the molecular polarizability, estimates the Abraham V as the COSMO calculated molecular volume, and computes the remaining AP S, A, and B jointly with a multiple linear regression using sixty-five solvent-water partition coefficients computed using the quantum mechanical COSMO-SAC solvation model. These solute parameters, referred to as Quantum Chemically estimated Abraham Parameters (QCAP), are further adjusted by fitting to experimentally based APs using QCAP parameters as the independent variables so that they are compatible with existing Abraham pp-LFERs. QCAP and adjusted QCAP for 1827 neutral chemicals are included. For 24 solvent-water systems including octanol-water, predicted log solvent-water partition coefficients using adjusted QCAP have the smallest root-mean-square errors (RMSEs, 0.314-0.602) compared to predictions made using APs estimated using the molecular fragment based method ABSOLV (0.45-0.716). For munition and munition-like compounds, adjusted QCAP has much lower RMSE (0.860) than does ABSOLV (4.45) which essentially fails for these compounds.


Radiographic progression of rheumatoid arthritis in patients from the Czech National Registry receiving infliximab treatment.
To evaluate the clinical status and radiographic progression in patients with rheumatoid arthritis (RA) being followed by the Czech National Registry of biological treatments. Patients who failed at least two disease-modifying antirheumatic drugs and had high disease activity (DAS28 > 5.1) were treated with infliximab. Radiographic progression was measured with a modified version of the Sharp score (TSS) after 54 weeks of treatment. Ninety-nine patients with an average disease duration of 13.7 years were enrolled. The DAS28 dropped from 6.66 to 4.07 (p < 0.001). Before treatment the mean TSS was 90.1 and the mean estimated yearly disease progression was 8.56. After 54 weeks of infliximab, radiographic progression was 4.15 times slower than the estimated rate before treatment and 63 patients did not show any radiographic progression at all. In the remaining 36 patients, the progression rate slowed to 3.8 +/- 0.9 from the estimated TSS of 10.9 +/- 6.9 before the initiation of treatment (p = 0.011). Data derived from the Czech National Registry, which reflect general clinical practice, show a significant retardation of radiographic progression in patients treated with anti-TNF and the magnitude of the improvement seen is similar to results from clinical trials.


The lower-lid retractors in congenital entropion and epiblepharon.
A case of congenital entropion is presented in which the lower-lid crease was lost during entropion surgery, yielding a postoperative condition resembling an epiblepharon. The case suggests that deficiencies in the lower-lid retractor fibers are a key factor in the pathogenesis of both congenital entropion and epiblepharon.


MiRNA-1/133a clusters regulate adrenergic control of cardiac repolarization.
The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.


Approaches toward High-Mannose-Type Glycan Libraries.
Asparagine-linked (N-linked) sugar chains are widely found in the rough endoplasmic reticulum (ER), which has attracted renewed attention because of its participation in the glycoprotein quality control process. In the ER, newly formed glycoproteins are properly folded to higher-order structures by the action of a variety of lectin chaperones and processing enzymes and are transported into the Golgi, while terminally misfolded glycoproteins are carried into the cytosol for degradation. A group of proteins related to this system are known to recognize subtle differences in the high-mannose-type oligosaccharide structures of glycoproteins; however, their molecular foundations are still unclear. In order to gain a more precise understanding, our group has established a strategy for the systematic synthesis of high-mannose-type glycans. More recently, we have developed "top-down" chemoenzymatic approaches that allow expeditious access to theoretically all types of high-mannose glycans. This strategy comprehensively delivered 37 high-mannose-type glycans, including G1M9-M3 glycans, and opened up the possibility of the elucidation of structure-function relationships with a series of high-mannose-type glycans.


Bacterial communities in the phylloplane of Prunus species.
Bacterial populations in the phylloplane of four different Prunus species were investigated by 16 S rRNA pyrosequencing. Bioinformatic analysis identified an average of 510 operational taxonomic units belonging to 159 genera in 76 families. The two genera, Sphingomonas and Methylobacterium, were dominant in the phylloplane of four Prunus species. Twenty three genera were commonly identified in the four Prunus species, indicating a high level of bacterial diversity dependent on the plant species. Our study based on 16 S rRNA sequencing reveals the complexity of bacterial diversity in the phylloplane of Prunus species in detail.


Seasonal Variations in Microtia of Chinese Population.
Seasonality of congenital birth defect could help to identify environmental risk factors. Data concerning the seasonality of the prevalence of microtia are little. This article aims to determine whether births of microtia follow a certain pattern. Data were obtained from 2669 patients with microtia who were admitted to Second Ear Reconstruction Center of Plastic Surgery Hospital, Chinese Academy of Medical Science from January 2007 to December 2013. The controls consist of all living births from the Obstetric Department of the Haidian Maternal & Child Health Hospital during the same time. Seasonal variations in months of births were analyzed by using χ test. A total of 2669 patients with microtia and 89,273 healthy living newborns were included in this study. Birth time peak of the patients occurred in autumn, especially in November, compared with the nadir in the spring, especially in April (P G 0.05). The birth time peak of male patients occurred in autumn, too, especially in October and November, While the valley occurred in spring (April, too). However, the seasonality in female patients is not so apparent with the peak occurred in the tail of summer and autumn, especially in August, November, and September orderly, while the valley occurred in March. There is a possible seasonality in birth months and a difference between sexes of patients with microtia in this native Chinese population. This approach could be useful to study the etiology of microtia.


To have but one true friend: implications for practice of research on alcohol use disorders and social network.
Although social networks play an integral role in the recognition and resolution of drinking problems, social network influences may be positive, negative, or mixed. The author reviewed empirical literature on positive and negative aspects of the structure of problem drinkers' social networks, the impact of the social network on problem recognition, social network predictors of treatment outcomes, treatments that involve the social network in treatment, and posttreatment changes in social network structure and functioning. Future directions for research and clinical implications of research findings are discussed.


