Interventions to decrease the risk of adverse cardiac events for post-surgery or chemotherapy patients taking serotonin (5-HT3) receptor antagonists: protocol for a systematic review and network meta-analysis.
Patients undergoing surgery or chemotherapy often experience nausea and vomiting. To increase their quality of life and treatment satisfaction, antiemetic medication, such as serotonin receptor antagonists, is often prescribed for patients experiencing these symptoms. However, early warning signs suggest that serotonin receptor antagonists can cause harm, including arrhythmia. Our objective is to identify the most effective interventions that mitigate the risk of adverse cardiac events associated with serotonin receptor antagonists in patients undergoing surgery and chemotherapy through a systematic review and network meta-analysis. We will search electronic databases (for example, MEDLINE, Embase) from inception onwards, as well as dissertations and governmental reports, to identify interventions (for example, telemetry, electrocardiography, electrolyte monitoring) that decrease the cardiac risk associated with serotonin receptor antagonists among surgery and chemotherapy patients. Eligible comparators include placebo or supportive care; eligible study designs are experimental studies (randomized controlled trials (RCTs), quasi-RCTs, non-RCTs), non-experimental studies (interrupted time series, controlled before-and-after studies), and cohort studies. Outcomes of interest include arrhythmia, sudden cardiac death, QT prolongation, PR prolongation, and all-cause mortality. We will include unpublished studies and studies published in languages other than English.Draft inclusion and exclusion criteria will be established and pilot tested amongst the team. Subsequently, two team members will screen the results in duplicate and resolve conflicts through discussion. The same process will be followed to screen full-text articles, data abstraction, and appraise quality or risk of bias. To determine validity of results, experimental and quasi-experimental studies will be assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias tool, while cohort studies will be appraised using the Newcastle-Ottawa Scale. We anticipate sufficient data and homogeneity to conduct random effects meta-analysis and network or mixed treatment comparisons meta-analysis, if appropriate. Our results will provide information regarding the utility of different strategies that can be used to mitigate cardiac risk amongst patients taking serotonin antagonist receptors. Such results are likely to be of use to clinicians prescribing these agents, as well as policy makers responsible for making decisions about antiemetic medications. PROSPERO registry number: CRD42013003565.


The effect of carbon dioxide on growth of juvenile Atlantic cod Gadus morhua L.
A trial was undertaken to investigate how exposure to graded hypercapnia affected the growth performance of juvenile (15-80 g) Atlantic cod. Juveniles were grown at 20‰ salinity and 10°C for 55 days under three hypercapnic regimes: low (2±0.9 mg L(-1) CO(2), 0.6mm Hg, 1000 μatm), medium (8±0.5 mg L(-1) CO(2), 2.8mm Hg, 3800 μatm) and high CO(2) exposure (18±0.2 mg L(-1) CO(2), 6.3mm Hg, 8500 μatm). All water quality parameters were within the range of what might normally be considered acceptable for good growth, including the CO(2) levels tested. Weight gain, growth rate and condition factor were substantially reduced with increasing CO(2) dosage. The size-specific growth trajectories of fish reared under the medium and high CO(2) treatments were approximately 2.5 and 7.5 times lower (respectively) than that of fish in the low treatment. Size variance and mortality rate was not significantly different amongst treatments, indicating that there was no differential size mortality due the effects of hypercapnia, and the CO(2) levels tested were within the adaptive capacity of the fish. In addition, an analysis was carried out of the test CO(2) concentrations reported in three other long-term hypercapnia experiments using marine fish species. The test concentrations were recalculated from the reported carbonate chemistry conditions, and indicated that the CO(2) concentration effect threshold may have been overestimated in two of these studies. Our study suggests that juvenile Atlantic cod are more susceptible to the chronic effects of environmental hypercapnia than other marine fish examined to date.


[The microwave resonance therapy of reflux esophagitis].
The authors investigated the efficacy of microwave resonance therapy of 180 patients with reflux esophagitis. The clinical positive effect in the group receiving microwave resonance therapy was 98.46 +/- 1.08% as compared with 80.00 +/- 5.66% in those treated without microwave resonance therapy and receiving only traditional treatment.


[The "direct mitogen" lead nitrate causes an intensification in lipid peroxidation and Ito cell activation in the rat liver].
We have used biochemical and immunohistochemical methods to study lipid peroxidation and activation of Ito cells in rat liver after a single administration of lead nitrate, a "direct mitogen". Lead nitrate was shown to injure hepatocytes through an increased lipid peroxidation. Response to the injury included increase in the proliferative activity of parenchymal and sinusoidal liver cells. In addition, activation of Ito cells has been noted, which manifested as increased expression of desmin and increased proliferation. However, no transformation of Ito cells into myofibroblasts has been observed. We discuss the possible role of Ito cell activation in creating conditions for the proliferation of liver parenchymal cells after the injury by lead nitrate.


