Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus.
Extracellular-signal regulated kinases/microtubule-associated protein kinases (Erk/MAPKs) and cyclin-directed kinases (Cdks) are key regulators of many aspects of cell growth and division, as well as apoptosis. We have cloned a kinase, Nlk, that is a murine homolog of the Drosophila nemo (nmo) gene. The Nlk amino acid sequence is 54. 5% similar and 41.7% identical to murine Erk-2, and 49.6% similar and 38.4% identical to human Cdc2. It possesses an extended amino-terminal domain that is very rich in glutamine, alanine, proline, and histidine. This region bears similarity to repetitive regions found in many transcription factors. Nlk is expressed as a 4. 0-kb transcript at high levels in adult mouse brain tissue, with low levels in other tissues examined, including lung, where two smaller transcripts of 1.0 and 1.5 kb are expressed as well. A 4.0-kb Nlk message is also present during embryogenesis, detectable at day E10. 5, reaching maximal steady state levels at day E12.5, and then decreasing. Nlk transiently expressed in COS7 cells is a 60-kDa kinase detectable by its ability to autophosphorylate. Mutation of the ATP-binding Lys-155 to methionine abolishes its ability to autophosphorylate, as does mutation of a putative activating threonine in kinase domain VIII, to valine, aspartic, or glutamic acid. Subcellular fractionation indicates that 60-70% of Nlk is localized to the nucleus, whereas 30-40% of Nlk is cytoplasmic. Immunofluorescence microscopy confirms that Nlk resides predominantly in the nucleus. Nlk and Nmo may be the first members of a family of kinases with homology to both Erk/MAPKs and Cdks.


Stress: a factor to be considered in heterotrophic microorganism enumeration from aquatic environments.
Heterotrophic microorganisms in water samples are susceptible to the transient stress of warmed agar used in the standard methods pour plate procedure, causing significantly decreased recoveries in comparison with a spread plate technique. Microbial starvation can increase susceptibility to a transient warming stress. The standard plate count procedure, as presently described, should not be considered for quantitation of microorganisms from aquatic environments.


The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate.
We analyzed the possible prognostic value of the recently discovered fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer. A FGFR3 mutation was found in 34 of 53 pTaG1-2 bladder cancers, whereas none of the 19 higher-staged tumors had a mutation (P < 0.0001). In 57 patients with superficial disease followed prospectively by cystoscopy for 12 months, 14 of 23 patients in the wild-type FGFR3 group developed recurrent bladder cancer compared with only 7 of 34 patients in the mutant group (P = 0.004). The recurrence rate per year was 0.24 for the FGFR3 mutant tumors and 1.12 for tumors with a wild-type FGFR3 gene. In addition, FGFR3 mutation status was the strongest predictor of recurrence when compared with stage and grade (P = 0.008). This is the first mutation in bladder cancer that selectively identifies patients with favorable disease characteristics. Our results suggest that the frequency of cystoscopic examinations can be reduced considerably in patients with FGFR3-positive tumors.


Fibronectin in the tear film.
Fibronectin plays an important role in corneal healing and has been detected previously in the tear film. To investigate the levels of fibronectin in normal human tears, the authors measured and compared fibronectin concentration in open-eye, closed-eye, and reflex tear fluid. The origin of fibronectin in the tear film was investigated by comparing fibronectin concentration in sequentially collected reflex tear samples with the concentrations of total protein and albumin in the same samples. Open-eye and closed-eye tears were collected from 11 noncontact lens wearers. From 7 subjects, 20 uninterrupted reflex tear samples (10 microliters each) subsequently were collected, using the sneeze reflex method of stimulation, followed by an additional 10 nonstimulated tear samples (3 microliters each) immediately after cessation of stimulus. Enzyme-linked immunosorbent assays were used to determine fibronectin and albumin concentrations, and bicinchoninic acid protein assays were used to determine total protein concentration in each sample. Fibronectin concentration in open-eye tears (19 +/- 24 eta g/ml, range 3 to 78 eta g/ml) was significantly different (P = 0.004) from that in closed-eyes tears (4127 +/- 3222 eta g/ml, range 1177 to 11384 eta g/ml). In the first 50 microliters of reflex tears, fibronectin concentrations were low (10 +/- 23 eta g/ml), but they increased significantly (P = 0.028) after 100 microliters of reflex tears had been collected (220 +/- 126 eta g/ml). There was a further marked transient increase (767 +/- 946 eta g/ml) after cessation of stimulus. Total protein concentration in the same samples decreased significantly during reflex tear collection compared to open-eye tears, and it increased gradually after cessation of stimulus. Albumin concentration in the same samples, analyzed for two subjects only, showed a pattern similar to that for fibronectin. Dilation of conjunctival blood vessels was noted in all subjects after reflex tear collection. Administration of a topical vasoconstrictor in two subjects eliminated the increase in fibronectin concentration during reflex tearing but did not affect total protein concentration. Under reducing conditions, the molecular mass of fibronectin in open-eye and reflex tears was 240 kDa, identical to commercially available purified plasma fibronectin, whereas fibronectin in closed-eye tears was degraded into small molecular mass fragments. These findings suggest that fibronectin in tear fluid is derived from plasma and that the increase in concentration in closed-eye and reflex tear fluid is caused by leakage from dilated conjunctival blood vessels.


Specifications of Clinical Quality Measures and Value Set Vocabularies Shift Over Time: A Study of Change through Implementation Differences.
Clinical quality measures (CQMs) aim to identify gaps in care and to promote evidence-based guidelines. Official CQM definitions consist of a measure's logic and grouped, standardized codes to define key concepts. In this study, we used the official CQM update process to understand how CQMs' meanings change over time. First, we identified differences between the narrative description, logic, and the vocabulary specifications offour standardized CQMs' definitions in subsequent versions (2015, 2016, and 2017). Next, we implemented the various versions in a quality measure calculation registry to understand how the differences affected calculated prevalence of risk and measure performance. Global performance rates changed up to 5.32%, and an increase of up to 28% new patients was observed for key conditions between versions. Updates to definitions that change a measure's logic and choices to include/exclude codes in value set vocabularies changes measurement of quality and likely introduces variation by implementation.


Outcome in a patient with systemic lupus erythematosus and concurrent chronic hepatitis B infection.
A 35-year-old Caucasian woman with proven systemic lupus erythematosus (SLE) had been effectively managed with hydroxychloroquine and methylprednisolone for many years. In 2005 she was admitted to the rheumatology clinic with a flare up of the disease and with proteinuria of 3.2 g/24 h. Renal biopsy was performed and revealed diffuse proliferative nephritis. Before the renal biopsy a positive HB(s)Ag was found with high virus replication (hepatitis B virus (HBV)-DNA-4 170 000 copies/ml). Liver biopsy revealed chronic hepatitis with minimal activity (TAIS=1). Lamivudine was administered with concomitant maintenance corticosteroid treatment, but without antimalarials. Pulsed methylprednisolone treatment for diffuse lupus nephritis was begun on the background of lamivudine therapy. The liver enzymes returned to normal values, HBV replication was suppressed, and the proteinuria disappeared. At present the patient is not being treated with lamivudine and there are no objective signs of nephritis and hepatitis, or HBV activation.


Rate variation in parasitic plants: correlated and uncorrelated patterns among plastid genes of different function.
The analysis of synonymous and nonsynonymous rates of DNA change can help in the choice among competing explanations for rate variation, such as differences in constraint, mutation rate, or the strength of genetic drift. Nonphotosynthetic plants of the Orobanchaceae have increased rates of DNA change. In this study 38 taxa of Orobanchaceae and relatives were used and 3 plastid genes were sequenced for each taxon. Phylogenetic reconstructions of relative rates of sequence evolution for three plastid genes (rbcL, matK and rps2) show significant rate heterogeneity among lineages and among genes. Many of the non-photosynthetic plants have increases in both synonymous and nonsynonymous rates, indicating that both (1) selection is relaxed, and (2) there has been a change in the rate at which mutations are entering the population in these species. However, rate increases are not always immediate upon loss of photosynthesis. Overall there is a poor correlation of synonymous and nonsynonymous rates. There is, however, a strong correlation of synonymous rates across the 3 genes studied and the lineage-speccific pattern for each gene is strikingly similar. This indicates that the causes of synonymous rate variation are affecting the whole plastid genome in a similar way. There is a weaker correlation across genes for nonsynonymous rates. Here the picture is more complex, as could be expected if there are many causes of variation, differing from taxon to taxon and gene to gene. The distinctive pattern of rate increases in Orobanchaceae has at least two causes. It is clear that there is a relaxation of constraint in many (though not all) non-photosynthetic lineages. However, there is also some force affecting synonymous sites as well. At this point, it is not possible to tell whether it is generation time, speciation rate, mutation rate, DNA repair efficiency or some combination of these factors.


Plasmon enhanced second harmonic generation by periodic arrays of triangular nanoholes coupled to quantum emitters.
Optical properties of periodic arrays of nanoholes of a triangular shape with experimentally realizable parameters are examined in both linear and nonlinear regimes. By utilizing a fully vectorial three-dimensional approach based on the nonlinear hydrodynamic Drude model describing metal coupled to Maxwell's equations and Bloch equations for molecular emitters, we analyze linear transmission, reflection, and nonlinear power spectra. Rigorous numerical calculations demonstrating second and third harmonic generation by the triangular hole arrays are performed. It is shown that both the Coulomb interaction of conduction electrons and the convective term contribute on equal footing to the nonlinear response of metal. It is demonstrated that the energy conversion efficiency in the second harmonic process is the highest when the system is pumped at the localized surface plasmon resonance. When molecular emitters are placed on a surface of the hole array line shapes, the second harmonic signal exhibits three peaks corresponding to second harmonics of the localized surface plasmon mode and upper and lower polaritonic states.