A New Technique to Map the Lymphatic Distribution and Alignment of the Penis.
The present study was to examine the distribution of lymphatic vessels in the penis of normal adult males, which could provide an anatomical basis for improvement of incisions in penile lengthening surgery, and may also help to prevent postoperative refractory edema. Thirteen normal adult male volunteers were recruited for this study. Contrast agent was injected subcutaneously in the foreskin of the penis, and after two minutes magnetic resonance lymphangiography (MRL) was performed. The acquired magnetic resonance images were analyzed to determine the changes in the number and diameter of lymphatic vessels in different parts of the penis. Maximum intensity projections (MIP) and materializes interactive medical image control system (MIMICS) were applied to analyze the overall distribution of lymphatic vessels in the penis. Magnetic resonance imaging (MRI) showed that the lymphatic vessels were in conspicuous contrast with surrounding tissues and could be clearly identified. Penile lymphatic vessels were clearly visible in the root of the penis. At the junction of the penis and the abdominal wall, all lymphatic vessels were found to be concentrated in the dorsal part of the penis. MIP two-dimensional reconstruction showed that the overall distribution of relatively large lymphatic vessels in the dorsal and ventral parts of the penis could be seen clearly on bilateral 45° position, but not inside the abdominal wall because some of lymphatic vessels were overlapped by other tissues in the abdomen. MIMICS three-dimensional reconstruction was able to reveal the overall spatial distribution of lymphatic vessels in the penis from any angle. The reconstruction results showed that there were 1-2 main lymphatic vessels on the root of dorsal penis, which coursed along the cavernous to the first physiological curvature of the penis. Lymphatic vessels merged on both sides of the ventral penis. At the root of the penis, lymphatic vessels gradually coursed to the dorsal surface of the penis and folded at the abdominal wall to the outside, and finally merged into the inguinal lymph nodes. The changes in distribution, number and diameter of the lymphatic vessels in the penis were observed by MRI. MIP and MIMICS reconstructions directly revealed the anatomical features of penile lymphatic vessels such as spatial distribution, overall alignment, and the relations to adjacent structures, drainage and reflux. The study will provide the anatomical basis for penile surgery, penile lymphatic reflux disorders caused by trauma or lymphatic vessels obstruction, and lymph node metastasis in penile cancer.


Orientational relaxation phenomena in Langmuir-Blodgett films at the air-water interface.
The nature of the orientational relaxation process of the director n to its equilibrium orientation n(eq), in the mono-(multi)layer(s) Langmuir-Blodgett film, during the lateral compression in absence of flow, is investigated. The relaxation time, during compression of 4-n-pentyl-4(')-cyanobiphenyl mono-(multi)layer(s) film on the water surface, using the Ericksen-Leslie theory, has been calculated for the number of dynamic regimes.


Renin-angiotensin system.
Renin, a protease that cleaves the prohormone angiotensinogen thereby releasing angiotensin I, plays a major role in regulating blood pressure and electrolyte balance. Although renin is synthesized mainly in the cortical cells of the kidney, the presence of renin or reninlike activity has been recognized in various extrarenal tissues of humans and animals, including such reproductive organs as LH-containing cells of the anterior pituitary, placentral trophoblasts, and Leydig cells of the male gonad. It has also been learned that the renin in these extrarenal tissues generates angiotensins locally, which may interact with angiotensin II receptors in a paracrine or autocrine manner. However, the precise roles of the renin-angiotensin system in extrarenal tissue are not yet understood. We demonstrated the renin-angiotensin system in human testis by measuring the plasma renin activity (PRA), plasma angiotensin II (PAII), and testosterone in the internal spermatic vein (ISV) simultaneously after treatment with hCG, and elucidated the relationship between the renin-angiotensin system and sex steroids from Leydig cells of the male gonad.


Efficient Dual-Function Catalyst: Palladium-Copper Nanoparticles Immobilized on Co-Cr LDH for Seamless Aerobic Oxidation of Benzyl Alcohol and Nitrobenzene Reduction.
Layered double hydroxides (LDHs) present exciting possibilities across various industries, ranging from catalytic applications to water remediation. By immobilizing nanoparticles, LDHs' characteristics and functionality can be enhanced, allowing for synergetic interactions that further expand their potential uses. A simple chemical method was developed to produce well-dispersed Pd-Cu NPs on a Co-Cr LDH support using a combination of in situ coprecipitation/hydrothermal and sol-immobilization techniques. The Pd-Cu@Co-Cr LDH catalysts was obtained, showing its catalytic activity in promoting the aerobic oxidation of alcohols and enabling the reduction of nitro-compounds through NaBH4 mediation. The physicochemical properties of the prepared catalyst were comprehensively investigated utilizing a range of analytical techniques, comprising FTIR, XRD, XPS, TGA, nitrogen adsorption isotherm, FESEM, and HRTEM-EDX. The findings showed the significance of immobilizing the bimetallic Pd-Cu nanoparticles on the Co-Cr LDH via an exceptional performance in the aerobic oxidation of benzyl alcohol (16% conversion, 99.9% selectivity to benzaldehyde) and the reduction of nitrobenzene (98.2% conversion, rate constant of 0.0921 min-1). The improved catalytic efficacy in benzyl alcohol oxidation and nitrobenzene reduction on the Pd-Cu@Co-Cr LDH catalyst is attributed to the uniform distribution and small size of the Pd-Cu NPs as active sites on the Co-Cr LDH surface. The prepared catalyst demonstrated exceptional stability during repeated runs. This study paves the way for multiple opportunities in tailoring, producing, and precisely controlling catalysts for various organic transformation reactions.


The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs.
The recently discovered mammalian molybdoprotein mARC1 is capable of reducing N-hydroxylated compounds. Upon reconstitution with cytochrome b(5) and b(5) reductase, benzamidoxime, pentamidine, and diminazene amidoximes, N-hydroxymelagatran, guanoxabenz, and N-hydroxydebrisoquine are efficiently reduced. These substances are amidoxime/N-hydroxyguanidine prodrugs, leading to improved bioavailability compared to the active amidines/guanidines. Thus, the recombinant enzyme allows prediction about in vivo reduction of N-hydroxylated prodrugs. Furthermore, the prodrug principle is not dependent on cytochrome P450 enzymes.


Extensive accumulation of an extracellular L-amino-acid oxidase during gametogenesis of Chlamydomonas reinhardtii.
In a previous study [Bulté, L. & Wollman, F.-A. (1992) Eur. J. Biochem. 204, 327-336], we identified a novel gamete-specific polypeptide of Chlamydomonas reinhardtii, M alpha. This 66-kDa polypeptide reacts with antibodies to cytochrome f and accumulates in gametes only in conditions that promote destabilisation of the cytochrome b6/f complex. Here, we show that M alpha is not a modification product of cytochrome f, but is part of protein M, a high-molecular-mass L-amino-acid oxidase located in the periplasm. It catalyzes oxidation of all L-amino acids tested, except cysteine. Using phenylalanine as a substrate, saturation of the enzymatic rate is reached at 2 microM. These characteristics suggest that protein M may operate in vivo as an efficient scavanger of ammonium from extracellular amino acids. The enzyme contains non-covalently bound FAD. It exists in two forms with essentially similar enzymatic properties, of 1.2-1.3 MDa and 0.9-1.0 MDa, respectively. The lighter form is an oligomer of M alpha, while the heavier form contains, in addition to M alpha, a second polypeptide of 135 kDa, M beta, in a molar ratio of 3-4 M alpha/M beta. Both polypeptides are glycosylated.


Proxy Graph: Visual Quality Metrics of Big Graph Sampling.
Data sampling has been extensively studied for large scale graph mining. Many analyses and tasks become more efficient when performed on graph samples of much smaller size. The use of proxy objects is common in software engineering for analysis and interaction with heavy objects or systems. In this paper, we coin the term 'proxy graph' and empirically investigate how well a proxy graph visualization can represent a big graph. Our investigation focuses on proxy graphs obtained by sampling; this is one of the most common proxy approaches. Despite the plethora of data sampling studies, this is the first evaluation of sampling in the context of graph visualization. For an objective evaluation, we propose a new family of quality metrics for visual quality of proxy graphs. Our experiments cover popular sampling techniques. Our experimental results lead to guidelines for using sampling-based proxy graphs in visualization.


Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock.
Adrenomedullin (AM) is a highly conserved peptide that can act as a potent vasodilator, anti-microbial factor and anti-inflammatory factor. Several studies have implicated diverse roles for AM in regulating the inflammatory and hemodynamic responses to septic shock. Moreover, during sepsis the receptors that mediate AM signaling [calcitonin receptor-like receptor (calcrl) and receptor activity modifying proteins (RAMP) 2 and 3] undergo dynamic and robust changes in their expression. Although numerous studies have used animal models to study the role of administered or increased AM in septic animals, genetic studies to determine the consequences of reduced AM during septic shock have not yet been performed. Here, we used a murine model of lipopolysaccharide (LPS)-induced septic shock to assess the inflammatory response in mice heterozygous for the AM gene. Following LPS challenge, AM(+/-) mice had higher expression of TNF-alpha and IL-1beta than LPS-treated wild-type (WT) controls. Consequently, serum TNF-alpha was also significantly elevated in LPS-treated AM(+/-) mice compared to WT LPS-treated mice. We also observed higher serum levels of liver enzymes, suggesting more advanced end-organ damage in mice with genetically reduced AM. Finally, we found that RAMP2 and calcrl expression levels were markedly reduced in LPS-treated mice, whereas RAMP3 expression was significantly elevated. Importantly, these changes in receptor gene expression were conserved in AM(+/-) mice, demonstrating that AM peptide itself does not impact directly on the expression of the genes encoding its receptors. We, therefore, conclude that during septic shock the dynamic modulation of AM and its receptors primarily functions to dampen the inflammatory response.


Soft tissue chondroma of hard palate associated with cleft palate.
Soft tissue chondroma of palate is very rare. It has never been reported in a cleft palate patient. We report a case of 22-year-old male who came with asymptomatic swelling on the palate since birth, along with complete cleft of secondary palate. He had symptoms related to cleft palate only, i.e., nasal regurgitation and speech abnormalities. Swelling was excised and the cleft palate was repaired. Histopathological examination revealed chondroma of the palate. The patient had no recurrence after 2 years of follow-up.


Post-traumatic stress disorder and HIV risk behaviors among rural American Indian/Alaska Native women.
We assessed the relationship between post-traumatic stress disorder (PTSD), binge drinking, and HIV sexual risk behavior by examining number of unprotected sex acts and number of sexual partners in the past 6 months among 129 sexually active American Indian women. A total of 51 (39.5%) young women met PTSD criteria. Among women who met the PTSD criteria, binge drinking was associated with a 35% increased rate of unprotected sex (IRR 1.35, p < .05), and there was a stronger association between increased binge drinking and risk of more sexual partners (IRR 1.21, p < .001) than among women who did not meet PTSD criteria (IRR 1.08, p < .01) with a difference of 13% (p < .05). HIV intervention and prevention interventions in this population likely would benefit from the inclusion of efforts to reduce binge drinking and increase treatment of PTSD symptoms.


Ambidirectional studies--an extension of longitudinal studies in psychiatry.
Both longitudinal and retrospective studies have inherent weaknesses. With psychiatric mortality studies as an example of longitudinal research, this article presents a study design, the ambidirectional study, that combines some of the advantages and minimizes some of the weaknesses inherent in longitudinal and retrospective studies respectively. The method involves 2 phases: first, definition of a base population some of whom proceed to encounter an event of interest (e.g. death, suicide, illness), secondly, a retrospective comparison of those emerging from the same base population with or without the event of interest. The advantages of this design are feasibility and freedom from confounding coherent effects, since cases and controls enter the study at the same point. The difficulties are those of retrospective data collection. Definition of controls, case matching and statistical methodology are discussed.


Health risks related to residential exposure to cadmium in Zhenhe County, China.
In this study, the authors examined the health risks to 1234 residents (15-80 yr of age) who lived near a lead-zinc mine and to 801 controls (15-80 yr of age) who lived 40 km from the mine. Subjects had higher levels of urinary cadmium, urinary beta2-microglobulin, and N-acetyl-beta-glucosaminidase (NAG) than controls (p < 0.0001), but subjects' urinary beta2-microglobulin and NAG were within normal ranges. Standardized death rates for cancer in the contaminated and control areas were 116.7/100,000 and 90.28/100,000, respectively, and for neonatal disease the respective rates were 89.83/100,000 and 16.74/100,000. Young girls residing in the contaminated areas had higher menstrual abnormalities than did controls (p = 0.002). The prevalence of difficulties in becoming pregnant and the proportion of premature births and stillbirths were higher among those in the contaminated areas (p < 0.0001). Individuals who lived around the lead-zinc mine had different health problems than those who lived far from the mine in Zhenhe County, Republic of China.


Medicaid: the lower tier of health care for women.
Being poor in the United States means being exposed to the Medicaid system, whose characteristics, as determined by both federal and state policy, affect access to health care. This paper examines those aspects of the Medicaid system which have a disparate impact on women because they are overrepresented in certain social strata, as well as some aspects which affect the ability of both sexes to utilize the health care system. Owing to the problems of women in society, women make up two-thirds of the Medicaid clientele. Thus the burdens created by the limitations of Medicaid are a significant gender issue. Policies regarding AFDC coverage and pregnancy particularly concern younger women, many of whom have problems related to marriage, childbirth, and absence of economic support from fathers which place them at risk for poverty. Regulations as to income and assets of elderly persons requiring long-term care are among the policies that affect older women whose spouses have become disabled. Mandating less restrictive eligibility standards and coverage during transition of Medicaid clients to work would help address the twin problems of inferiority and uncertainty with regard to health care.


Photosynthetic and Growth Responses in a Pioneer Tree (Japanese White Birch) and Competitive Perennial Weeds (Eupatorium sp.) Grown Under Different Regimes With Limited Water Supply to Waterlogging.
For a successful natural regeneration of Japanese white birch (Betula platyphylla var. japonica), competitive vegetation should be managed. Here, we clarified how soil water condition modifies the competitiveness of Japanese white birch against perennial weeds, Eupatorium species, based on an ecophysiological approach combining a glasshouse experiment and a field survey. We investigated photosynthetic and growth responses to various water regimes from water deficit to waterlogging (two times-a-week irrigation, three times-a-week irrigation, half waterlogging, and full waterlogging) in pot-grown seedlings of Japanese white birch and the competitive weed Eupatorium makinoi. The ratio of seedling height of Japanese white birch to seedling height of E. makinoi showed a decreasing trend from two times-a-week irrigation to full waterlogging, which suggests a lower competitiveness for light resource in Japanese white birch with increasing soil wetness. The maximum rate of Rubisco carboxylation (Vc,max) based on unit N was lower in waterlogging treatments than in two times- and three times-a-week irrigation in Japanese white birch, whereas E. makinoi showed the opposite response. This suggests that N partitioning into Rubisco and/or Rubisco activation might be suppressed in Japanese white birch but enhanced in E. makinoi under waterlogging. The maximum photochemical efficiency of photosystem II (Fv/Fm) was also lower in seedlings of Japanese white birch grown under waterlogging treatments. We further conducted a field survey on the relationship between Fv/Fm and topographic wetness index (TWI) in seedlings of Japanese white birch and E. glehnii (closely related to E. makinoi) naturally grown in a study site 5 years after canopy tree cutting. Lower Fv/Fm was observed in seedlings of Japanese white birch with increasing TWI, whereas no significant trend was observed in E. glehnii, in agreement with the glasshouse experiment. Thus, keeping soils not always humid might be favorable to photosynthetic performance and growth competitive ability of Japanese white birch against Eupatorium species.