[Renal metastases of a squamous cell carcinoma of the lung. Case report and bibliographic review].
We report a new case of renal metastasis of a lung carcinoma. 59-year-old male presenting to the outpatient clinic with a clinical picture compatible with renal colic and hematuria. Ultrasound showed a solid-cystic tumor in the lower pole of the kidney without hydronephrosis. Abdominal-pelvic CT scan reported retroperitoneal adenopathies > 1 cm in the area of the aorta-cava and a 5 cm heterogeneous mass. Renal metastatic lesions of patients with lung cancer present more frequently due to the higher accuracy of radiological tests and have, as well as the primary tumors, very poor survival rates.


A family with diabetes and heart failure.
The case of a middle-aged woman with early-onset diabetes mellitus, hypertrophic cardiomyopathy, premature sensorineural hearing loss and neuropsychiatric symptoms is described. The patient's family history revealed the classical pattern of maternally inherited diabetes and deafness (MIDD) and isolation of mitochondrial DNA from peripheral blood leucocytes showed an A3243G transition in the gene encoding for the tRNA(Leu(UUR)). Thus, the suspected diagnosis of a mitochondrial disorder was confirmed. Cardiac involvement turned out to be the dominating clinical feature in the patient. She died of cardiogenic shock and multiple organ failure within 1 year of diagnosis. Three out of nine affected family members had hypertrophic cardiomyopathy.


[Parathyrotoxic encephalopathy without hypercalcemia].
Two patients with severe, repeated confusional episodes of apparent fluctuating dementia type, and electroencephalographic alterations (permanent, diffuse slow waves) on recordings, were found to have elevated parathormonemia and slightly raised or normal levels of calcemia. The only other sign of hyperparathyroidism was intermittent hypophosphoremia. Exploratory cervicotomy identified a parathyroid microadenoma in one case and a parathyroid adenoma in the other. Recovery of intellectual functions was slow but complete. The possible direct role of parathormone in the genesis of this parathyrotoxic encephalopathy is discussed.


Functional inactivation of wild-type p53 protein correlates with loss of IL-2 dependence in HTLV-I transformed human T lymphocytes.
Human T cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T cell leukemia (ATL) transforms human T cells in vitro and in vivo. Tax, the major transactivator of HTLV-I is critical for the initial events involved in transformation, however, the later steps required for progression from an IL-2 dependent state to one of IL-2 independence remain to be clarified. We investigated the potential role of p53 protein in this process employing several IL-2 dependent and independent HTLV-I transformed cell lines. All cell lines examined were found to be wild-type in the p53 coding region usually associated with inactivating mutations using RT-PCR-SSCP analysis and DNA sequencing. Levels of p53 protein were consistently higher in IL-2 independent lines compared to IL-2 dependent ones. Lack of functional p53 activity was observed only in IL-2 independent cell lines using a transfection assay with a B-galactosidase reporter gene construct responsive to wild-type p53 protein. Increased steady state levels of wild-type p53 protein associated with its functional inactivation appear to be linked to the loss of IL-2 dependent growth in HTLV-I transformed lymphocytes.


Unicompartmental knee replacement. A minimum 15 year followup study.
One hundred forty Marmor cemented unicompartmental knee replacements were inserted in 103 patients between 1975 and 1982. Fifty-two patients were women and 51 were men. One hundred twenty-five were medial compartment knee replacements and 15 were lateral knee replacements. At minimum 15 year followup 34 patients with 48 knee replacements were living; only four patients with four knee replacements were lost to followup. Average preoperative and final followup Hospital for Special Surgery knee scores were 57 and 82 points, respectively for the knees of living patients. Average preoperative and final followup Knee Society clinical and Knee Society functional scores were 31 and 42, and 85 and 71 points, respectively. For all knees, 10.2% (14 knees) were revised [4.4% (six knees) for tibial loosening, 5.1% (seven knees) for disease progression, and .7% (one knee) for pain]. For patients living 15 years, 12.5% (six knees) were revised [2.1% (one knee) for tibial loosening, and 10.4% (five knees) for disease progression]. Revision for failure of fixation of these unicompartmental replacements was comparable with that reported for fixed bearing total knee replacement. Disease progression (46%; 62 of 136 knees) and tibial subsidence with wear (10.4%; 15 of 136 knees, five of which required revision) were the major long term problems in this group of patients.