Discharge disposition to skilled nursing facility after endovascular reperfusion therapy predicts a poor prognosis.
We explore the impact of discharge disposition (independent rehabilitation facility (IRF) vs skilled nursing facility (SNF)) on 90 day outcomes in persons with stroke who received acute endovascular treatment. Using a database from a single primary care stroke center, discharge disposition, National Institutes of Health Stroke Scale (NIHSS), Totaled Health Risks in Vascular Events (THRIVE), Houston Intra-Arterial Therapy 2 (HIAT-2), and Acute Physiology and Chronic Health Evaluation (APACHE II) scores, and successful reperfusion were obtained. Univariate analysis was performed to assess predictors of good clinical outcome, as defined by 90 day modified Rankin Scale (mRS) scores ≤2. A binary logistic regression model was used to determine the impact of placement to an IRF versus an SNF on clinical outcomes. 147 subjects were included in the analysis with a mean age of 63±14 years and median NIHSS of 18 (IQR 14-21). Final infarct volumes, and modified APACHE II, THRIVE, and HIAT-2 scores were similar between those discharged to an IRF and those discharged to an SNF.However, their 90 day outcomes were significantly different, with far fewer patients at SNFs achieving good clinical outcomes (25% vs 46%; p=0.023). Disposition to SNF was significantly associated with a lower probability of achieving an mRS score of 0-2 at 90 days (OR = 0.337 (95% CI 0.12 to 0.94); p<0.04). Subjects discharged to SNFs and IRFs after thrombectomy have similar medical and neurological severity at admission and similar final infarct volumes at discharge. Despite these similarities, patients discharged to an SNF had a significantly lower probability of achieving a good neurological outcome. These results have implications for future acute stroke trial design.


Pressure and breast thickness in mammography--an exploratory calibration study.
To perform a calibration study to provide data to help improve consistency in the pressure that is applied during mammography. Automatic readouts of breast thickness accuracy vary between mammography machines; therefore, one machine was selected for calibration. 250 randomly selected patients were invited to participate; 235 agreed, and 940 compression data sets were recorded (breast thickness, breast density and pressure). Pressure (measured in decanewtons) was increased from 5 daN through 1-daN intervals until the practitioner felt that the pressure was appropriate for imaging; at each pressure increment, breast thickness was recorded. Graphs were generated and equations derived; second-order polynomial trend lines were applied using the method of least squares. No difference existed between breast densities, but a difference did exist between "small" (15×29 cm) and "medium/large" (18×24/24×30 cm) paddles. Accordingly, data were combined. Graphs show changes in thickness from 5-daN pressure for craniocaudal and mediolateral oblique views for the small and medium/large paddles combined. Graphs were colour coded into three segments indicating high, intermediate and low gradients [≤-2 (light grey); -1.99 to -1 (mid-grey); and ≥-0.99 (dark grey)]. We propose that 13 daN could be an appropriate termination pressure on this mammography machine. Using patient compression data we have calibrated a mammography machine to determine its breast compression characteristics. This calibration data could be used to guide practice to minimise pressure variations between practitioners, thereby improving patient experience and reducing potential variation in image quality. For the first time, pressure-thickness graphs are now available to help guide mammographers in the application of pressure.


Epstein-Barr virus, methotrexate, and lymphoma in patients with rheumatoid arthritis and primary Sjögren's syndrome: case series.
Rheumatoid arthritis (RA) and primary Sjögren's syndrome (SS) are associated with an increased risk of lymphoma. Epstein-Barr virus (EBV), a ubiquitous herpes virus, has been linked etiologically to lymphoma in patients with RA and primary SS. Recently, methotrexate (MTX) has also been linked to the development of these lymphomas. We investigated the frequency of EBV in lymphoma tissue of patients with RA and primary SS and the association of MTX with lymphomagenesis. Twenty-three patients with RA and 9 with primary SS with a history of lymphoma were identified by writing to all Arthritis Foundation member rheumatologists in Washington State. Formalin fixed, paraffin embedded tissue blocks were then requested from pathology laboratories. Lymph nodes from 5 RA patients without lymphoma were also studied. In situ hybridization using a biotinylated EBER-1 oligonucleotide probe was used to detect EBV in tissue sections. Positive and negative laboratory controls were used to ensure procedural integrity. Specimens from 21 RA patients were obtained, with 2 subsequently excluded due to specimen quality. Specimens from 6 patients with primary SS were obtained. In situ hybridization for EBV was positive in 5/19 (26%) RA patients and 1/6 patients with primary SS. In the nonmalignant lymph nodes no patient showed EBV. One primary SS and 12 RA patients were known to be taking MTX at the time of lymphoma diagnosis. Of the EBV positive RA lymphoma patients, 4/5 were receiving MTX at the time of diagnosis. These results show that EBV is present in lymphoma tissue of some patients with RA and very few with primary SS. EBV is over-represented in the lymphomas of patients with RA, but whether MTX plays a role in predisposing patients with RA and primary SS to the development of lymphoma, perhaps by influencing behavior of EBV, remains unclear.


A Unique Lymphaticovenous Supermicrosurgery Training Curriculum: Reflections on Validation and Competency Thresholds.
Supermicrosurgery is becoming a commonly used technique in various subspecialties of reconstructive surgery. However, there is a lack of standardization and validation in novel supermicrosurgical training. Current simulation training programs are not adequately focused on the challenges encountered during clinical supermicrosurgery practice. This article describes the authors' experience utilizing a supermicrosurgery competency-based training curriculum, in a simulation-based environment, toward safe clinical practice for lymphatic submillimeter supermicrovascular surgery. This article demonstrates the senior authors' (I.K.) Halstedian competency-based curriculum for lymphaticovenous anastomosis training. Further, a step-by-step training utilizing the chicken thigh and the living rat high fidelity simulation models, which subsequently allows supervised one-to-one clinical training with verified clinical competency outcomes, are demonstrated.


Oxygen-induced inhibition of mouse brain lactate dehydrogenase.
The lactate dehydrogenase (LDH) activity of mouse brain homogenates was examined after exposure to hyperbaric oxygen (5763.8 mm Hg Po2) and compared to room air controls (158.8 mm Hg Po2). The effect of reduced glutathione on LDH activity after hyperbaric oxygen exposure was also examined. The activity of LDH after treatment with hyperbaric oxygen was significantly diminished when compared with controls. In the presence of reduced glutathione, homogenates exposed to hyperbaric oxygen demonstrated higher activity than did homogenates incubated without glutathione. It is concluded that oxygen-induced inhibition occurs through the oxidation of essential free sulfhydryl groups and that this oxidation can either be prevented by reduced glutathione or the disulfide bridges may be reduced to free sulfhydryl groups by the glutathione after oxidation.


Factors affecting water balance and percolate production for a landfill in operation.
Percolate production and precipitation data for a full-scale landfill in operation measured over a 13-year period were used to evaluate the impact and importance of the hydrological conditions of landfill sections on the percolate production rates. Both active (open) and closed landfill sections were included in the evaluation. A simple top cover model requiring a minimum of input data was used to simulate the percolate production as a function of precipitation and landfill section hydrology. The results showed that changes over time in the hydrology of individual landfill sections (such as section closure or plantation of trees on top of closed sections) can change total landfill percolate production by more than 100%; thus, percolate production at an active landfill can be very different from percolate production at the same landfill after closure. Furthermore, plantation of willow on top of closed sections can increase the evapotranspiration rate thereby reducing percolate production rates by up to 47% compared to a grass cover. This process, however, depends upon the availability of water in the top layer, and so the evaporation rate will be less than optimal during the summer where soil-water contents in the top cover are low.


Itching for an answer: A review of potential mechanisms of scalp itch in psoriasis.
Scalp psoriatic itch is a common complaint and often poses a therapeutic challenge. The pathophysiology of this phenomenon is unclear. The unique anatomy of the scalp contains richly innervated hair follicles, abundant vasculature and perifollicular inflammatory cytokines which may all contribute to this common sensory complaint. The mast cell, in particular, is portrayed as one of the main itch conductors for its ability to trigger neurogenic inflammation, activate the peripheral hypothalamic-pituitary-adrenal-axis, process and integrate itch signalling through its interactions with the scalp hair follicles. Herein, we explain and speculate upon potential mechanisms underlying itchy scalp psoriasis, involving interconnections between the neuroimmune, neurovascular and neuroendocrine systems. Many factors may play roles in itchy scalp psoriasis including the scalp hair structure, immune system, endocrine system, nervous system and vascular system. These may warrant further exploration as therapeutic targets that go beyond the application of mere anti-inflammatory agents.


Pituitary response to thyrotropin-releasing hormone in depression.
Plasma thyrotropin (TSH) levels varied relatively little over minutes to days in the same individual not subjected to challenge with thyrotropin-releasing hormone (TRH). Thus, the TSH response to stimulation with TRH is not likely to be confounded by spontaneous changes of comparable degree. Variable numbers of depressed patients showed a blunted response to TRH stimulation of the pituitary, but the exact prevalence of this phenomenon remains to be clearly defined. In any case, the pituitary response to TRH stimulation was not correlated with the prevailing level of depression, nor did this response to an initial TRH challenge predict the degree of clinical change during a 15-day treatment during which three intravenous doses of 600 mug of TRH were given. Depressed patients, as do schizophrenics and normal patients, show diminished TSH responses to repeated challenges with TRH. Whether or not these three groups differ in regard to the rate at which the pituitary response can be abolished remains to be determined.


[Correction of motor and affective symptoms of parkinsonism by selective serotonine reuptake inhibition antidepressant].
A study included 68 patients with parkinsonism: 43 of them were treated with proflusak (fluoxetin), which efficacy was assessed in the frames of randomized placebo-controlled study. The levels of motor disability, anxiety, depression and serum serotonin (S) concentration were measured. The prevalence of rigidity and hypokinesia caused the increase of the depression level, along with decreasing of S concentration. Severity of tremor was positively correlated with the level of anxiety and blood S. Significant differences between patients receiving proflusak and placebo were found. No changes in the levels of motor-affective symptoms were observed in the placebo group. In patients treated with proflusak, the subjective improvement of health was accompanied by the significant decrease of depression severity and reduction of movement deficit, in particular rigidity and hypokinesia. The blood concentration of S decreased significantly in comparison to the placebo group. Taking into account the mechanism of action of the drug studied (its belonging to SSRIs), these changes may reflect the alterations of serotonergic metabolism in the brain synapses.