Genetic diversity and population structure of yellow catfish Pelteobagrus fulvidraco from five lakes in the middle and lower reaches of the Yangtze River, China, based on mitochondrial DNA control region.
Genetic diversity and population structure of yellow catfish Pelteobagrus fulvidraco were examined by using mitochondrial DNA control region sequences in 143 specimens sampled from five lakes in the middle and lower reaches of the Yangtze River, China; 151 polymorphic sites defined 72 distinct haplotypes. Haplotype diversity indices (0.903-0.953) and nucleotide diversity indices (0.00378-0.00970) demonstrated low genetic diversity of the yellow catfish populations in the five lakes. The analysis of molecular variance and the fixation index (F(st) = 0.0896) revealed insignificant genetic difference between samples from different lakes. In addition, neutral tests and analysis of mismatch distribution suggested that yellow catfish might have undergone a population expansion. Neighbor-joining tree indicated a correlation between these population genetic differences and geographic distance. This study revealed the extant population genetic diversity and structure of the yellow catfish and was in favor of the related fishery management issues including fishery stock identification, conservation, and artificial breeding.


Successful treatment of fetal cardiac arrest by left ventricular exchange transfusion.
A 36-year-old pregnant woman with anti-HPA1a antibodies underwent six fetal platelet concentrate transfusions. During the second, at 28 weeks' gestation, fetal asystole occurred in association with a post-transfusion platelet count of 813 x 10(9)/l. Asystole was reversed by an intracardiac partial exchange transfusion of normal saline for fetal blood, simultaneously reducing fetal plasma viscosity and enabling re-commencement of the fetal circulation.


Resource costs for asthma-related care among pediatric patients in managed care.
In 1998, the economic burden of asthma in the United States was estimated to be 12.7 billion dollars. Yet few studies have examined the relationship between the total costs of asthma-related care and measures of asthma morbidity. Understanding the relationship between total costs of asthma-related care and morbidity can assist in designing the most cost-effective asthma care strategies to improve patient outcomes and minimize total costs. To investigate correlates of asthma costs for children with mild-to-moderate persistent asthma and, specifically, to characterize how closely the percentage of predicted forced expiratory volume in 1 second (FEV1) and symptom days were correlated with costs of illness. A total of 638 parents and children with mild-to-moderate persistent asthma in 4 managed care delivery systems in 3 different US geographic regions were enrolled. Symptom burden and annual resource utilization were determined from reports of physician visits, hospitalizations, emergency department visits, medication use, and parental missed workdays. Spirometry was conducted on children who were 5 years and older. To characterize the relationship between symptom days and the percentage of predicted FEV1 with costs, we specified a multivariate regression model. The median total annual asthma-related cost for the group was 564 dollars (interquartile range [IQR], 131 dollars-1602 dollars). Indirect costs represented 54.6% of total costs. Medicines accounted for 52.6% of direct costs. The mean percentage of predicted FEV1 was 101.6% (range, 39.3%-183.5%; IQR, 91.6%-111.3%), with 91.4% of patients with a percentage of predicted FEV1 of more than 80%. Based on multivariate modeling, increasing asthma severity, use of peak expiratory flow rate meters, younger age, low-income status and nonwhite race, and longer duration of asthma were significantly associated with increasing cost. Symptom days (P < 0.001) predicted annual costs better than percentage of predicted FEV1 (P < 0.16) in this group of children. For the large number of children with mild-to-moderate persistent asthma and normal or near-normal lung function, symptom days are predictive of health care costs. For these insured children receiving care from 3 large managed care providers, low-income status and nonwhite race were the strongest correlates for increased asthma-related costs.


Clinicopathological study of Kikuchi's disease.
Kikuchi's disease (KD) is a necrotizing lymphadenopathy with a self-limiting course commonly affecting young people. We conducted a clinico-pathological study of 20 cases of KD received at our department between July 2000 and December 2003. Our study confirmed that KD commonly involves the cervical lymph nodes of young adults, with a female predominance. One patient had associated cutaneous involvement. The hematological parameters were non-specific. The histological features were distinctive and included easy fragmentation on handling, karyorrhexis, crescentic histiocytes and the absence of neutrophils. The differential diagnosis on histology is also discussed.


Problem-solving skills, solving problems and problem-based learning.
This paper reviews the empirical evidence in support of the three concepts in the title. To the extent that a skill should be a general strategy, applicable in a variety of situations, and independent of the specific knowledge of the situation, there is little evidence that problem-solving skills, as described and measured in medical education, possess these characteristics. Instead there is an accumulation of evidence that expert problem-solving in medicine is dependent on (I) a wealth of prior specific experiences which can be used in routine solution of problems by pattern recognition processes, and (2) elaborated conceptual knowledge applicable to the occasional problematic situation. The use of problem-based learning (PBL) as an educational strategy is explored. In particular, the evidence suggesting the compatibility of PBL with this theory of expertise is discussed. Finally, I review some issues in the design of PBL curricula from the perspective of the proposed model of expertise.


Inter-reader variability in follicular lymphoma grading: Conventional and digital reading.
Pathologists grade follicular lymphoma (FL) cases by selecting 10, random high power fields (HPFs), counting the number of centroblasts (CBs) in these HPFs under the microscope and then calculating the average CB count for the whole slide. Previous studies have demonstrated that there is high inter-reader variability among pathologists using this methodology in grading. The objective of this study was to explore if newly available digital reading technologies can reduce inter-reader variability. IN THIS STUDY, WE CONSIDERED THREE DIFFERENT READING CONDITIONS (RCS) IN GRADING FL: (1) Conventional (glass-slide based) to establish the baseline, (2) digital whole slide viewing, (3) digital whole slide viewing with selected HPFs. Six board-certified pathologists from five different institutions read 17 FL slides in these three different RCs. Although there was relative poor consensus in conventional reading, with lack of consensus in 41.2% of cases, which was similar to previously reported studies; we found that digital reading with pre-selected fields improved the inter-reader agreement, with only 5.9% lacking consensus among pathologists. Digital whole slide RC resulted in the worst concordance among pathologists while digital whole slide reading selected HPFs improved the concordance. Further studies are underway to determine if this performance can be sustained with a larger dataset and our automated HPF and CB detection algorithms can be employed to further improve the concordance.