Risk Factors Associated With 90-Day Readmissions After Degenerative Lumbar Fusion: An Examination of the Michigan Spine Surgery Improvement Collaborative (MSSIC) Registry.
Most studies have evaluated 30-d readmissions after lumbar fusion surgery. Evaluation of the 90-d period, however, allows a more comprehensive assessment of factors associated with readmission. To assess the reasons and risk factors for 90-d readmissions after lumbar fusion surgery. The Michigan Spine Surgery Improvement Collaborative (MSSIC) registry is a prospective, multicenter, and spine-specific database of patients surgically treated for degenerative disease. MSSIC data were retrospectively analyzed for causes of readmission, and independent risk factors impacting readmission were found by multivariate logistic regression. Of 10 204 patients who underwent lumbar fusion, 915 (9.0%) were readmitted within 90 d, most commonly for pain (17%), surgical site infection (16%), and radicular symptoms (10%). Risk factors associated with increased likelihood of readmission were other race (odds ratio [OR] 1.81, confidence interval [CI] 1.22-2.69), coronary artery disease (OR 1.57, CI 1.25-1.96), ≥4 fused levels (OR 1.41, CI 1.06-1.88), diabetes (OR 1.34, CI 1.10-1.63), and surgery length (OR 1.09, CI 1.03-1.16). Factors associated with decreased risk were discharge to home (OR 0.63, CI 0.51-0.78), private insurance (OR 0.79, CI 0.65-0.97), ambulation same day of surgery (OR 0.81, CI 0.67-0.97), and spondylolisthesis diagnosis (OR 0.82, CI 0.68-0.97). Of those readmitted, 385 (42.1%) patients underwent another surgery. Ninety-day readmission occurred in 9.0% of patients, mainly for pain, wound infection, and radicular symptoms. Increased focus on postoperative pain may decrease readmissions. Among factors impacting the likelihood of 90-d readmission, early postoperative ambulation may be most easily modifiable. Optimization of preexisting medical conditions could also potentially decrease readmission risk.


Quality assessment: is the focus on providers or on patients?
Most studies of ambulatory care quality are based on chart reviews of episodes of care in single settings, rather than on care received by a patient over time and across settings. The purpose of this study was to compare ambulatory care quality scores based on information from the usual source of care to scores based on information from all providers seen during a year. The quality of well child care for 55 two-year-olds and asthma care for 70 children and adults continuously enrolled in the Maryland Medicaid program throughout 1988 was assessed. Combining data from multiple providers changed quality scores in both directions. For well child care, quality scores generally improved because of an increased opportunity to perform desirable actions, such as lead screening. However, quality scores for asthma care generally decreased because undesirable clinician actions, such as the failure to document follow-up plans, increased as more problems were uncovered. Thus, the findings of quality assessments differ according to whether the focus is on care delivered by individual providers or on care received by patients. The direction of the difference will depend upon whether the indicators of quality represent omission of recommended care or commission of improper care.


Identifying new therapeutic targets via modulation of protein corona formation by engineered nanoparticles.
We introduce a promising methodology to identify new therapeutic targets in cancer. Proteins bind to nanoparticles to form a protein corona. We modulate this corona by using surface-engineered nanoparticles, and identify protein composition to provide insight into disease development. Using a family of structurally homologous nanoparticles we have investigated the changes in the protein corona around surface-functionalized gold nanoparticles (AuNPs) from normal and malignant ovarian cell lysates. Proteomics analysis using mass spectrometry identified hepatoma-derived growth factor (HDGF) that is found exclusively on positively charged AuNPs ((+)AuNPs) after incubation with the lysates. We confirmed expression of HDGF in various ovarian cancer cells and validated binding selectivity to (+)AuNPs by Western blot analysis. Silencing of HDGF by siRNA resulted s inhibition in proliferation of ovarian cancer cells. We investigated the modulation of protein corona around surface-functionalized gold nanoparticles as a promising approach to identify new therapeutic targets. The potential of our method for identifying therapeutic targets was demonstrated through silencing of HDGF by siRNA, which inhibited proliferation of ovarian cancer cells. This integrated proteomics, bioinformatics, and nanotechnology strategy demonstrates that protein corona identification can be used to discover novel therapeutic targets in cancer.


Generalized juvenile polyposis coli. Clinical management based on long-term observations.
Generalized juvenile polyposis occurred in five patients (age range, 18 months to 16 years). Clinical findings included abdominal pain, weakness, rectal bleeding, diarrhea, rectal prolapse, intussusception, clubbing, and failure to thrive. Laboratory findings included anemia, hypoalbuminemia, hypokalemia, and skin test anergy. Diagnosis is achieved by double contrast enema, endoscopy, and biopsy. Unlike patients with solitary juvenile polyps, patients with generalized involvement require surgical intervention. Subtotal colectomy and ileoproctostomy are the procedures of choice, and we performed them in four cases. An ileoanal-endorectal pull-through procedure was required in one patient with continued rectal disease. All five patients are currently alive and well. Long-term follow-up is important as polyps may persist into adult life. Family members are at risk for developing gastrointestinal tract tumors and should be screened.


Overexpression of Bcl(XL) in B cells promotes Th1 response and exacerbates collagen-induced arthritis.
B cells play a pathogenic or regulatory role in many autoimmune diseases through production of autoantibodies, cytokine production, and Ag presentation. However, the mechanisms that regulate these B cell functions under different autoimmune settings remain unclear. In the current study, we found that when B cells overexpress an antiapoptotic gene, Bcl(XL), they significantly increased production of IFN-gamma and enhanced Th1 response. Consistently, Bcl-x(L) transgenic mice developed more severe and sustained collagen-induced arthritis due to the enhanced Th1 response. The production of autoantibodies in Bcl(XL) transgenic mice was comparable to that in wild-type mice. Thus, our results indicate a novel role of Bcl(XL) in regulating B cell functions and immune responses. In patients with rheumatoid arthritis, arthritogenic B cells often up-regulate Bcl(XL) expression, which may not only render B cells resistant to apoptosis but also alter the ability of the autoreactive B cells to produce cytokines and modulate the inflammatory response. This may have therapeutic implications if Bcl(XL) expression can be down-regulated in autoreactive B cells.


Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids.
The branched-chain amino acids (BCAA) valine (Val) and isoleucine (Ile) are considered to be among the next-limiting amino acids for growth in piglets. In earlier studies, we estimated the standardized ileal digestible (SID) Val : Lys (lysine) requirement to be at least 70%, whereas the Ile : Lys requirement may be as low as 50%. Because the BCAA partially share a common route of catabolism, the supply of one BCAA may affect the availability of the other BCAA. Four experiments were conducted to determine the response of 6-week-old piglets to the Val supply in relation to the other BCAA. A deficient supply of Val or Ile typically results in a reduction in average daily feed intake (ADFI). Experiment 1 was designed to determine the effect of a limiting Val supply, independent of the effect on feed intake. In a dose-response study using restrictively fed piglets, nitrogen retention did not increase for an SID Val : Lys supply greater than 64%. In the remaining experiments, piglets were offered feed ad libitum using ADFI, average daily gain (ADG) and gain-to-feed ratio as response criteria. The interaction between the Val and leucine (Leu) was studied in Experiment 2 in a 2 × 2 factorial design (60% and 70% SID Val : Lys, and 111% and 165% SID Leu : Lys). Performance was considerably lower in piglets receiving 60% Val : Lys compared with those receiving 70% Val : Lys and was lowest in piglets receiving the diet with low Val and high Leu content. To further evaluate the interaction between Val and Leu, a dose-response study was carried out in which the response to Val supply was studied in combination with high Leu supply (165% Leu : Lys). Using a curvilinear-plateau model, the average SID Val : Lys requirement was 72%. However, low Val supply (60% SID Val : Lys) reduced performance by 13% to 38%, which was much greater than what we observed in earlier studies. Experiment 4 was carried out to test the hypothesis that the Val requirement is not affected by low Ile supply (50% SID Ile : Lys). Performance was not improved for Val : Lys supplies greater than 65%, which may indicate that Ile (and not Lys) was second-limiting in this study. In conclusion, the first response of piglets to deficient Val supply appears to be a reduction in ADFI, rather than a reduction in ADG or nitrogen retention. A large supply of Leu may not affect the Val requirement per se, but may aggravate the consequences of Val deficiency.


A review of correlates of physical activity of children and adolescents.
Understanding the factors that influence physical activity can aid the design of more effective interventions. Previous reviews of correlates of youth physical activity have produced conflicting results. A comprehensive review of correlates of physical activity was conducted, and semiquantitative results were summarized separately for children (ages 3-12) and adolescents (ages 13-18). The 108 studies evaluated 40 variables for children and 48 variables for adolescents. About 60% of all reported associations with physical activity were statistically significant. Variables that were consistently associated with children's physical activity were sex (male), parental overweight status, physical activity preferences, intention to be active, perceived barriers (inverse), previous physical activity, healthy diet, program/facility access, and time spent outdoors. Variables that were consistently associated with adolescents' physical activity were sex (male), ethnicity (white), age (inverse), perceived activity competence, intentions, depression (inverse), previous physical activity, community sports, sensation seeking, sedentary after school and on weekends (inverse), parent support, support from others, sibling physical activity, direct help from parents, and opportunities to exercise. These consistently related variables should be confirmed in prospective studies, and interventions to improve the modifiable variables should be developed and evaluated.


Familial hypercholesterolaemia: a study protocol for identification and investigation of potential causes and markers of subclinical coronary artery disease in the Faroe Islands.
Familial hypercholesterolaemia (FH) is the most common monogenic autosomal dominant genetic disorder and is associated with a high risk of premature atherosclerotic cardiovascular disease. The prevalence of FH has been reported to be particularly high in certain founder populations. The population of the Faroe Islands is a founder population, but the prevalence of FH has never been investigated here. We aim to assess the prevalence of FH and to describe the genetic and clinical characteristics and potential causes of FH in the Faroe Islands. Furthermore, we aim to investigate whether indicators of subclinical coronary artery disease are associated with FH. The prevalence of FH will be estimated based on an electronic nationwide laboratory database that includes all measurements of plasma lipid levels in the Faroe Islands since 2006. Subsequently, we will identify and invite subjects aged between 18 and 75 years registered with a plasma low-density lipoprotein cholesterol above 6.7 mmol/L for diagnostic evaluation. Eligible FH cases will be matched to controls on age and sex. We aim to include 120 FH cases and 120 controls.Detailed information will be collected using questionnaires and interviews, and a physical examination will be undertaken. An adipose tissue biopsy and blood samples for genetic testing, detailed lipid analyses and samples for storage in a biobank for future research will be collected. Furthermore, FH cases and controls will be invited to have a transthoracic echocardiography and a cardiac CT performed. The project has been approved by the Ethical Committee and the Data Protection Agency of the Faroe Islands. The project is expected to provide important information, which will be published in international peer-reviewed journals.