PATENT DUCTUS ARTERIOSUS CLOSURE: EXPERIENCE FROM A TERTIARY REFERRAL CENTER.
To characterize the number and methods of closure of Persistent Ductus Arteriosus (PDA) over a span of 16 years in a third level maternity hospital. Retrospective study of neonates born between January 2003 and Deccember 2018, who underwent ductus arteriosus closure by pharmacological, surgical and/or transcatheter methods. Gestational age, birth weight, number and methods of closures per year were evaluated. The success rate of the pharmacologic method was calculated, as well as the mortality rate. The association between mortality and birthweight, treatment used and treatment failure was explored. There were 47,198 births, 5,156 were preterm, 325 presented PDA and 106 were eligible for closure (median gestational age - 27 weeks, birthweight <1000 g - 61%). Frequency of PDA closure decreased during the study period, especially starting in 2010. Success rate with pharmacologic treatment was 62% after the first cycle and 74% after the second. After drug failure, 12 underwent surgical ligation and two underwent transcatheter closure. Exclusive surgical ligation was indicated in four infants. Ibuprofen replaced indomethacin in 2010, and acetaminophen was used in three infants. Among the 106 infants, hospital mortality was 12% and it was associated with birthweight <1000 g (13/65 <1000 vs. 0/41 >1000 g; p=0.002) and with failure in the first pharmacologic treatment cycle (13/27 with failure, vs. 0/75 without failure; p<0.001). The national consensus published in 2010 for the diagnosis and treatment of PDA in preterm infants led to a decrease in the indication for closure. Pharmacological closure was the method of choice, followed by surgical ligation. Birthweight <1000 g and first cycle of pharmacologic treatment failure were associated with higher mortality.


Characterization of a prolidase from Lactobacillus delbrueckii subsp. bulgaricus CNRZ 397 with an unusual regulation of biosynthesis.
Lactobacillus delbrueckii subsp. bulgaricus CNRZ 397 (Lb. bulgaricus) is characterized by a high level of peptidase activities specific to proline-containing peptides. A prolidase (PepQ, EC 184.108.40.206) was purified to homogeneity and characterized as a strict dipeptidase active on X-Pro dipeptides, except Gly-Pro and Pro-Pro. The values for Km and Vmax were, respectively, 2.2 mM and 0.33 mmol min(-1) mg(-1), with Leu-Pro as the substrate. The enzyme exhibited optimal activity at 50 degrees C and pH 6.0, and required the presence of Zn2+. Size exclusion chromatographies and SDS-PAGE analysis led to the conclusion that this prolidase was a homodimer. Antibodies raised against the purified protein allowed the detection of PepQ among several Lactobacillus species but not lactococci. The pepQ gene and the upstream region were isolated and sequenced. The deduced peptide sequence showed that PepQ belongs to the M24 family of metallopeptidases. The pepR1 gene is located immediately upstream of pepQ and its product is homologous to the transcription factor CcpA, which is involved in catabolite repression of catabolic operons from Gram-positive bacteria. The pepR1-pepQ intergenic region contains a consensus catabolite-responsive element (CRE) which could be a target for PepR1 protein. Moreover, in contrast to other proline-specific enzymes from Lb. bulgaricus, PepQ biosynthesis was shown to be dependent on the composition of the culture medium, but not on the peptide concentration. A possible regulation mechanism is discussed.


Comparative Effectiveness and Safety of Seizure Prophylaxis Among Adults After Acute Ischemic Stroke.
Older adults occasionally receive seizure prophylaxis in an acute ischemic stroke (AIS) setting, despite safety concerns. There are no trial data available about the net impact of early seizure prophylaxis on post-AIS survival. Using a stroke registry (American Heart Association's Get With The Guidelines) individually linked to electronic health records, we examined the effect of initiating seizure prophylaxis (ie, epilepsy-specific antiseizure drugs) within 7 days of an AIS admission versus not initiating in patients ≥65 years admitted for a new, nonsevere AIS (National Institutes of Health Stroke Severity score ≤20) between 2014 and 2021 with no recorded use of epilepsy-specific antiseizure drugs in the previous 3 months. We addressed confounding by using inverse-probability weights. We performed standardization accounting for pertinent clinical and health care factors (eg, National Institutes of Health Stroke Severity scale, prescription counts, seizure-like events). The study sample included 151 patients who received antiseizure drugs and 3020 who did not. The crude 30-day mortality risks were 219 deaths per 1000 patients among epilepsy-specific antiseizure drugs initiators and 120 deaths per 1000 among noninitiators. After standardization, the estimated mortality was 251 (95% CI, 190-307) deaths per 1000 among initiators and 120 (95% CI, 86-144) deaths per 1000 among noninitiators, corresponding to a risk difference of 131 (95% CI, 65-200) excess deaths per 1000 patients. In the prespecified subgroup analyses, the risk difference was 52 (95% CI, 11-72) among patients with minor AIS and 138 (95% CI, 52-222) among moderate-to-severe AIS patients. Similarly, the risk differences were 86 (95% CI, 18-118) and 157 (95% CI, 57-219) among patients aged 65 to 74 years and ≥75 years, respectively. There was a higher risk of 30-day mortality associated with initiating versus not initiating seizure prophylaxis within 7 days post-AIS. This study does not support the role of seizure prophylaxis in reducing 30-day poststroke mortality.


The correlation between serum 25-hydroxyvitamin D level and ulcerative colitis: a systematic review and meta-analysis.
The incidence of UC has increased yearly. Many studies have suggested that patients with ulcerative colitis have abnormal vitamin D levels. A systematic review and meta-analysis were conducted to investigate the association between vitamin D levels and ulcerative colitis. We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang and China Science and Technology Journal Database (VIP) from inception to December 2022. We included case-control studies comparing the differences in vitamin D levels between patients with ulcerative colitis and healthy populations. Meta-analysis was performed using Review Manager5.4, Stata17.0 and other software. Sixteen eligible observational studies were selected from 473 articles involving 2234 subjects, and they included 987 patients with ulcerative colitis and 1247 controls. The results showed that the serum level of vitamin D in patients with ulcerative colitis was significantly lower than that in healthy controls (SMD = -0.83, 95% CI: -1.18, -0.48). Vitamin D deficiency was reported in five studies. The prevalence of vitamin D deficiency was significantly higher in the ulcerative colitis group than in the healthy control group (OR = 1.90, 95% CI: 1.38, 2.62). Serum vitamin D levels were significantly lower in patients with ulcerative colitis than in healthy controls.


Colliding beam fusion reactor
Recent results with Tokamak experiments provide insights into the problem of magnetic confinement. They demonstrate how to avoid anomalous transport and thus solve the major problems of Tokamak reactors: size, the production of 14-megaelectron volt neutrons, and maintenance. An alternate confinement system, the field-reversed configuration, confines beams of protons and boron-11. For the proton-boron-11 fusion reaction, the fusion products are all charged particles for which direct conversion is feasible and neutron flux is negligible.


Effects of three different stretching techniques on vertical jumping performance.
The aim of this study was to evaluate 3 different flexibility techniques: (a) ballistic stretching (BS), (b) proprioceptive neuromuscular facilitation stretching (PNF) + BS, and (c) PNF + static stretching (SS) on vertical jump (VJ) performance and to determine the most appropriate stretching method during warm-up period before explosive force disciplines. One hundred voluntary male athletes participated in this study. All subjects performed aerobic warm-up (5-minute jog) followed by BS (5 seconds for each stretching exercise), PNF + BS (PNF performed followed by 5 seconds of BS), and PNF + SS (PNF performed followed by 30 seconds of SS) treatment protocol, respectively in the same day. Each stretching treatment was applied for 4 sets bilaterally. In all stretching treatments, lumbar extensor, gluteus maximus, and hamstring muscles were stretched with a single stretching exercise. After a 2-minute brief rest period, participants performed 3 trials of VJ test followed by one of the treatment protocols. Vertical jump performance was evaluated by countermovement jump (CMJ). Participants were divided into 3 groups according to their flexibility and prejump performances after warm-up. For each individual group and the whole group, after all treatments, differences in CMJ values were obtained (p ≤ 0.05). Ballistic stretching increased the VJ performance in the groups with low and average flexibility, poor prejumping performance, and also in the whole group (p ≤ 0.05). Proprioceptive neuromuscular facilitation stretching + BS affected VJ performance in the group of participants with high flexibility (p ≤ 0.05). Proprioceptive neuromuscular facilitation + SS decreased VJ performance in groups of participants with high flexibility, moderate, and high prejumping performance and in whole group (p ≤ 0.05). Ballistic stretching method increased VJ height, therefore seems to be more suitable than PNF + SS and PNF + BS before events that rely on explosive power as a part of warm-up period.


High-resolution x-ray imaging of extended lasing plasmas.
An x-ray imaging system with a bent focusing crystal was used for time-resolved one-dimensional imaging of a long plasma column of highly ionized aluminum. This scheme uses a focusing geometry with a spherically bent crystal and a slit on the Rowland circle. Alternative schemes of x-ray monochromatic imaging are briefly discussed. The homogeneity of the up to 40-mm-long laser-generated plasma column was studied with a temporal resolution of 100 ps. The potential spatial resolution of the instrument is 90 microm or better. Monochromatic images taken on the resonance He alpha line of Al XII characterize the homogeneity of a plasma generated to study a recombination x-ray laser scheme, giving an amplified spontaneous emission in Al XI.


Tauroursodeoxycholic acid administration as adjuvant therapy in cirrhotic patients on transplantation waiting lists.
The lack of organ availability and an increased number of end-stage cirrhotic patients has led to the lengthening of liver transplantation waiting lists. The progressive worsening of clinical and functional performance in patients awaiting the graft is one of the factors implicated in the increased mortality during the wait and in poor transplantation outcome. In this work our aim was to evaluate the effects of tauroursodeoxycholic acid administration on biochemical, clinical and functional parameters in a group of cirrhotic patients consecutively placed onto our liver transplantation waiting list. Ten cirrhotic patients underwent biochemical, clinical and functional evaluation at the time of entering on our liver transplantation waiting list, then tauroursodeoxycholic acid was administered until liver transplantation. Complete evaluation was repeated every 2 months. The results were compared to those of a comparable historical control group that had undergone liver transplantation the year before the study. All patients were transplanted within 6 months from insertion on the waiting list. Longitudinal analysis of the treated group showed that cholestasis and cytolisis parameters constantly decreased and that gamma-glutamyl transpeptidase was significantly lower compared to baseline values at the 4th month of therapy. Clinical and functional parameters remained stable during follow-up. Comparison with the control group showed that gamma-glutamyl transpeptidase, alkaline phosphatase and both aminotransferases were reduced at the 4th month of therapy. Fewer days of hospital stay and less intensive care were required in the treated group. Treatment of end-stage cirrhotic patients awaiting liver transplantation with tauroursodeoxycholic acid improves biochemical parameters of cytolisis and cholestasis, and furthermore helps to maintain clinical and functional stability during the wait. Improved biochemical conditions and steady clinical-functional performance may promote better short-term transplant outcome.