Properties of the insulin receptor ectodomain.
To study the properties of the extracellular insulin-binding domain of the human insulin receptor (hIR), we have expressed portions of the parent molecule in mammalian cells. Receptor cDNAs encoding the entire hIR ectodomain, the alpha subunit of the hIR alone, or a portion of the alpha subunit containing the cysteine-rich region were placed within an expression vector and in turn used to transfect CHO cells. Only cells expressing mRNA for the entire hIR ectodomain secreted hIR-related protein, suggesting that the truncated versions of this domain are unstable. The ectodomain molecules were extensively glycosylated, properly processed heterotetramers. Further, they bound insulin with an affinity similar to that of the intact hIR. In the electron microscope the secreted ectodomains appeared as discrete globular structures. After incubation with roughly equimolar quantities of insulin, the ectodomains associated to form loops or branched and folded linear macroarrays. However, these structures were not restricted to the specific ligand, insulin, since epidermal growth factor also produced the effect. Nevertheless, it seems that the receptor ectodomains can exist in two structural states. The conversion of the singular to the aggregated state may somehow be associated with transmembrane communication and activation of the biological response.


Being born and growing up in the Ribeirão Preto and São Luís cohorts.
This thematic issue consists of 14 articles derived from studies of the BRISA birth cohort (Ribeirão Preto, State of São Paulo and São Luís, State of Maranhão, northeastern Brazil, a socially and economically less developed region). In these more than 40 years of existence, these cohorts have been able to document the increase in women's education, the improvement of health conditions, the creation of a public Unified Health System (SUS) that provides universal and free access to health care, eradication of hunger, and transition of the nutritional status characterized by a decrease in malnutrition rates and an increase in obesity in Brazil. Particularly in reproductive health, the country experienced a significant drop in fertility, a decrease in maternal and child mortality, and an increase in breastfeeding rates. Universal access to prenatal care and hospital delivery was accompanied by an excessive number of cesareans without clinical indication and early-term births and premature births, largely due to scheduled cesareans. Articles with a longitudinal and transversal methodological approach are presented, using structural equation analysis and propensity score, together with multivariate regressions, which gave a robust analytical treatment to articles in this thematic issue.


Distribution of multidrug-resistant bacterial infections in diabetic foot ulcers and risk factors for drug resistance: a retrospective analysis.
To investigate the distribution, drug resistance and risk factors of multi-drug resistant bacterias (MDROs) in patients with Type 2 diabetic foot ulcers (DFU). The clinical data, foot secretions, pathogenic microorganisms and drug sensitivity tests of 147 patients with type 2 diabetes admitted to our department from January 2018 to December 2021 were analyzed. Patients were divided into two groups according to whether they had been infected with MDROs or not. Seventy-one cases were infected with MDROs as the case group, and the remaining 76 cases were the control group. Chi-square test and t-test were used to analyze the results of MDROs infection and DFU, and logistic multivariate regression was used to evaluate the risk factors of MDROs infection. A total of 71 strains were isolated from the MDROs-positive group, with the top three being Staphylococcus aureus (46.48%), Escherichia coli (22.53%), and Pseudomonas aeruginosa (18.31%), respectively. Logistic multifactorial regression analysis showed that history of previous antimicrobial exposure, neuroischemic wound, Wagner grade 3-5, and combined osteomyelitis were associated with Type 2 diabetic foot infection MDROs (P < 0.05). Previous history of antimicrobial exposure, neuroischemic wounds, Wagner grade 3-5, and combined osteomyelitis are independent risk factors for MDROs, which can identify the risk factors for MDROs at an early stage and help to identify people at high risk of MDROs infection and take relevant comprehensive treatment in time to slow down the development of the disease.


Dissociating contributions of ventral and dorsal striatum to reward learning.
Reward learning plays a central role in decision making and adaptation. Accumulating evidence suggests that the striatum contributes enormously to reward learning but that its subregions may have distinct functions. A recent article by Tricomi and Lempert (J Neurophysiol. First published 22 October 2014, doi:10.1152/jn.00086.2014.) found that ventral striatum tracks reward value, whereas dorsolateral and dorsomedial striatum track the trialwise reward probability. In this Neuro Forum we reinterpret their findings and provide additional insights.


Coronary Artery Bypass Grafting vs. Drug-Eluting Stent Implantation for Multivessel Disease in Patients with Chronic Kidney Disease.
There is currently a limited amount of data that demonstrate the optimal revascularization strategy for chronic kidney disease (CKD) patients with multivessel coronary artery disease (CAD). We compared the long-term outcomes of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass graft surgery (CABG) for multivessel CAD in patients with CKD. We analyzed 2108 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2) with multivessel CAD that were treated with PCI with DES (n=1165) or CABG (n=943). The primary outcome was a composite of all causes of mortality, myocardial infarction, or stroke. The mean age was 66.9±9.1 years. Median follow-up duration was 41.4 (interquartile range 12.1-75.5) months. The primary outcome occurred in 307 (26.4%) patients in the PCI group compared with 304 (32.2%) patients in the CABG group (adjusted hazard ratio [HR], 0.941; 95% confidence interval [CI], 0.79-1.12; p=0.493). The two groups exhibited similar rates of all-cause mortality (adjusted HR, 0.91; 95% CI, 0.77-1.09; p=0.295), myocardial infarction (adjusted HR, 1.86; 95% CI, 0.85-4.07; p=0.120) and stroke (3.2% vs. 4.8%; HR, 0.93; 95% CI, 0.57-1.61; p=0.758). However, PCI was associated with significantly increased rates of repeat revascularization (adjusted HR, 4.72; 95% CI, 3.20-6.96; p<0.001). Among patients with CKD and multivessel CAD, PCI with DES when compared with CABG resulted in similar rates of composite outcome of mortality from any cause, MI, or stroke; however, a higher risk of repeat revascularization was observed.


The effects of a 2-stage injection technique on inferior alveolar nerve block injection pain.
The purpose of this prospective, randomized, single-blinded, crossover study was to compare the pain of a traditional 1-stage inferior alveolar nerve (IAN) block injection to a 2-stage IAN block technique. Using a crossover design, 51 subjects randomly received, in a single-blinded manner, either the traditional IAN block or the 2-stage IAN block in 2 appointments spaced at least 1 week apart. For the 2-stage injection, the needle was inserted submucosally and 0.4 mL of 2% lidocaine with epinephrine was slowly given over 1 minute. After 5 minutes, the needle was reinserted and advanced to the target site (needle placement), and 1.8 mL of 2% lidocaine with epinephrine was deposited. For the traditional IAN block, following needle penetration, the needle was advanced while depositing 0.4 mL of 2% lidocaine with epinephrine (needle placement) and then 1.8 mL of 2% lidocaine with epinephrine was deposited at the target site. A Heft-Parker visual analogue scale was used to measure the pain of needle insertion, needle placement, and anesthetic solution deposition. There were no significant differences, as analyzed by Wilcoxon matched-pairs signed-ranks test, between needle insertion and solution deposition for the 2 techniques in men or women. However, there was significantly less pain with the 2-stage injection for needle placement in women. In conclusion, the 2-stage injection significantly reduced the pain of needle placement for women when compared to the traditional IAN technique.