[Expression of proliferating cell nuclear antigen of the intestinal mucosa during critical intraperitoneal infection].
To explore the expression and significance of proliferating cell nuclear antigen (PCNA) in intestinal epithelial cells during critical intraperitoneal infection. A total of 60 SD rats were divided randomly to two groups: control group and infection group (30 rats in each group). Cecal ligation and puncture (CLP) was done in the infection group, and laparotomy only in the control group. Immunohistochemical technique was applied for assaying PCNA index of the jejunum and ileum samples on postoperative day 1, day 2 and day 4. The inflammatory reaction of small intestine mucous membrane was severer in the infection group than the control group. Compared with the control group, the PCNA indexes on day 1 and day 2 in the infection group were higher significantly (both P<0.01). The highest PCNA index was seen on postoperative day 1 in the infection group, then it lowered gradually (both P<0.01). The PCNA index of intestinal epithelial cells is elevated during the early period of critical intraperitoneal infection. The findings indicate that PCNA index is related with the injury and repair of intestinal mucosa during critical intraperitoneal infection.


Public stigma against people with mental illness in the Gilgel Gibe Field Research Center (GGFRC) in Southwest Ethiopia.
Public understanding about mental illnesses and attitudes towards people with mental illness (PWMI) play a paramount role in the prevention and treatment of mental illness and the rehabilitation of PWMI. The aim of this study was to measure public stigma against PWMI and the factors associated with stigma in the Gilgel Gibe Field Research Center (GGFRC) in Southwest Ethiopia. This community-based, cross-sectional study was conducted from June to August 2012 among 845 randomly selected respondents by using the Community Attitudes towards the Mentally Ill (CAMI) scale, an interviewer-administered questionnaire. Data was entered with EPI-DATA and then exported to STATA for analysis. Simple descriptive and linear regression analyses were performed to identify predictors of stigma against PWMI. Of the total of 845 respondents, 68.17% were from rural districts. The mean stigma score was 2.62 on a 5-point score. The majority of the respondents (75.27%) believed that mental illness can be cured. Stress, poverty, and rumination were the most often perceived causes of mental illness. Rural residents had significantly higher stigma scores (std. β = 0.61, P<0.001). A statistically significant inverse relationship was found between the level of education and degree of stigma (std. β = -0.14, P<0.01), while higher income was significantly associated with more stigma (std. β = 0.07, P<0.05). Respondents with higher scores for perceived supernatural causes (std. β = -0.09, P<0.01) and perceived psychosocial and biological causes (std. β = -0.14, P<0.001) had significantly lower stigma levels. The study found a more undermining but less avoidant attitude towards PWMI. Rural residents showed higher levels of stigma. Stigma against PWMI was lower in people with an explanatory concept about the causes of mental illness and a higher level of education. Information, education, and communication about the causes, signs, and nature of mental illnesses would help to reduce stigma.


The impact of recurrence of primary glomerulonephritis on renal allograft outcome.
Twenty-yr patient and death-censored graft survival of 348 kidney transplant recipients with primary glomerulonephritis (GN) and of 696 matched controls were 82.2% in GN patients and 75% in controls (p = 0.037) and 49.5% and 54%, respectively (p = 0.013). GN patients had a higher incidence of graft failure than controls even considering death as a competing risk (p = 0.004). In the GN group, graft survival of deceased and of living donor recipients was similar. At multivariate analysis, GN as primary disease (RR: 1.47), delayed graft function recovery (RR: 2.34), acute rejection (RR: 2.36), and any PRA positivity (RR: 1.01) were predictive of graft loss. GN recurred in 85 of 348 grafts (24.4%), and 43 were lost for recurrence. In non-recurrent patients, graft survival at 20 yr was significantly better than in recurrent patients (59.4% vs. 24.4%, p = 0.000), but not different from that of controls (59.4 vs. 54%, p = 0.9). At multivariate analysis, young age at transplantation (RR: 0.97), shorter duration of dialysis (RR: 1.05 per each dialysis year), and graft from living donors (RR: 1.668) were independent predictors of recurrence. Patients with primary GN have reduced graft survival in comparison with controls, and this is mainly due to recurrence of original disease. However, the most frequent recurrence in living recipients does not compromise graft survival.


[Effect of dipyridamole and papaverine on adenosine absorption by the lymphocytes].
It was shown that dipyridamole and papaverine induce concentration-dependent inhibition of the absorption of [14C] adenosine by thymocytes. This action is different in lymphocytes from different lymphoid organs and blood. Dipyridamole enhances the effect of various papaverine concentrations on the absorption of adenosine by thymocytes, but it does not exceed the maximal effect, achieved by the latter in high doses. It is supposed, that dipyridamole inhibits the cell transport of adenosine and papaverine influences the adenine-nucleotide metabolism.