Prosthodontic Rehabilitation of Arabic Speaking Individuals with Velopharyngeal Incompetence: A Preliminary Study.
Hypernasality is a frequently encountered problem in the speech of individuals with velopharyngeal incompetence. The use of palatal lift appliance (PLA) is the main treatment option for correction of velopharyngeal incompetence. The literature on the outcomes of using prosthetics treatment for Arabic speaking patients is scarce. The aim of this study was to investigate the effect of using PLA on hypernasality of Arabic speaking patients with velopharyngeal incompetence. Six participants with age ranging from 9 to 61 years (4 males and 2 females) were recruited between October 2013 and August 2014. Written informed consents were taken from all the adult participants/the guardians of under-aged participants. All patients exhibited hypernasality with different etiologies for velopharyngeal incompetence (head injury, cerebrovascular accident, and neurological disorders). They were treated with PLAs which were constructed to elevate the dysfunctional soft palate. Nasalance scores and perceptual speech acceptability ratings were measured/evaluated in both situations; with and without appliances. Paired t-test was used to analyze the perceptual ratings and nasalance scores in order to detect any significant change in hypernasality pre and post insertion of PLA. There was a statistically significant decrease (p>0.05) in nasalance scores (Pa, Pi, Ma, Mi, a, i) after PLA insertion. The subtest /u/ showed insignificant change (p= 0.056). Perceptual ratings showed significant reduction in hypernasality which was consistent with nasalance measurements. PLAs can reduce hypernasality in Arabic speaking patients who suffer from velopharyngeal impairment.


Effects of GABA in the morphine-tolerant longitudinal muscle, myenteric plexus preparation of the guinea pig.
The effect of chronic treatment with morphine via pellet implantation on the sensitivity of the longitudinal smooth muscle-myenteric plexus of the guinea pig ileum to the contractile effects of gamma-aminobutyric acid (GABAA)-receptor agonists was assessed. GABA and muscimol elicited concentration-dependent contractions of the longitudinal smooth muscle which were due to the release of acetylcholine because the contractile effects were markedly attenuated by atropine (10 nM). The contractile action of GABA agonists does not involve an intermediate step mediated by nicotinic receptors because the concentration-response curves for GABA were unaffected by hexamethonium (1 mM). Bicuculline (10 microM) produced nearly equivalent rightward shifts of the concentration-response curves for both GABA and muscimol, indicating mediation of the contractile effects of these agents by GABAA receptors. Chronic exposure to morphine via pellet implantation did not alter the sensitivity of this preparation to either GABA or muscimol. This is in contrast to the development of supersensitivity of the longitudinal smooth muscle-myenteric plexus to other excitatory agonists (nicotine, 5-hydroxytryptamine and potassium), which accompanies the development of tolerance to opioids. GABA induces depolarization of myenteric neurons that is observed most prominently in AH neurons and rarely in S neurons. The stimulatory effects of nicotine and of GABA were inhibited by morphine (a predominantly mu opioid agonist) and by U50,488H (a predominantly kappa opioid agonist). The results are discussed within the context that supersensitivity to neuronal stimulants of the myenteric plexus in morphine-tolerant preparations is limited to substances which depolarize S neurons.


New cationic and neutral Ru(II)- and Os(II)-dmso carbonyl compounds.
The preparation and structural characterization of three cationic Ru(II)-dmso carbonyls and of four neutral mono- and dicarbonyl Os(II)-dmso derivatives is reported. The two monocarbonyl species fac-[Ru(CO)(dmso-O)3(dmso-S)2][PF6]2 (11) and cis,cis,cis-[RuCl(CO)(dmso-O)2(dmso-S)2][PF6] (12) were obtained from the neutral monocarbonyl precursor cis,trans,cis-[RuCl2(CO)(dmso-O)(dmso-S)2] (3) upon stepwise replacement of the chlorides with dmso, that binds in each case through the oxygen atom. The dicarbonyl cationic complex cis,cis,trans-[Ru(CO)2(dmso-O)2(dmso-S)Cl][PF6] (13) was instead obtained upon treatment of the neutral tricarbonyl precursor fac-[RuCl2(CO)3(dmso-O)] (8) with AgPF6 in the presence of DMSO: replacement of a Cl(-) with a dmso-O implied also the substitution of one CO ligand by another dmso (that binds through S trans to Cl). The Os(II) carbonyls trans,trans,trans-[OsCl2(CO)(dmso-O)(dmso-S)2] (17), trans,cis,cis-[OsCl2(CO)2(dmso-O)2] (18), cis,mer-[OsCl2(CO)(dmso-S)3] (19), and cis,trans,cis-[OsCl2(CO)(dmso-O)(dmso-S)2] (20) were obtained by treatment of the Os(II)-dmso precursors trans-[OsCl2(dmso-S)4] (14) and cis,fac-[OsCl2(dmso-O)(dmso-S)3] (15) with CO. Each one of them is structurally similar to an already known Ru(II) analog, even though--in agreement with the expected greater inertness of Os(II)--more forcing reaction conditions were required for their preparation. Interestingly, compound 20 could not be isolated in pure form, but only as a 1:1 cocrystallized mixture with its precursor 15. The dmso ligand is always bound through the oxygen atom when trans to CO. We are confident that the new Ru(II)- and Os(II)-dmso carbonyl species described here represent a contribution to expand the pool of complexes bearing some easily replaceable dmso ligands to be used as well-behaved precursors in inorganic synthesis.


Amino acid sequence of a proline-rich phosphoglycoprotein from parotid secretion of the subhuman primate Macaca fascicularis.
The complete amino acid sequence of the macaque proline-rich phosphoglycoprotein (MPRP) was determined by automated Edman degradation of the protein, fragments F-1 and F-2 derived from the protein by an intrinsic salivary protease, and chymotryptic, tryptic, Staphylococcus aureus V8 protease, and endoproteinase lysine-C peptides. MPRP contains 115 amino acid residues including phosphorylated serine at residues 1, 2, 6, 12, and 15, and 6 O-glycosidic carbohydrate units at residues 69, 75, 87 (threonine) and 96, 103, and 106 (serine). The Mr of the polypeptide moiety of the protein is 12,656. The amino-terminal domain contains all 5 phosphoserine residues and most of the other negatively charged and hydrophilic residues, whereas the carboxyl-terminal domain contains 24 of 25 proline residues, and 6 O-glycosidic oligosaccharides. Comparison of MPRP with the four major anionic proline-rich proteins (PRPs) from human glandular secretion shows that 57% of the amino acid residues are identical if gaps are introduced to maximize homology, suggesting that these proteins are phylogenetically related. Significant structural and functional differences occur between the macaque and human proteins. MPRP has 5 phosphoserines, PRPs have 2. MPRP is a glycoprotein, PRPs are not. MPRP inhibits the spontaneous precipitation (primary precipitation) of calcium phosphate salts from supersaturated solutions in addition to inhibiting seeded crystal growth (secondary precipitation) (Oppenheim, F. G., Offner, G. D., and Troxler, R. F. (1982) J. Biol. Chem. 257, 9271-9282), whereas PRPs inhibit only secondary precipitation. MPRP is the only major anionic proline-rich protein in macaque glandular secretion; in contrast, there are four major anionic PRPs and these display a genetic polymorphism. The significance of these structural differences with respect to biological function and the possible relationship of MPRP to salivary mucins are discussed.


N-acetyl-L-cysteine enhances interleukin-1beta-induced nitric oxide synthase expression.
The effect of N-acetyl-L-cysteine on interleukin-1beta-induced nitric oxide synthase expression was studied in rat vascular smooth muscle cells to determine if the reduction/oxidation state would modulate cytokine-induced changes. Interleukin-1beta induced the production of nitrite, a stable metabolite of nitric oxide in a time- and dose-dependent manner. Cytokine-induced nitrite production was enhanced by the addition of N-acetyl-L-cysteine in a dose-dependent manner, with a >50% increase produced by the addition of 1 mmol/L N-acetyl-L-cysteine. There was no influence on nitrite production when the cells were treated with N-acetyl-L-cysteine alone. Northern and Western blot analyses revealed that the upregulation of interleukin-1beta-induced nitric oxide production by N-acetyl-L-cysteine resulted from an enhanced expression of inducible nitric oxide synthase. Interferon-gamma or tumor necrosis factor-alpha when used alone had no influence on nitrite production in the absence or presence of N-acetyl-L-cysteine. Nitrite accumulation was higher by the cells treated with interleukin-1beta combined with either interferon-gamma or tumor necrosis factor-alpha compared with those treated with interleukin-1beta alone. N-Acetyl-L-cysteine upregulated nitrite production and inducible nitric oxide synthase expression induced by combination treatment with interleukin-1beta and either interferon-gamma or tumor necrosis factor-alpha. However, N-acetyl-L-cysteine had no significant influence in cytokine-induced activation of nuclear factor-kappaB or signal transducer and activator of transciption-1, as assessed by electrophoretic mobility shift assays. These results demonstrate that N-acetyl-L-cysteine possibly acted as a thiol-containing reducing agent and facilitated the expression of inducible nitric oxide synthase in rat vascular smooth muscle cells by cytokines through a mechanism that is independent of nuclear factor-kappaB or signal transducer and activator of transciption-1.


Distending Media Used During Hysteroscopy: Perioperative Nursing Implications.
Hysteroscopy is a gynecological procedure that may be indicated for abnormal uterine bleeding, diagnosis and management of infertility, contraception, or sterilization. Surgeons use distending media during hysteroscopy to view the uterine cavity. Media options include carbon dioxide gas and both electrolytic and nonelectrolytic fluids. All distending media is absorbed by the patient's body, but the manner in which each media is absorbed is unique to its chemical composition. Understanding the properties of each distending medium and the risks involved with its use is critical to safe perioperative nursing care for patients undergoing hysteroscopy. This article provides perioperative nurses with a review of uterine anatomy and evidence-based information on the types of distending media used during hysteroscopy and the corresponding perioperative nursing implications.