The Influence of Prescribed Fire, Habitat, and Weather on Amblyomma americanum (Ixodida: Ixodidae) in West-Central Illinois, USA.
The distribution of Amblyomma americanum (L.) is changing and reports of tick-borne disease transmitted by A. americanum are increasing in the USA. We used flagging to collect ticks, surveyed vegetation and collected weather data in 2015 and 2016. A. americanum dominated collections in both years (97%). Ticks did not differ among burn treatments; however, tick abundance differed between years among total, adult, and larval ticks. Habitat variables showed a weak negative correlation to total ticks in respect to: Shannon diversity index, percent bare ground, perennial cover, and coarse woody debris. Nymphal ticks showed a weak negative correlation to percent bare ground and fewer adults were collected in areas with more leaf litter and coarse woody debris. Conversely, we found larvae more often in areas with more total cover, biennials, vines, shrubs, and leaf litter, suggesting habitat is important for this life stage. We compared weather variables to tick presence and found, in 2015, temperature, precipitation, humidity, and sample period influenced tick collection and were life stage specific. In 2016, temperature, precipitation, humidity, wind, and sample period influenced tick collection and were also life stage specific. These results indicate that spring burns in an oak woodland do not reduce ticks; other variables such as habitat and weather are more influential on tick abundance or presence at different life stages.


Compressed single pixel imaging in the spatial frequency domain.
We have developed compressed sensing single pixel spatial frequency domain imaging (cs-SFDI) to characterize tissue optical properties over a wide field of view ( 35 ?? mm × 35 ?? mm ) using multiple near-infrared (NIR) wavelengths simultaneously. Our approach takes advantage of the relatively sparse spatial content required for mapping tissue optical properties at length scales comparable to the transport scattering length in tissue ( l tr ? 1 ?? mm ) and the high bandwidth available for spectral encoding using a single-element detector. cs-SFDI recovered absorption ( ? a ) and reduced scattering ( ? s ? ) coefficients of a tissue phantom at three NIR wavelengths (660, 850, and 940 nm) within 7.6% and 4.3% of absolute values determined using camera-based SFDI, respectively. These results suggest that cs-SFDI can be developed as a multi- and hyperspectral imaging modality for quantitative, dynamic imaging of tissue optical and physiological properties.


The light and electron microscopic changes in the skeletal muscles during paralysis in thyrotoxic periodic paralysis.
Light microscopy of the biopsied quadriceps muscles during paralysis in 17 patients with thyrotoxic periodic paralysis (TPP) showed no abnormalities in 23.5 per cent, sarcolemmal nuclear proliferation in 35.5 per cent, atrophy of muscle fibers in 29.4 per cent, central nuclei in 23.5 per cent, fatty infiltration in 17.6 per cent, vacuolation in 11.8 per cent, and sarcoplasmic masses in 11.8 per cent. The muscle specimens were also examined by electron microscopy in ten of these patients; the main changes observed were vacuolation (90 per cent), mitochondrial abnormalities (100 per cent), glycogen granules accumulation (100 per cent), disruption of the myofibers (50 per cent), and changes in the T-system (40 per cent). The light and electron microscopic changes in the skeletal muscles during paralysis were not well correlated with the severity of the muscle weakness of hypokalemia.


Morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results.
Halo (Sutton's) phenomenon has been described as a depigmented halo that is associated most commonly with acquired melanocytic nevi; but it may be associated with various types of melanocytic skin tumors, melanoma being the most concerning. Different authors have been preoccupied with elucidating morphological features of melanocytic tumors associated with a depigmented halo. We reviewed the literature and discussed the main features of melanocytic halo tumors regarding histopathological, immune microenvironment profile and dermatoscopic appearance. We highlighted similarities and differences between Sutton's nevus and halo melanoma, also presenting relevant aspects of our results. Depigmented halo must be regarded as a phenomenon that may be associated with different types of melanocytic tumors and with a broad spectrum of histopathological atypia degree. Certain correlations between the shape, diameter, symmetry observed in clinical examination, histopathological appearance, dermatoscopic aspect of peritumoral halo and central tumor type could not be established due to insufficient data and contrasting results. Further studies are expected to add valuable information regarding the depigmented halo tumors features.


Glass eels (Anguilla anguilla) imprint the magnetic direction of tidal currents from their juvenile estuaries.
The European eel (Anguilla anguilla) hatches in the Sargasso Sea and migrates to European and North African freshwater. As glass eels, they reach estuaries where they become pigmented. Glass eels use a tidal phase-dependent magnetic compass for orientation, but whether their magnetic direction is innate or imprinted during migration is unknown. We tested the hypothesis that glass eels imprint their tidal-dependent magnetic compass direction at the estuaries where they recruit. We collected 222 glass eels from estuaries flowing in different cardinal directions in Austevoll, Norway. We observed the orientation of the glass eels in a magnetic laboratory where the magnetic North was rotated. Glass eels oriented towards the magnetic direction of the prevailing tidal current occurring at their recruitment estuary. Glass eels use their magnetic compass to memorize the magnetic direction of tidal flows. This mechanism could help them to maintain their position in an estuary and to migrate upstream.


Growth of TiO2 nanorods on a Ta substrate by metal-organic chemical vapor deposition.
TiO2 nanorods were successfully grown on Tantalum (Ta) substrates using titanium tetra isopropoxide (TTIP) as a single precursor without any carriers or bubbling gases. For characterization of the TiO2 structures, scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) were employed. For substrate temperatures below 800 degrees C, a rough film structure without nanorods could be found. However, at a sample temperature of 800 degrees C, nanorod structures with a respective diameter and length of 0.1 approximately 0.2 microm and 0.7 approximately 1.5 microm, respectively, could be synthesized. The nanorods exhibited a rutile phase with a 2:1 stoichiometry of O:Ti, identified using XRD and XPS. When the growth temperature exceeded 800 degrees C, agglomeration of the nanorods was identified.


Sensitivity of photoelectron circular dichroism to structure and electron dynamics in the photoionization of carvone and related chiral monocyclic terpenone enantiomers.
The photoelectron circular dichroism that arises in the angular distribution of photoelectrons emitted from the carbonyl group in randomly oriented pure enantiomers of carvone, and a number of carvone derivatives, is investigated by continuum multiple scattering calculations. Core ionization of carbonyl C 1s orbitals is examined for six different isopropenyl tail conformations of carvone. These show clear differences of behavior both between axial and equatorial conformations, and between the three rotational conformers of each. The pronounced dependence of the dichroism on orientation of a tail grouping, itself remote from the localized initial C 1s site, indicates the presence of long range final state photoelectron scattering effects. Analogous data for the outermost valence orbital, partially localized on the carbonyl group, are also presented. The apparently enhanced sensitivity of the dichroism exhibited in this work is discussed in terms of the particular dependence on photoelectron interference effects that is probed by the dichroism measurement and is contrasted with the usual beta parameter and cross section determinations.