Wideband laser locking to an atomic reference with modulation transfer spectroscopy.
We demonstrate that conventional modulated spectroscopy apparatus, used for laser frequency stabilization in many atomic physics laboratories, can be enhanced to provide a wideband lock delivering deep suppression of frequency noise across the acoustic range. Using an acousto-optic modulator driven with an agile oscillator, we show that wideband frequency modulation of the pump laser in modulation transfer spectroscopy produces the unique single lock-point spectrum previously demonstrated with electro-optic phase modulation. We achieve a laser lock with 100 kHz feedback bandwidth, limited by our laser control electronics. This bandwidth is sufficient to reduce frequency noise by 30 dB across the acoustic range and narrows the imputed linewidth by a factor of five.


A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial.
Aripiprazole and risperidone are the only FDA approved medications for treating irritability in autistic disorder, however there are no head-to-head data comparing these agents. This is the first prospective randomized clinical trial comparing the safety and efficacy of these two medications in patients with autism spectrum disorders. Fifty nine children and adolescents with autism spectrum disorders were randomized to receive either aripiprazole or risperidone for 2 months. The primary outcome measure was change in Aberrant Behavior Checklist (ABC) scores. Adverse events were assessed. Aripiprazole as well as risperidone lowered ABC scores during 2 months. The rates of adverse effects were not significantly different between the two groups. The safety and efficacy of aripiprazole (mean dose 5.5 mg/day) and risperidone (mean dose 1.12 mg/day) were comparable. The choice between these two medications should be on the basis of clinical equipoise considering the patient's preference and clinical profile.


Effect of bisphosphonates on pain and quality of life in patients with bone metastases.
Bone is the most common organ for tumor metastasis, especially in patients with cancers of the breast or prostate. Bone metastases disrupt skeletal metabolism and result in considerable skeletal morbidity, including intractable, chronic bone pain, hypercalcemia of malignancy, pathologic fracture and spinal-cord compression. In addition to the chronic pain caused by bone metastases, skeletal-related events (SREs) such as pathologic fractures and spinal-cord compression can result in acute increases in pain. These effects can severely impair mobility and contribute to a general decrease in quality of life. Palliative options to treat bone metastases include radiotherapy, analgesics, surgery and bisphosphonates. These drugs bind to the surface of the bone and impair osteoclast-mediated bone resorption, and reduce the tumor-associated osteolysis that is initiated by the development of skeletal metastases. In addition to preventing SREs, bisphosphonates can palliate bone pain caused by a variety of solid tumors. This Review summarizes the clinical trial data of bisphosphonates for the prevention of SREs and the palliation of bone pain. Among these agents, nitrogen-containing bisphosphonates are recognized as the most effective, and zoledronic acid has demonstrated the broadest clinical utility.


Tuning the catalytic activity of colloidal noble metal nanocrystals by using differently charged surfactants.
The catalytic activity of metal nanocrystals is mainly tuned through the control of their shapes and sizes. However, the shapes and sizes of many metal nanocrystals are difficult to control and therefore their catalytic activity is hard to tune. Here, we demonstrate another approach, using differently charged surfactants, for tuning the catalytic activity of metal nanocrystals. Au and Pd nanocrystals capped with cationic cetyltrimethylammonium bromide (CTAB) and anionic citrate are chosen to study the effect of surfactant charges on the catalytic activity. The oxidation of o-phenylenediamine to 2,3-diaminophenazine by H2O2 is selected as a model reaction. The prepared Au and Pd nanocrystals are initially capped with CTAB, which is changed to citrate through surfactant exchange. Owing to the relatively weak electrostatic interaction of CTAB with the nanocrystals, the surfactant exchange does not induce observable changes in nanocrystal shapes and sizes. In contrast, the catalytic activity is greatly improved by the surfactant exchange. XPS analysis and theoretical calculations indicate that the adsorption of anionic citrate enriches the electrons of the nanocrystal surfaces, while the adsorption of CTAB depletes the electrons of the nanocrystal surfaces. The different catalytic activities of CTAB and citrate-capped nanocrystals arise from the different behaviors of electron transfer between the surfactants and the nanocrystal surface. Since the surfacants that electrostatically bind to the metal nanocrystals are facile to exchange into other surfactants, our findings provide an effective way to tuning the catalytic activity of metal nanocrystals.