SNPs near the cysteine proteinase cathepsin O gene (CTSO) determine tamoxifen sensitivity in ERα-positive breast cancer through regulation of BRCA1.
Tamoxifen is one of the most commonly employed endocrine therapies for patients with estrogen receptor α (ERα)-positive breast cancer. Unfortunately the clinical benefit is limited due to intrinsic and acquired drug resistance. We previously reported a genome-wide association study that identified common SNPs near the CTSO gene and in ZNF423 associated with development of breast cancer during tamoxifen therapy in the NSABP P-1 and P-2 breast cancer prevention trials. Here, we have investigated their roles in ERα-positive breast cancer growth and tamoxifen response, focusing on the mechanism of CTSO. We performed in vitro studies including luciferase assays, cell proliferation, and mass spectrometry-based assays using ERα-positive breast cancer cells and a panel of genomic data-rich lymphoblastoid cell lines. We report that CTSO reduces the protein levels of BRCA1 and ZNF423 through cysteine proteinase-mediated degradation. We also have identified a series of transcription factors of BRCA1 that are regulated by CTSO at the protein level. Importantly, the variant CTSO SNP genotypes are associated with increased CTSO and decreased BRCA1 protein levels that confer resistance to tamoxifen. Characterization of the effect of both CTSO SNPs and ZNF423 SNPs on tamoxifen response revealed that cells with different combinations of CTSO and ZNF423 genotypes respond differently to Tamoxifen, PARP inhibitors or the combination of the two drugs due to SNP dependent differential regulation of BRCA1 levels. Therefore, these genotypes might be biomarkers for selection of individual drug to achieve the best efficacy.


Iron indices: what do they really mean?
Routine monitoring of body iron stores is an essential component of overall management for the patient on hemodialysis. Adequate iron levels are important for the prevention and treatment of iron-deficiency anemia, which is associated with reduced physical functioning, cardiovascular disease, and poor quality of life. Hemodialysis patients are at especially high risk for iron-deficiency anemia, owing to continuous blood losses and supraphysiologic levels of erythropoiesis driven by recombinant human erythropoietin therapy. Unfortunately, the accurate determination of iron status in these patients can be a challenging task, which is made more difficult by inflammation, infections, and the large number of comorbid conditions that can affect commonly used indices of body iron stores. Despite their limitations, transferrin saturation (TSAT) and serum ferritin remain the cornerstones of iron status assessment. Because these values can be altered by a number of non-iron-related factors, it is necessary to go beyond these measures and draw upon additional sources of information to determine the patient's iron status. Other important factors to consider when assessing the need for iron therapy include evidence of underlying inflammatory processes that may block iron mobilization and distort the standard iron indices, the results of alternative iron indices, and the patient's recent history of iron administration. Frequently, the response to a gram of intravenous (i.v.) iron is a safe and effective way to determine the role of iron deficiency in the anemia of the problematic patient. The chronic inflammatory state associated with malnutrition and clinical or subclinical infections substantially increases the risk of misdiagnosing the patient with iron overload and may place the patient at risk of iron deficiency owing to inappropriate withdrawal of i.v. iron therapy. To avoid the risks of withholding iron therapy, the nephrologist must keep this relationship in mind whenever serum ferritin testing suggests replete iron stores, whereas TSAT testing suggests insufficient iron availability.


Using the knee-specific Hughston Clinic Questionnaire, EQ-5D and SF-6D following arthroscopic partial meniscectomy surgery: a comparison of psychometric properties.
To compare the psychometric properties of the Hughston Clinic Questionnaire (HCQ), EQ-5D and SF-6D in patients following arthroscopic partial meniscectomy surgery. A total of 84 participants (86% men; mean age 40) were recruited. The questionnaires were completed on average 5 days, 6 weeks and 6 months after surgery and compared for internal consistency, convergent validity, sensitivity to change and floor and ceiling effects. Internally, the HCQ was the most consistent instrument (α = 0.923) followed by the SF-6D and EQ-5D. The EQ-5D and SF-6D were moderately correlated with the HCQ (ρ = 0.499 and 0.394, respectively). Six weeks after surgery, the most sensitive measures were the HCQ and EQ-5D (effect size: 2.04 and 0.99, respectively), at 6 months, with a smaller cohort (n = 42), again it was the HCQ and EQ-5D (effect size: 2.03 and 1.04, respectively). The SF-6D demonstrated no ceiling or floor effect during the study; the HCQ demonstrated a ceiling affect for 5% of respondents at 6 months after surgery compared to 26% of respondents for the EQ-5D. For this patient population, our findings indicated that the EQ-5D was more consistently responsive to change over time, as a utility index was better at distinguishing differences between groups and reflected the results of the joint-specific HCQ for knee recovery better than the SF-6D. It is therefore recommended that for similar populations, the EQ-5D is preferable to the SF-6D for utilisation alongside the HCQ.


Genotyping analysis of the factor V Nara mutation, Hong Kong mutation, and 16 single-nucleotide polymorphisms, including the R2 haplotype, and the involvement of factor V activity in patients with recurrent miscarriage.
: Recurrent miscarriage can arise from a large diversity of causes and the factors responsible have not been fully clarified. The coagulation factor V R506Q (Leiden) mutation is a well known risk factor for recurrent miscarriage, although it has not been found in Japanese populations. We examined whether the factor V Nara and Hong Kong mutations, the factor V gene (F5) 16 single-nucleotide polymorphisms (SNPs), including the factor V R2 haplotype, and plasma factor V activity (FV:C) were risk factors for recurrent miscarriage. A cross-sectional study was conducted among 88 patients with a history of unexplained recurrent miscarriage and 95 fertile controls. None of the patients or controls was homozygous or heterozygous for the factor V Nara or Hong Kong mutation. In the 16 SNPs of F5, frequencies of the G/T and T/T genotypes at Ser156Ser were significantly lower in patients than in controls (OR 0.45, 95% CI 0.22-0.91, OR 0.32, 95% CI 0.14-0.72) and the allele frequency of C at Leu1288Leu was significantly higher in patients than that in controls (OR 1.66, 95% CI 1.02-2.71). The mean FV:C values were not significantly different between patients and controls. However, the prevalence of patients with a high or low FV:C (>95th or <fifth percentile) was significantly greater than the controls (OR 3.59, 95% CI 1.11-11.60: OR 3.94, 95% CI 1.23-12.60). These results suggest that some SNPs of F5 and a high or low FV:C level might be associated with recurrent miscarriage.


Flat metasurfaces to collimate electromagnetic waves with high efficiency.
Directional beaming of electromagnetic waves passing through a subwavelength aperture has attracted considerable interests in photonics, but the traditional approach of utilizing gratings to directionally couple surface waves (SWs) to a desired far-field direction faces the low-efficiency issue owing to high-order diffractions. Here we experimentally demonstrate that directional beaming of light can be realized with very high efficiencies, in which two specifically designed metasurfaces (MTSs) are placed at two sides of the aperture to serve as SW to propagating-wave meta-couplers. Different from the grating couplers, the well-designed phase-gradient meta-couplers can freely select the desired diffraction orders by suppressing the undesired diffraction orders. We design and fabricate MTSs with different phase gradients, and perform both far-field and near-field measurements to verify the predicted high-efficiency on/off-axis directional beaming effects. Experimental results are in good agreement with full wave simulations and theoretical analyses.


The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia.
Neonatal encephalopathy (NE) is a leading cause of childhood death and disability in term infants. Treatment options for perinatal brain injury are limited and developing therapies that target multiple pathways within the pathophysiology of NE are of great interest. Pifithrin-µ (PFT-µ) is a drug with striking neuroprotective abilities in a preclinical model of hypoxia-ischemia (HI)-induced NE wherein cell death is a substantial cause of injury. Work from neurons and tumor cells reports that PFT-µ is able to inhibit p53 binding to the mitochondria, heat shock protein (HSP)-70 substrate binding and activation of the NF-kB pathway. The purpose of this study is to understand whether the neuroprotective effects of PFT-µ also include direct effects on microglia. We utilized the microglial cell line, BV2, and we studied the dose-dependent effect of PFT-µ on M1-like and M2-like phenotype using qRT-PCR and Western blotting, including the requirement for the presence of p53 or HSP-70 in these effects. We also assessed phagocytosis and the effects of PFT-µ on genes within metabolic pathways related to phenotype. We noted that PFT-µ robustly reduced the M1-like (lipopolysaccharide, LPS-induced) BV2 response, spared the LPS-induced phagocytic ability of BV2 and had no effect on the genes related to metabolism and that effects on phenotype were partially dependent on the presence of HSP-70 but not p53. This study demonstrates that the neuroprotective effects of PFT-µ in HI-induced NE may include an anti-inflammatory effect on microglia and adds to the evidence that this drug might be of clinical interest for the treatment of NE.


Anisotropic Magnetic Resonance in Random Nanocrystal Quantum Dot Ensembles.
Magnetic anisotropy critically determines the utility of magnetic nanocrystals (NCs) in new nanomagnetism technologies. Using angular-dependent electron magnetic resonance (EMR), we observe magnetic anisotropy in isotropically arranged NCs of a nonmagnetic material. We show that the shape of the EMR angular variation can be well described by a simple model that considers magnetic dipole-dipole interactions between dipoles randomly located in the NCs, most likely due to surface dangling bonds. The magnetic anisotropy results from the fact that the energy term arising from the magnetic dipole-dipole interactions between all magnetic moments in the system is dominated by only a few dipole pairs, which always have an anisotropic geometric arrangement. Our work shows that magnetic anisotropy may be a general feature of NC systems containing randomly distributed magnetic dipoles.


Biopsychosocial Effects of a Conventional Exercise Program and Culturally Relevant Activities in Older Women From Mozambique.
This randomized controlled trial compared the effects of a Conventional Exercise Program (CEP) and Culturally Relevant Activities (CRA) on body mass, cardiovascular risk, functional fitness (strength, flexibility, cardiorespiratory fitness, and agility), self-efficacy, and self-esteem in older women dwelling in Mozambique. Fifty-seven women (67 [7] y) underwent 60-minute sessions of CEP (n = 28) or CRA (n = 29) performed 3 days per week for 12 weeks. CRA included Mozambican traditional dances and games (intensity corresponding to scores 3-4 of BORG-CR10 scale), and CEP included 20-minute stationary cycling (65%-75% heart rate reserve) and a resistance training circuit (8 exercises, 15-repetition maximum). CEP and CRA (P < .05) showed increased percent fat (3.4% and 5.3%), waist circumference (3.3% and 5.8%), and cardiorespiratory fitness (14.4% and 9.4%), and decreased triglycerides (-20.0% and -77.8%). In CEP (P < .05), body mass (2.9%), body mass index (3.2%), and high-density lipoprotein (10.0%) increased, while glycemia (-4.8%) and total cholesterol (-9.8%) decreased. Blood pressure slightly increased in CEP (6.2%, P > .05) and CRA (4.3%, P < .05). Self-efficacy and self-esteem increased to similar levels in both groups (15%, P < .05). CEP and CRA were capable to improve biopsychosocial health-related variables in Mozambican older women. Culturally referenced PA interventions should be considered as an alternative in African countries.