DNA double-strand break in vivo at the 3' extremity of exons located upstream of group II introns. Senescence and circular DNA introns in Podospora mitochondria.
In the filamentous fungus Podospora anserina, the unavoidable phenomenon of senescence is associated with the amplification of the first intron of the mitochondrial cox1 that accumulates as circular DNA molecules consisting of tandem repeats. This group II intron (cox1-i1 or alpha) is able to transpose and contains an open reading frame with significant amino acid similarity with reverse transcriptases. The generation of these intronic circular DNA molecules, their amplification and their involvement in the senescence process are unresolved questions. We demonstrate here that: (1) another group II intron, the fourth intron of gene cox1, cox1-i4, is also able to give precise DNA end to end junctions; (2) this intronic sequence can be found amplified during senescence, although to a lesser extent than cox1-i1; (3) the amplification of the DNA multimeric cox1-i1 molecules likely does not proceed by autonomous replication; (4) the generation of the DNA intronic circles does not require efficient intron splicing; (5) a DNA double-strand break occurs in vivo at the 3' extremity of the cox1-e1 and cox1-e4 exons preceding the group II introns that form circular DNAs. On the whole, these results show that the ability to form DNA circular molecules is a property of some group II introns and they demonstrate the occurrence of a specific DNA cleavage at or near the integration site of these group II introns. The results strongly suggest that this cleavage is involved in the formation of the group II intronic DNA circles and could also be involved in the phenomenon of group II intron homing.


CONE DENSITY LOSS ON ADAPTIVE OPTICS IN EARLY MACULAR TELANGIECTASIA TYPE 2.
To determine whether cone photoreceptors are impaired early in macular telangiectasia type 2 (MacTel 2) progression. Eight patients with MacTel 2 lacking intraretinal cavitation underwent multimodal retinal imaging including adaptive optics. Cone packing metrics were determined in 5 sampling windows at different eccentricities from the fovea. Results were compared with a previously established normative database. In MacTel 2 eyes, cone density was significantly lower than normal at all eccentricities (P < 0.0001). Mean cone spacing and mean percentage of hexagonally organized cone photoreceptors were respectively significantly larger and lower than normal at all eccentricities (P = 0.0488 and P < 0.0001). In MacTel 2 patients, adaptive optics showed an irregular patchy disturbance of the cone mosaic corresponding to some fragmentation of the interdigitation zone on optical coherence tomography. The ellipsoid zone remained intact in the studied area. Adaptive optics showed that the macular cone density was lower than normal even outside the telangiectasia in MacTel 2 lacking intraretinal cavitation, although the ellipsoid zone remained intact on optical coherence tomography. These findings do not indicate that the cone density loss is causative of the disease as it might be secondary to Müller cell or rod loss in this area. However, cone density assessment could become a useful parameter to monitor disease progression.


Programmed cell death: necrosis versus apoptosis.
Cell death remains poorly understood, despite its obvious importance in every organ and tissue in a wide variety of biological processes, including, of course, the many pathological. The past few years have seen an amazing expansion of interest in cell death in normal development and maturation, in the pathogenesis of many acute and chronic diseases, and in the therapy of some diseases, especially malignant neoplastic diseases and some hyperplastic diseases such as psoriasis. This expansion has included an unusual interest in a supposedly new form of cell death, a "programmed cell death," designated "apoptosis." This is proposed as a hitherto undescribed form of cell death in contrast to the classical cell death, necrosis. Apoptosis is considered by some, especially by nonpathologists, to represent quite a different type of cell death. A review of the literature on on apoptosis, programmed cell death, necrosis, etc. indicates that there is no field of basic cell biology and cell pathology that is more confusing and more unintelligible than the area of apoptosis versus necrosis. If any degree of clarity is to develop in our understanding of the fundamental principles underlying cell death of any type, it is incumbent upon us to rethink "from square one" the scientific analysis of how cells die and how can we assess cell death in a reasonably rational manner.


Meningiomas involving the anterior clinoid process.
We report a series of 34 clinoidal meningiomas treated surgically and analyse the results according to cavernous sinus involvement. Fifteen tumours extended into the cavernous sinus. Only four of these could be resected completely, and global outcome was improved or stable in 10 cases. Overall, 20 tumours had a total resection and 14 had a partial resection. Complete removal of the sphenoid wing, including the anterior clinoid and part of the planum sphenoidale, allows early devascularization of the tumour and minimizes brain retraction when associated with resection of the zygomatic arch. The most frequent postoperative complication was transient CSF leak, occurring in three patients. Two patients died postoperatively, and three suffered permanent complications. There was no recurrence after total removal, but five patients showed signs of progressive tumour growth after partial removal, treated by radiotherapy in three and by surgery in two cases. Twenty patients showed preoperative visual impairment. Outcome of vision was improved or stable in 13 (68%) and worse in six cases (32%). We suggest that progressive visual impairment should lead to aggressive surgical treatment, especially when complete resection of cavernous sinus involvement can be performed.


Phenytoin-induced hypothermia.
A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?


Reduction of CD19 autoimmunity marker on B cells of paediatric SLE patients through repressing PU.1/TNF-α/BAFF axis pathway by miR-155.
microRNA-155 (miR-155) is implicated in regulating B-cell activation and survival that is important in systemic lupus erythematosus (SLE) pathogenesis. PU.1, a target for miR-155, is a crucial regulator of B-cell development and enhances Tumour-Necrosis-factor-alpha (TNF-α) expression. TNF-α induces the expression of B-cell-activating-factor (BAFF). BAFF is reported to increase the expression of the autoimmunity marker; CD19. This study aimed to investigate the regulation of expression of PU.1 in pediatric-systemic-lupus-erythematosus (pSLE) patients by miR-155, and hence evaluate its impact on TNF-α/BAFF/CD19 signalling pathway. Screening revealed that PU.1 is upregulated in PBMCs and B-cells of pSLE patients. PU.1 expression directly correlated with systemic-lupus-erythematosus disease-activity-index-2 K SLEDAI-2K. Ectopic expression of miR-155 and knockdown of PU.1 suppressed PU.1, TNF-α and BAFF. Finally, miR-155 decreased the proportion of BAFF-expressing-B-cells and CD19 protein expression. These findings suggest that miR-155 suppresses autoimmunity through transcriptional repression of PU.1 and TNF-α, which in turn suppresses BAFF and CD19 protein expression.