A rich medium-chain triacylglycerol diet benefits adiposity but has adverse effects on the markers of hepatic lipogenesis and beta-oxidation.
We investigated the increasing amounts of medium-chain triacylglycerol (MCT) in the diet on hepatic lipid metabolism. Mature C57BL/6 male mice were randomly divided into five groups (n = 10/group). The animals received their diet for 12 weeks, as a control (C group, 10% of energy from lipids); high-fat lard (HF group, isoenergetic diet, 50% of energy from lipids with lard); a mixture of lard and MCT oil (with a gradual replacement of lard by MCT: HF-MCT25%, HF-MCT75%, and HF-MCT100% groups). At euthanasia, we collected blood and dissected the liver for analyses (glucose, insulin, HOMA-IR, QUICK index, and triacylglycerol, light microscopy, western blotting, and RT-qPCR). The HF diet groups showed a greater body mass gain compared to the C group, but the HF-MCT100% group showed diminished adiposity and amelioration of insulin resistance. All the HF groups also showed a clear increase in hepatic lipid accumulation, increased lipogenesis and decreased PPAR-alpha expression, although HF-MCT groups showed improved local insulin signaling. Lastly, the HF-MCT100% group had raised markers of beta-oxidation (UCP3 and MCAD) and mitochondrial biogenesis (PGC1-alpha and NRF1). In conclusion, the findings demonstrated that a high amount of MCT (HF-MCT100% group) added to an HF diet reduces the body fat accumulation and insulin resistance. However, the lipid accumulation as well as the lipid metabolism is altered in the liver of animals fed with a very high MCT diet, indicating that higher doses of MCT may be harmful in a long-term.


Treatment policy of neuroendocrine small cell cancer of the cervix.
Small cell cancers of the cervix are very rare and aggressive tumours. It is difficult to manage these tumours. They are often diagnosed in an advanced stage and their prognosis is generally poor. There are no clinical trials, due to their rarity, that would suggest optimal treatment. The present report describes a patient with a neuroendocrine small cell cancer of the cervix Stage IB2 with a positive lymph node. The treatment consisted of radical hysterectomy and node dissection, adjuvant chemotherapy, chemoradiation and brachytherapy. Currently, after 52 months, the patient is well and free of disease. Since 1996, there has been a classification for neuroendocrine tumours (NETs) of the cervix in four categories (large cell, small cell, typical carcinoid and atypical carcinoid). The aggressive behaviour of neuroendocrine small cell cancer is demonstrated by the high percentage of early lymphatic node and vessel invasion (68 and 90%). Almost half of the patients with Stage I and II will recur with an estimated 5-year survival from 14% to a maximum of 55%. Multimodal therapy for these tumours appears to give good response but often implies severe side-effects.


Cutaneous sarcoidal granulomas and the development of systemic sarcoidosis.
Studies of patients with systemic sarcoidosis have indicated that those patients with cutaneous lesions have a poorer prognosis with a greater incidence of symptomatic pulmonary and ocular sarcoidosis. We examined 18 patients who had biopsy-proved cutaneous sarcoidosis for evidence of systemic involvement. Of the 13 patients who had no history of previously documented sarcoidosis, six had no evidence of systemic disease on history and physical examination, chest roentgenogram, pulmonary function testing, ocular examination, skin testing, and baseline laboratory testing. The seven remaining patients had evidence of sarcoidosis in another organ system, but six of the seven were essentially asymptomatic and required no therapy. The poorer prognosis associated with cutaneous sarcoidal granulomas drawn from populations with proved systemic sarcoidosis does not seem to apply to generally healthy outpatients with skin lesions as the initial manifestation of their disease.


Contractile effect of the chemotactic factors f-Met-Leu-Phe and C5a on the human isolated umbilical artery. Role of cyclooxygenase products and tissue macrophages.
Factors that are chemotactic for phagocytic leukocytes are known to elicit important acute circulatory changes, and the role of circulating leukocytes in these models is controversial. To evaluate the role of the blood vessel wall in the absence of circulating cells, spiral strips of human umbilical artery were exposed in vitro to the chemotactic peptides f-Met-Leu-Phe (1-100 nM) or C5a (2.5-25 nM). Contractile responses were observed for both peptides. Certain agonist analogues and a selective antagonist of the chemotactic action of f-Met-Leu-Phe behaved correspondingly as agonists and antagonist of the contractile effect on umbilical artery. The anaphylatoxin C3a also exerted a contractile effect on the tissue (25 nM and above), but this effect was highly tachyphylactic. Inhibitory drugs were used to examine the contributions of secondary mediators in eliciting the effects of C5a and f-Met-Leu-Phe. The contractile effect of both peptides was massively inhibited either by indomethacin or the thromboxane A2/prostaglandin H2 antagonist SQ 29548. Dazmegrel, a thromboxane A2 synthetase inhibitor, had partial inhibitory effects on contractions induced by either peptide. The contractile effect of C3a was prevented by indomethacin pretreatment. Vascular strips did not release measurable histamine in the bathing fluid after challenge with C5a or f-Met-Leu-Phe. The tissue apparently contains neither histamine nor mast cells. Autoradiography of 125I-labeled C5a or f-Met-Leu-Phe analogue showed specific binding of the peptides to cells dispersed in the vessel wall, but more frequently at the periphery. Cells stained positively for alpha-naphthyl acetate esterase showed a similar distribution. Pure cultures of smooth muscle cells derived from the umbilical artery failed to release prostanoids when exposed to f-Met-Leu-Phe or C5a, whereas fresh strips of this artery released more thromboxane B2 than the baseline in response to these peptides. We conclude that macrophagelike cells, present in the vessel wall, are the likely target cells for the chemotactic peptides. These cells trigger a contractile effect of the smooth muscle by generating cyclooxygenase products.