Cardiopulmonary bypass weaning difficulty due to anomalous origin of coronary artery -A case report-.
We report a case of hemodynamic instability after aortic valve replacement, due to the anomalous origin of the right coronary artery. During the cardiopulmonary bypass weaning process, hemodynamic instability occurred. The cause was not identified at first, and compression of the anomalous right coronary artery was thought to be the culprit, thereafter.


Conformational Plasticity of Hepatitis C Virus Core Protein Enables RNA-Induced Formation of Nucleocapsid-like Particles.
Many of the unanswered questions associated with hepatitis C virus assembly are related to the core protein (HCVcp), which forms an oligomeric nucleocapsid encompassing the viral genome. The structural properties of HCVcp have been difficult to quantify, at least in part because it is an intrinsically disordered protein. We have used single-molecule Förster Resonance Energy Transfer techniques to study the conformational dimensions and dynamics of the HCVcp nucleocapsid domain (HCVncd) at various stages during the RNA-induced formation of nucleocapsid-like particles. Our results indicate that HCVncd is a typical intrinsically disordered protein. When it forms small ribonucleoprotein complexes with various RNA hairpins from the 3' end of the HCV genome, it compacts but remains intrinsically disordered and conformationally dynamic. Above a critical RNA concentration, these ribonucleoprotein complexes rapidly and cooperatively assemble into large nucleocapsid-like particles, wherein the individual HCVncd subunits become substantially more extended.


Optimized microwave-assisted extraction of 6-gingerol from Zingiber officinale Roscoeand evaluation of antioxidant activity in vitro.
6-Gingerol is one of the most pharmacologically active and abundant components in ginger, which has a wide array of biochemical and pharmacologic activities. In recent years, the application of microwave-assisted extraction (MAE) for obtaining bioactive compounds from plant materials has shown tremendous research interest and potential. In this study, an efficient microwave-assisted extraction (MAE) technique was developed to extract 6-gingerol from ginger. The extraction efficiency of MAE was also compared with conventional extraction techniques. Fresh gingers (Zingiber officinale Rose.) were harvested at commercial maturity (originally from Shandong, laiwu, China). In single-factor experiments for the recovery of 6-gingerol, proper ranges of ratio of liquid to solid, ethanol proportion, microwave power, extraction time were determined. Based on the values obtained in single-factor experiments, a Box-Behnken design (BBD) was applied to determine the best combination of extraction variables on the yield of 6-gingerol. The optimum extraction conditions were as follows: microwave power 528 W, ratio of liquid to solid 26 mL·g(-1), extraction time 31 s and ethanol proportion 78%. Furthermore, more 6-gingerol and total polyphenols contents were extracted by MAE than conventional methods including Maceration (MAC), Stirring Extraction (SE), Heat reflux extraction (HRE), Ultrasound-assisted extraction (UAE), as well as the antioxidant capacity. Microwave-assisted extraction showed obvious advantages in terms of high extraction efficiency and antioxidant activity of extract within shortest extraction time. Scanning electron microscopy (SEM) images of ginger powder materials after different extractions were obtained to provide visual evidence of the disruption effect. To our best knowledge, this is the first report about usage of MAE of 6-gingerol extraction from ginger, which could be referenced for the extraction of other active compounds from herbal plants.


Left atrial volume and adverse cardiovascular outcomes in unselected patients with and without CKD.
Patients with CKD have increased cardiovascular morbidity and mortality. This study investigated the prognostic value of common clinical echocardiographic parameters. There were 289 unselected consecutive patients who had a transthoracic echocardiogram between January and June 2003. Patients with stage 3 or 4 CKD (n=49) were compared with those with eGFR≥60 ml/min per 1.73 m(2), n=240). Left ventricular volume, ejection fraction and mass, left atrial volume, and function parameters were measured. The primary endpoint, determined a priori, was a composite of cardiac death, myocardial infarction, and congestive cardiac failure. Patients were followed for a median 5.6 years. The incidence of the primary endpoint was higher in patients with CKD (29% versus 12%, P=0.001), who were older and had a higher prevalence of hypertension and ischemic heart disease. Indexed left ventricular mass (LVMI) and left atrial volume (LAVI) were higher in patients with CKD. Furthermore, patients with LAVI>32 ml/m(2) had significantly lower event-free survival than patients with normal (<28 ml/m(2)) or mildly dilated LAVI (28-32 ml/m(2)) (P<0.001). Multivariate analysis showed that age (odds ratio [OR], 1.19; 95% confidence interval [95% CI], 1.08 to 1.31; P=0.001) and LVMI (OR, 3.66; 95% CI, 2.47 to 5.41; P<0.001) were independently associated with LAVI>32 ml/m(2). Multivariate Cox regression analysis demonstrated that CKD (hazard ratio [HR], 1.13; 95% CI, 1.01 to 1.26; P=0.04), hypertension (HR, 2.18; 95% CI, 1.05 to 4.54; P=0.04), and a larger LAVI (HR, 1.35; 95% CI, 1.02 to 1.77; P=0.04) were independent predictors of the primary endpoint. Patients with CKD were at higher risk for cardiovascular events. LAVI was significantly larger in the CKD group and was a predictor of adverse cardiac events.


The burden of alcohol on health care during COVID-19.
Alcohol's impact on global health is substantial and of a similar order of magnitude to that from COVID-19. Alcohol now also poses specific concerns, such as increased risk of severe lung infections, domestic violence, child abuse, depression and suicide. Its use is unlikely to aid physical distancing or other preventative behavioural measures. Globally, alcohol contributes to 20% of injury and 11.5% of non-injury emergency room presentations. We provide some broad comparisons between alcohol-attributable and COVID-19-related hospitalisations and deaths in North America using most recent data. For example, for Canada in 2017 it was recently estimated there were 105 065 alcohol-attributable hospitalisations which represent a substantially higher rate over time than the 10 521 COVID-19 hospitalisations reported during the first 5 months of the pandemic. Despite the current importance of protecting health-care services, most governments have deemed alcohol sales to be as essential as food, fuel and pharmaceuticals. In many countries, alcohol is now more readily available and affordable than ever before, a situation global alcohol producers benefit from and have helped engineer. We argue that to protect frontline health-care services and public health more generally, it is essential that modest, evidence-based restrictions on alcohol prices, availability and marketing are introduced. In particular, we recommend increases in excise taxation coupled with minimum unit pricing to both reduce impacts on health-care services and provide much-needed revenues for governments at this critical time.


Frontal cortex selectively overrides auditory processing to bias perception for looming sonic motion.
Rising intensity sounds signal approaching objects traveling toward an observer. A variety of species preferentially respond to looming over receding auditory motion, reflecting an evolutionary perceptual bias for recognizing approaching threats. We probed the neural origins of this stark perceptual anisotropy to reveal how the brain creates privilege for auditory looming events. While recording neural activity via electroencephalography (EEG), human listeners rapidly judged whether dynamic (intensity varying) tones were looming or receding in percept. Behaviorally, listeners responded faster to auditory looms confirming a perceptual bias for approaching signals. EEG source analysis revealed sensory activation localized to primary auditory cortex (PAC) and decision-related activity in prefrontal cortex (PFC) within 200 ms after sound onset followed by additional expansive PFC activation by 500 ms. Notably, early PFC (but not PAC) activity rapidly differentiated looming and receding stimuli and this effect roughly co-occurred with sound arrival in auditory cortex. Brain-behavior correlations revealed an association between PFC neural latencies and listeners' speed of sonic motion judgments. Directed functional connectivity revealed stronger information flow from PFC → PAC during looming vs. receding sounds. Our electrophysiological data reveal a critical, previously undocumented role of prefrontal cortex in judging dynamic sonic motion. Both faster neural bias and a functional override of obligatory sensory processing via selective, directional PFC signaling toward auditory system establish the perceptual privilege for approaching looming sounds.


The influence of do-not-resuscitate status on the outcomes of patients undergoing emergency vascular operations.
Do-not-resuscitate (DNR) orders allow patients to communicate their wishes regarding cardiopulmonary resuscitation. Although DNR status may influence physician decision making regarding resuscitation, the effect of DNR status on outcomes of patients undergoing emergency vascular operation remains unknown. The aim of this study was to analyze the effect of DNR status on the outcomes of emergency vascular surgery. The National Surgical Quality Improvement Program database was queried to identify all patients requiring emergency vascular surgical interventions between 2005 and 2010. Demographics, clinical data, and outcomes were extracted. Patients were compared according to DNR status. The primary outcome measure was 30-day mortality. During the study period, 16,678 patients underwent emergency vascular operations (10.8% of the total vascular surgery population). Of those, 548 patients (3.3%) had a DNR status. The differences in rates of open or endovascular repair or of intraoperative blood requirement between the two groups were not significant. After adjusting for differences in demographics and clinical data, DNR patients were more likely to have higher rates of graft failure (8.7% vs 2.4%; adjusted P < .01) and failure to wean from mechanical ventilation (14.9 % vs 9.9%; adjusted P < .001). DNR status was associated with a 2.5-fold rise in 30-day mortality (35.0% vs 14.0%; 95% confidence interval, 1.7-2.9; adjusted P < .001). The presence of a DNR order was independently associated with mortality. Patient and family counseling on surgical expectations before emergency vascular operations is warranted because the risks of perioperative events are significantly elevated when a DNR order exists.


Prediction of Fuhrman grade of renal clear cell carcinoma by multimodal MRI radiomics: a retrospective study.
To explore the value of multimodal magnetic resonance imaging (MRI) radiomics combined with traditional radiologist-defined semantic characteristics and conventional (cMRI) and functional MRI (fMRI) texture features in predicting Fuhrman grade of clear cell renal cell carcinoma (ccRCC). The data of 89 patients with histopathologically proven ccRCC (low-grade, 54; high-grade, 35) were collected. Texture features were extracted from cMRI (T1- and T2-weighted imaging) and fMRI (Dixon-MRI; blood-oxygen-level dependent [BOLD]-MRI; and susceptibility-weighted imaging [SWI]) images, and the traditional characteristics (TC) were evaluated. Logistic regression analysis was performed to develop models based on TC, cMRI, and fMRI texture features for grading. Receiver operating characteristic (ROC) curve analysis and leave-group-out cross-validation (LGOCV) were performed to test the reliability of combined models. Two T2-weighted imaging-based, two Dixon_W-based, one Dixon_F-based, one BOLD-based, and three SWI-based texture features, and three TC were extracted for feature selection. TC, cMRI, fMRI, cMRI+fMRI, cMRI+TC, fMRI+TC, and cMRI+fMRI+TC models were constructed. The AUC of the cMRI+fMRI+TC model for differentiating high- from low-grade ccRCC was 0.74, with 81.42% accuracy, 75.93% sensitivity, and 91.43% specificity. The fMRI+TC model exhibited a performance similar to that of the cMRI+fMRI+TC model (p>0.05). The areas under the curve (AUCs) of the fMRI+TC and cMRI+fMRI+TC models were significantly higher than those of the other five models (all p<0.05). For the cMRI+fMRI+TC model, the mean accuracy was 85.40% after 100 LGOCV for the test sets. Multimodal MRI radiomics combined with TC, cMRI, and fMRI texture features may be a reliable quantitative approach for differentiating high-grade ccRCC from low-grade ccRCC.