Curcumin as a potential protective compound against cardiac diseases.
Curcumin, which was first used 3000 years ago as an anti-inflammatory agent, is a well-known bioactive compound derived from the active ingredient of turmeric (Curcuma longa). Previous research has demonstrated that curcumin has immense therapeutic potential in a variety of diseases via anti-oxidative, anti-apoptotic, and anti-inflammatory pathways. Cardiac diseases are the leading cause of mortality worldwide and cause considerable harm to human beings. Numerous studies have suggested that curcumin exerts a protective role in the human body whereas its actions in cardiac diseases remain elusive and poorly understood. On the basis of the current evidence, we first give a brief introduction of cardiac diseases and curcumin, especially regarding the effects of curcumin in embryonic heart development. Secondly, we analyze the basic roles of curcumin in pathways that are dysregulated in cardiac diseases, including oxidative stress, apoptosis, and inflammation. Thirdly, actions of curcumin in different cardiac diseases will be discussed, as will relevant clinical trials. Eventually, we would like to discuss the existing controversial opinions and provide a detailed analysis followed by the remaining obstacles, advancement, and further prospects of the clinical application of curcumin. The information compiled here may serve as a comprehensive reference of the protective effects of curcumin in the heart, which is significant to the further research and design of curcumin analogs as therapeutic options for cardiac diseases.


Discovery of wall-selective carbon nanotube growth conditions via automated experimentation.
Applications of carbon nanotubes continue to advance, with substantial progress in nanotube electronics, conductive wires, and transparent conductors to name a few. However, wider application remains impeded by a lack of control over production of nanotubes with the desired purity, perfection, chirality, and number of walls. This is partly due to the fact that growth experiments are time-consuming, taking about 1 day per run, thus making it challenging to adequately explore the many parameters involved in growth. We endeavored to speed up the research process by automating CVD growth experimentation. The adaptive rapid experimentation and in situ spectroscopy CVD system described in this contribution conducts over 100 experiments in a single day, with automated control and in situ Raman characterization. Linear regression modeling was used to map regions of selectivity toward single-wall and multiwall carbon nanotube growth in the complex parameter space of the water-assisted CVD synthesis. This development of the automated rapid serial experimentation is a significant progress toward an autonomous closed-loop learning system: a Robot Scientist.


Microfluidic mixing and the formation of nanoscale lipid vesicles.
We investigate the formation of unilamellar lipid vesicles (liposomes) with diameters of tens of nanometers by controlled microfluidic mixing and nanoparticle determination (COMMAND). Our study includes liposome synthesis experiments and numerical modeling of our microfluidic implementation of the batch solvent injection method. We consider microfluidic liposome formation from the perspective of fluid interfaces and convective-diffusive mixing, as we find that bulk fluid flow parameters including hydrodynamically focused alcohol stream width, final alcohol concentration, and shear stress do not primarily determine the vesicle formation process. Microfluidic device geometry in conjunction with hydrodynamic flow focusing strongly influences vesicle size distributions, providing a coarse method to control liposome size, while total flow rate allows fine-tuning the vesicle size in certain focusing regimes. Although microfluidic liposome synthesis is relatively simple to implement experimentally, numerical simulations of the mixing process reveal a complex system of fluid flow and mass transfer determining the formation of nonequilibrium vesicles. These results expand our understanding of the microfluidic environment that controls liposome self-assembly and yield several technological advances for the on-chip synthesis of nanoscale lipid vesicles.


[Mid-term radiographic results in Th12 and L1 fractures after anterior column reconstruction with tibial shaft bone allograft].
Frozen tibial shaft bone allografts filled with autologous cancellous bone chips were used for anterior column reconstruction in Th12 and L1 fractures. The aim of this retrospective study was to evaluate the five-year results of the treatment on the basis of radiographic findings. Twenty-six patients treated in 2005 and 2006 for isolated Th12 or L1 fractures, with no neurological deficit, were evaluated. In all patients, the spine was stabilised from an isolated anterior approach or through a combined posterior and anterior approach, and angle-stable implants were used. On radiographic examination the loss of correction and lateral compression of the segment involved were measured on standard X-ray views. Data on bone union at graft-bone interfaces were obtained from spiral CT scans. For assessment of the stage of bone healing, a scale of 0-25-50-75-100 % was established, and each patient was evaluated by two independent radiologists. Based on the average results, bone union was defined as non-union, 0-24 %; incomplete union, 25-74 %; complete union, 75-100 %. The average loss of correction measured by Beck's method was 0.77 degree. In four patients, the lateral compression angle deteriorated on the average by 1.1 degree (range, 0.7°-1.8°) during the treatment. The proximal graft-bone interface showed complete union in 19 patients (73 %), and the distal interface was completely healed in 20 patients (77 %). Incomplete bone union at the proximal and the distal interface was found in seven (27 %) and six (23 %) patients, respectively. Nonunion was not recorded. No complications occurred. The use of tibial shaft bone allografts filled with autologous cancellous bone chips resulted in stable reconstruction of the anterior column of the thoracolumbar spine which showed a low loss of correction and good bone union.


Separation of ephedrine and pseudoephedrine enantiomers using a polysaccharide-based chiral column: A normal phase liquid chromatography-high-resolution mass spectrometry approach.
Chiral considerations are found to be very much relevant in various aspects of forensic toxicology and pharmacology. In forensics, it has become increasingly important to identify the chirality of doping agents to avoid legal arguments and challenges to the analytical findings. The scope of this study was to develop an liquid chromatography-mass spectrometry (LCMS) method for the enantiomeric separation of typical illicit drugs such as ephedrines (ie, 1S,2R(+)-ephedrine and 1R,2S(-)-ephedrine) and pseudoephedrine (ie, R,R(-)-pseudoephedrine and S,S(+)-pseudoephedrine) by using normal phase chiral liquid chromatography-high-resolution mass spectrometry technique. Results show that the Lux i-amylose-1 stationary phase has very broad and balancing-enantio-recognition properties towards ephedrine analogues, and this immobilized chiral stationary phase may offer a powerful tool for enantio-separation of different types of pharmaceuticals in the normal phase mode. The type of mobile phase and organic modifier used appear to have dramatic influences on separation quality. Since the developed method was able to detect and separate the enantiomers at very low levels (in pico grams), this method opens easy access for the unambiguous identification of these illicit drugs and can be used for the routine screening of the biological samples in the antidoping laboratories.


Sustained timber yield claims, considerations, and tradeoffs for selectively logged forests.
What is meant by sustainability depends on what is sustained and at what level. Sustainable forest management, for example, requires maintenance of a variety of values not the least of which is sustained timber yields (STYs). For the 1 Bha of the world's forests subjected to selective or partial logging, failure to maintain yields can be hidden by regulatory requirements and questionable auditing practices such as increasing the number of commercial species with each harvest, reducing the minimum size at which trees can be harvested and accepting logs of lower quality. For assertions of STY to be credible, clarity is needed about all these issues, as well as about the associated ecological and economic tradeoffs. Lack of clarity about sustainability heightens risks of unsubstantiated claims and unseen losses. STY is possible but often requires cutting cycles that are longer and logging intensities that are lower than prescribed by law, as well as effective use of low-impact logging practices and application of silvicultural treatments to promote timber stock recovery. These departures from business-as-usual practices will lower profit margins but generally benefit biodiversity and ecosystem services.