Justice at any cost? The impact of cost-benefit salience on criminal punishment judgments.
This study investigated the effect of cost-benefit salience on simulated criminal punishment judgments. In two vignette-based survey experiments, we sought to identify how the salience of decision costs influences laypeople's punishment judgments. In both experiments (N1 = 109; N2 = 398), undergraduate participants made sentencing judgments with and without explicit information about the direct, material costs of incarceration. Using a within-subjects design, Experiment 1 revealed that increasing the salience of incarceration costs mitigated punishments. However, when costs were not made salient, punishments were no lower than those made when the costs were externalized (i.e., paid by a third party). Experiment 2 showed the same pattern using a between-subjects design. We conclude that, when laypeople formulate sentencing attitudes without exposure to the costs of the punishment, they are prone to discount those costs, behaving as if punishment is societally cost-free. However, when cost information is salient, they utilize it, suggesting the operation of a genuine, albeit labile, punishment preference. We discuss the implications of these findings for psychological theories of decision making and for sentencing policy, including the degree of transparency about the relevant costs of incarceration during the decision process.


Relationship between race and mortality and morbidity after valve replacement surgery.
Previous studies have shown that black race is an independent predictor of increased operative mortality after coronary artery bypass surgery. Given the higher incidence of hypertension and hypertension-associated left ventricular hypertrophy in blacks, we hypothesized that black race might be associated with increased risk of mortality and morbidity after aortic valve replacement (AVR) or mitral valve replacement (MVR). We could not identify a previous study that used a multivariable model to evaluate the association between race and operative mortality after AVR or MVR. The Society of Thoracic Surgeons National Cardiac Database was used for a retrospective review of 3137 black and 46,249 white patients who underwent MVR alone or AVR alone from 1999 through 2002. Multivariate logistic regression was used to assess the association between race and mortality and 6 other adverse outcomes (stroke, renal failure, prolonged ventilation, prolonged postoperative stay, sternal infection, and bleeding) after adjustment for covariates. Unadjusted operative mortality for MVR only was 5.60% for blacks versus 6.18% for whites (OR 0.90 [95% CI 0.71 to 1.14]) and 4.60% for blacks versus 3.62% for whites for AVR only (OR 1.28 [95% CI 1.02 to 1.62]). After adjustment for other risk factors, black race was not a significant predictor of operative mortality after AVR or MVR; however, black race was associated with an increased risk of several complications: prolonged ventilation after AVR or MVR, postoperative stay >14 days after AVR or MVR, reoperation for bleeding after AVR, and postoperative renal failure after MVR. There was no significant association between race and the risk of stroke or deep sternal wound infection for either AVR or MVR. In contrast to previously published results that defined race as an independent risk factor for operative mortality after coronary artery bypass surgery, race does not appear to be a significant predictor of operative mortality after isolated AVR or MVR; however, there is evidence of an association between race and certain complications.


MRI of impingement syndromes of the shoulder.
The diagnosis of shoulder impingement is primarily a clinical one. Imaging has a role in assisting clinicians in developing a treatment strategy by identifying and characterizing the cause of shoulder impingement. In this review, the relevant anatomy, cause/pathomechanics, clinical features, and magnetic resonance imaging (MRI) findings of the different types of impingement syndromes are presented.


Musculoskeletal Pain in Patients With Chronic Myeloid Leukemia After Tyrosine Kinase Inhibitor Therapy Cessation.
Clinical trials have shown that for some patients with chronic myeloid leukemia in chronic phase receiving tyrosine kinase inhibitors (TKIs), treatment-free remission (TFR) is achievable and safe. TFR is now a treatment goal for select patients who have experienced a sustained deep molecular response. An expected result of TFR would be a decrease in the frequency or intensity of adverse events (AEs) associated with TKI therapy. Unexpectedly, however, some clinical trials have reported new or worsening AEs, typically described as musculoskeletal pain, in patients attempting TFR. These AEs are hypothesized to be a TKI withdrawal syndrome, although the underlying mechanism is not known. Overall, musculoskeletal pain has been reported in approximately 20% to 30% of patients attempting TFR and is typically transient and easily managed. TKI cessation would be expected to improve patients' quality of life (QOL); however, in studies assessing QOL, patients have reported little change after ceasing TKI therapy, perhaps because they must tolerate long-term TKI therapy before they can attempt TFR. Here we review reports of musculoskeletal pain during TFR and changes in QOL after TKI cessation in clinical trials. As more patients attempt TFR in routine practice, the health care community will play an important role in helping these patients understand the benefits and risks of TFR, the effect it may have on their QOL, and the potential for musculoskeletal pain.


Effect of Vitamin E in Prevention of Intraventricular Hemorrhage in Preterm Neonates.
Germinal matrix-intraventricular hemorrhage (IVH) is the most common brain hemorrhage in preterm neonates. The importance of this hemorrhage lies in its severe complications. There is no definite treatment for IVH in neonates; therefore, the prevention of IVH should be considered. Some studies have shown that Vitamin E can probably decrease the risk of IVH and the other study has not shown its efficacy. The aim of this study is to evaluate the effects of Vitamin E on incidence and severity of IVH in preterm neonates. This study is a randomized clinical trial conducted on 76 neonates with gestational age of ≤30 weeks in the Isfahan University of Medical Science. The neonates were divided into two groups. The group one was administered with 10 units of Vitamin E for 3 days and the second group with placebo. In the 4th and 7th days after birth, brain sonography was conducted to evaluate IVH. The presence of sepsis, incidence of necrotizing enterocolitis, and hypotension were examined. In this study, 76 neonates with the mean age of 28.49 ± 1.46 weeks participated. The incidence of hemorrhage in the 4th day was 26.3% in cases and 42.1% in controls with no significant difference (P = 0.3). The findings of the second sonography reported the incidence of IVH in 17.1% of cases and 36.8% of control group. Based on findings of the current study, Vitamin E use did not significantly decrease IVH in neonates. Further studies with larger sample size are needed.


Myelopathy due to ossification or calcification of the ligamentum flavum: radiologic and histologic evaluations.
The clinical, radiologic, and histologic features of ossification and calcification of the ligamentum flavum were studied in 18 patients. Ossification (15 patients) usually occurred in the lower thoracic spine in men of various ages, while calcification (three patients) was found exclusively in the cervical region of older women. Histologic examinations of ossification showed mature lamellar bone associated with proliferated cartilage replacing the ligamentum flavum (endochondral ossification). This corresponded well with radiographic and computed tomographic (CT) appearances. In the cases with calcification of the ligamentum flavum, calcification within the degenerated ligamentous fibers was observed on histologic examination, and correlated well with an oval nodular density on radiographs and CT. The two conditions differ in clinical, radiologic, and histologic considerations. Pathomechanisms in the development of these lesions and clinical significance are also discussed.


Multi-UAV Collaborative Search and Attack Mission Decision-Making in Unknown Environments.
To address the challenge of coordinated combat involving multiple UAVs in reconnaissance and search attacks, we propose the Multi-UAV Distributed Self-Organizing Cooperative Intelligence Surveillance and Combat (CISCS) strategy. This strategy employs distributed control to overcome issues associated with centralized control and communication difficulties. Additionally, it introduces a time-constrained formation controller to address the problem of unstable multi-UAV formations and lengthy formation times. Furthermore, a multi-task allocation algorithm is designed to tackle the issue of allocating multiple tasks to individual UAVs, enabling autonomous decision-making at the local level. The distributed self-organized multi-UAV cooperative reconnaissance and combat strategy consists of three main components. Firstly, a multi-UAV finite time formation controller allows for the rapid formation of a mission-specific formation in a finite period. Secondly, a multi-task goal assignment module generates a task sequence for each UAV, utilizing an improved distributed Ant Colony Optimization (ACO) algorithm based on Q-Learning. This module also incorporates a colony disorientation strategy to expand the search range and a search transition strategy to prevent premature convergence of the algorithm. Lastly, a UAV obstacle avoidance module considers internal collisions and provides real-time obstacle avoidance paths for multiple UAVs. In the first part, we propose a formation algorithm in finite time to enable the quick formation of multiple UAVs in a three-dimensional space. In the second part, an improved distributed ACO algorithm based on Q-Learning is introduced for task allocation and generation of task sequences. This module includes a colony disorientation strategy to expand the search range and a search transition strategy to avoid premature convergence. In the third part, a multi-task target assignment module is presented to generate task sequences for each UAV, considering internal collisions. This module provides real-time obstacle avoidance paths for multiple UAVs, preventing premature convergence of the algorithm. Finally, we verify the practicality and reliability of the strategy through simulations.


Clinical research in breast surgery: reduction and postmastectomy reconstruction.
In the last decade, entirely new techniques in breast reduction and reconstruction have evolved. What remains unclear is whether or not these new procedures, some of which carry additional surgical risk and cost, are superior from a patient perspective. Thus, plastic surgeons are ever more reliant on clinical research to provide high-level evidence to facilitate clinical decision-making, as well as policy negotiations and advocacy. This article provides an overview of the strengths and weaknesses of different study designs, the appropriateness of various outcome measures, and the importance of establishing a strong evidence base in breast surgery.


[Inhibition of free-radical lipid oxidation in the mechanisms of immediate and long-term adaptation to stress].
The literary data and own results concerning the stages of free radical lipid oxidation inhibition during the adaptation of animals to stress are reviewed. Using the chronic stress models such as immobilization, experimental neurosis, it has been shown, that in general adaptation syndrome the stage of permanent adaptation to stress corresponds to a permanent inhibition of free radical processes in animal tissues. This stage is accompanied by the activation of superoxide radical scavenging and corresponding changes of lipid composition. similar results are obtained on the model of the development of permanent compensation processes after brain injury. Studying the acute stress it has been found, that during first minutes the inhibition of lipid peroxidation which precedes its further activation takes place. This stage corresponds to the realization of urgent adaptation phase to stress. The role of inhibition of free radical processes in mechanisms of urgent and permanent adaptation to stress is under discussion.


[Nonparametric method of determining the RBE coefficients of accelerated charged particles by the incidence of neoplasms in rats].
The nonparametric method was used to determine RBE coefficients of accelerated charged particles (helium ions of 4 GeV/nucleon and 645 MeV protons) by the incidence of tumors localized in different rat organs or by the absence of tumors. The nonparametric method permitted to find the dose dependence of the RBE coefficients and to make statistical analysis of the results obtained with due regard for come features of developing damages which were not revealed by conventional methods of determining RBE coefficients.


Endoprosthetic reconstructions: results of long-term followup of 139 patients.
Our primary goal in doing this study was to determine the effect of prosthesis location, patient age, periprosthetic infection, and primary versus revision placement on endoprosthetic survival. We also examined our endoprosthetic survival rates and reasons for failure. We retrospectively studied 139 endoprosthetic reconstructions performed between 1984 and 2002, including 57 distal femur, 27 proximal femur, 26 proximal tibia, 17 proximal humerus, 4 distal humerus, 3 total scapula, 3 total femur, and 2 total humerus reconstructions. Location of reconstruction and presence of periprosthetic infection significantly affected endoprosthetic survival. Survival was not affected by patient age or primary versus revision placement. Overall, Kaplan-Meier event-free endoprosthetic survival was 86%, 80%, and 69% at 3, 5, and 10-year followup. The trend for endoprosthetic survival from best to worst was proximal femur, proximal humerus, distal femur, proximal tibia, and distal humerus. Reasons for failure included mechanical failure (eight patients), tumor recurrence (eight patients), aseptic loosening (six patients), dislocation (two patients), periprosthetic infection (two patients), and endoprosthetic malalignment (one patient). Our periprosthetic infection rate was 2.2%. The local recurrence rate in patients treated for primary malignant tumors was 6.8%, similar to previous limb-salvage and amputation studies. Overall, we have found that endoprosthetic reconstruction is a reliable limb-salvage technique. Therapeutic study, Level IV-2 (case series). See the Guidelines for Authors for a complete description of levels of evidence.


Electroacupuncture Stimulation Alleviates Inflammatory Pain in Male Rats by Suppressing Oxidative Stress.
In the present study, we focused on whether the analgesic effect of Electroacupuncture (EA) is related to the regulation of oxidative stress. We established a chronic inflammatory pain model in male rats by a single injection of complete Freund's adjuvant (CFA) and then treated the animals with daily EA stimulation at the site of "zusanli". The analgesic effect of EA was evaluated by measuring the paw withdrawal threshold (PWT) when rats received mechanical and thermal pain stimulation. The levels of inflammation-related molecules and oxidative stress-related markers in the spinal cord were measured by western blotting or ELISA kits. EA stimulation and antioxidants effectively increased the PWT in CFA rats. Co-treatment of CFA rats with the ROS donor t-butyl hydroperoxide (t-BOOH) further decreased the PWT and weakened the analgesic effect of EA. EA treatment inhibited inflammation and oxidative stress, as shown by decreased levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and MDA and increased activity of SOD and catalase. Moreover, EA reduced the expression of p-p38, p-ERK, and p-p65 and simultaneously downregulated the expression of TRPV1 and TRPV4 in CFA rats. In an in vitro study, direct stimulation with t-BOOH to the C6 cells increased the production of TNF-alpha, IL-1beta, IL-6, activated p38, ERK, and p65 and up-regulated the expression of TRPV1 and TRPV4, and these effects could be prevented by the ROS scavenger PBN. Taken together, our data indicate that the inhibition of oxidative stress and the generation of ROS contribute to the analgesic effect of EA in male CFA rats.


Cortical contribution to sensory volleys recorded at thalamic nuclei of lemniscal and paralemniscal pathways.
In order to elucidate the role of cortical input on sensory information processing in different thalamic somatosensory nuclei we recorded potentials evoked (EPs) by whisker deflections of short duration from ventral posteromedial (VPm) and medial posterior (POm) nuclei while manipulating cortico-thalamic activity by means of local cooling, lidocaine application or electrical stimulation. It appeared that only the earliest sub-component of the first negative wave of the EPs resulted from peripheral input, while the rest of the potential's negativity depended on cortical feedback. The latencies and amplitudes of EPs recorded at both nuclei were not significantly different, which might be attributed to urethane anesthesia.


Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes.
The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. We identified two 9p21.3-variants, rs4977574 (P < 4×10(-4)) and rs2383207 (P < 1.5×10(-3)) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82×10(-2). Further investigation showed that rs10738610 (P < 1.99×10(-2)) was found to be significantly associated with severity of CAD in subjects with T2D. The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.


Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia.
Clozapine is the drug of choice for treatment-resistant schizophrenia. However, its use is associated with variable clinical responses and serious adverse effects. Polymorphisms in genes encoding proteins involved in synaptic neurotransmission may account for such variability. Here, we studied independent and epistatic genetic associations of polymorphisms in DRD4 (120-bp duplication) and COMT (Val158Met) with clinical response to clozapine in people with treatment-resistant schizophrenia. We studied 93 participants who were on stable doses of clozapine for at least 12 weeks. A total score of less than or equal to 35 on the Brief Psychiatric Rating Scale was defined as a clinical response. The genetic associations were tested using logistic regression analyses. Neither polymorphism studied was found to be independently associated with response to clozapine. However, a statistically significant gene-gene interaction was observed between the polymorphisms. Participants with the COMT Val/Met or Met/Met genotype, who also had one or two DRD4 120-bp alleles (120/240 and 120/120), showed significantly better clinical response to clozapine. Our results highlight the importance of investigating gene-gene interactions, while studying the pharmacogenetics of clozapine.


The role of CTLA-4 in regulating Th2 differentiation.
To examine the role of CTLA-4 in Th cell differentiation, we used two newly generated CTLA-4-deficient (CTLA-4-/-) mouse strains: DO11. 10 CTLA-4-/- mice carrying a class II restricted transgenic TCR specific for OVA, and mice lacking CTLA-4, B7.1 and B7.2 (CTLA-4-/- B7.1/B7.2-/- ). When purified naive CD4+ DO11.10 T cells from CTLA-4-/- and wild-type mice were primed and restimulated in vitro with peptide Ag, CTLA-4-/- DO11.10 T cells developed into Th2 cells, whereas wild-type DO11.10 T cells developed into Th1 cells. Similarly, when CTLA-4-/- CD4+ T cells from mice lacking CTLA-4, B7. 1, and B7.2 were stimulated in vitro with anti-CD3 Ab and wild-type APC, these CTLA-4-/- CD4+ T cells produced IL-4 even during the primary stimulation, whereas CD4+ cells from B7.1/B7.2-/- mice did not produce IL-4. Upon secondary stimulation, CD4+ T cells from CTLA-4-/- B7.1/B7.2-/- mice secreted high levels of IL-4, whereas CD4+ T cells from B7.1/B7.2-/- mice produced IFN-gamma. In contrast to the effects on CD4+ Th differentiation, the absence of CTLA-4 resulted in only a modest effect on T cell proliferation, and increased proliferation of CTLA-4-/- CD4+ T cells was seen only during secondary stimulation in vitro. Administration of a stimulatory anti-CD28 Ab in vivo induced IL-4 production in CTLA-4-/- B7.1/B7.2-/- but not wild-type mice. These studies demonstrate that CTLA-4 is a critical and potent inhibitor of Th2 differentiation. Thus, the B7-CD28/CTLA-4 pathway plays a critical role in regulating Th2 differentiation in two ways: CD28 promotes Th2 differentiation while CTLA-4 limits Th2 differentiation.


Cost Effectiveness of the Oncotype DX Genomic Prostate Score for Guiding Treatment Decisions in Patients With Early Stage Prostate Cancer.
To determine the cost-effectiveness of using the Oncotype DX Genomic Prostate Score (GPS), a 17-gene expression assay that can be used to inform decisions regarding active surveillance (AS) vs immediate treatment. We developed a Markov model simulating 20-year outcomes for 65-year-old men with very low-, low-, or favorable intermediate-risk prostate cancer undergoing AS vs immediate treatment using GPS vs no testing. Utilities, costs, and probabilities were extracted from the literature and National Medicare Fee Schedules to determine incremental cost-effectiveness ratios (ICER) from a payer perspective. In the overall cohort, the ICER of GPS-guided therapy was $31,394 per quality-adjusted life-year (QALY). When stratified by risk group, the ICER was $25,343 per QALY in very low-risk, $28,911 per QALY in low-risk, and $39,695 per QALY in favorable intermediate-risk patients. On sensitivity analysis, findings were robust against a willingness-to-pay of $100,000 per QALY to variations in key model parameters, including the cost of annual management of AS, probability of exiting AS to treatment, cost of treatment, and probability of biochemical failure post-treatment. However, the cost-effectiveness was sensitive to small differences in the utility of AS and the utility of no evidence of disease post-treatment states. The use of the GPS was cost-effective in guiding treatment decisions regarding AS vs immediate treatment. The cost-effectiveness was sensitive to small differences in the utilities of the AS and no evidence of disease post-treatment states, highlighting the importance of assessing patient preferences.


Photoacoustic lifetime imaging of dissolved oxygen using methylene blue.
Measuring distribution of dissolved oxygen in biological tissue is of prime interest for cancer diagnosis, prognosis, and therapy optimization. Tumor hypoxia indicates poor prognosis and resistance to radiotherapy. Despite its major clinical significance, no current imaging modality provides direct imaging of tissue oxygen. We present preliminary results demonstrating the potential of photoacoustic lifetime imaging (PALI) for noninvasive, 3-D imaging of tissue oxygen. The technique is based on photoacoustic probing of the excited state lifetime of methylene blue (MB) dye. MB is an FDA-approved water soluble dye with a peak absorption at 660 nm. A double pulse laser system (pump probe) is used to excite the dye and probe its transient absorption by detecting photoacoustic emission. The relaxation rate of MB depends linearly on oxygen concentration. Our measurements show high photoacoustic signal contrast at a probe wavelength of 810 nm, where the excited state absorption is more than four times higher than the ground state absorption. Imaging of a simple phantom is demonstrated. We conclude by discussing possible implementations of the technique in clinical settings and combining it with photodynamic therapy (PDT) for real-time therapy monitoring.