Ethical Considerations of Biopsies in Early-Stage Pancreatic Cancer.
The standard of care in resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC) has evolved to include neoadjuvant treatment before surgical resection. Current guidelines call for obtaining histologic tissue diagnosis via endoscopic ultrasound fine-needle aspiration before administration of neoadjuvant therapy, which differ from guidelines discouraging delay in surgical resection for a biopsy. Whether to proceed with treatment before a biopsy confirms that malignancy is a nuanced decision and includes considerations of physical and psychological risks entailed in both pursuing and forgoing a biopsy. Accuracy of imaging and biopsy results, the presence of contributing clinical signs/symptoms, and the existing precedents of considering biopsies as waivable such as in scenarios with high clinical suspicion and primary surgical resection. When considering the aspects of ethical medical practice including beneficence (doing good), nonmaleficence (avoiding harm), autonomy (allowing patients to make decisions about their care), and utilitarianism (doing the most good for the most people), analysis of whether guidelines guiding biopsies should continue to differ between resection and neoadjuvant treatments in PDAC is prudent.


Brittle culm15 encodes a membrane-associated chitinase-like protein required for cellulose biosynthesis in rice.
Plant chitinases, a class of glycosyl hydrolases, participate in various aspects of normal plant growth and development, including cell wall metabolism and disease resistance. The rice (Oryza sativa) genome encodes 37 putative chitinases and chitinase-like proteins. However, none of them has been characterized at the genetic level. In this study, we report the isolation of a brittle culm mutant, bc15, and the map-based cloning of the BC15/OsCTL1 (for chitinase-like1) gene affected in the mutant. The gene encodes the rice chitinase-like protein BC15/OsCTL1. Mutation of BC15/OsCTL1 causes reduced cellulose content and mechanical strength without obvious alterations in plant growth. Bioinformatic analyses indicated that BC15/OsCTL1 is a class II chitinase-like protein that is devoid of both an amino-terminal cysteine-rich domain and the chitinase activity motif H-E-T-T but possesses an amino-terminal transmembrane domain. Biochemical assays demonstrated that BC15/OsCTL1 is a Golgi-localized type II membrane protein that lacks classical chitinase activity. Quantitative real-time polymerase chain reaction and β-glucuronidase activity analyses indicated that BC15/OsCTL1 is ubiquitously expressed. Investigation of the global expression profile of wild-type and bc15 plants, using Illumina RNA sequencing, further suggested a possible mechanism by which BC15/OsCTL1 mediates cellulose biosynthesis and cell wall remodeling. Our findings provide genetic evidence of a role for plant chitinases in cellulose biosynthesis in rice, which appears to differ from their roles as revealed by analysis of Arabidopsis (Arabidopsis thaliana).


Nontraumatic surgical emergencies in children.
Clinical conditions that require operative intervention are frequent causes of emergency department visits. Common causes such as pyloric stenosis, intussusception, inguinal hernias, torsion of the testicle, and ingested foreign bodies are discussed, and aids in diagnosis and early intervention are addressed. Conditions that mimic surgical problems also are mentioned.


Reduction of paediatric head CT utilisation at a rural general hospital emergency department.
Blunt head injury is a common pediatric injury and often evaluated in general emergency departments. It estimated that 50% of children will undergo a head computed tomography (CT), often unnecessarily exposing the child to ionizing radiation. Pediatric academic centers have shown quality improvement (QI) measures can reduce head CT rates within their emergency departments. We aimed to reduce head CT utilization at a rural community emergency department. Children presenting with a complaint of blunt head injury and were evaluated with or without a head CT. Head CT rate was the primary outcome. We developed a series of interventions and presented these to the general emergency department over the duration of the study. The pre and intervention data was analysed with control charts. The preintervention and intervention groups consisted of 576 children: 237 patients with a median age of 8.0 years and 339 patients with a median age of 9.00 years (p=0.54), respectively. The preintervention HCT rate was 41.8% (95% CI 35.6% to 48.1%) and the postintervention rate was 27.7% (95% CI 23.3% to 32.7%), a decrease of 14.1% (95% CI 6.2% to 21.9%, p=0.0004). During the intervention period, there was a decrease in HCT rate of one per month (OR 0.96, 95% CI 0.92 to 1.00, p=0.07). The initial series of interventions demonstrated an incremental decrease in HCT rates corresponding with a special cause variation. The series of interventions dispersed over the intervention period was an effective methodology and successfully reduced HCT utilisation among children with blunt head injury at a rural community emergency department.


Life Course Racism and Depressive Symptoms among Young Black Women.
The objective of this study is to evaluate the life course effects of racism on depressive symptoms in young Black women and to identify particularly sensitive periods. Guided by life-course theory and using logistic regression, we analyzed baseline data on racism frequency and stress from racism at two time periods (before age 20 and during the 20s) and follow-up data (at approximate 20-month intervals) on depressive symptoms (using a modified 11-item Center for Epidemiologic Studies Depression Scale, CES-D) among 1612 Black women participants aged 23-34 years living in Detroit, MI. Of the 1612 women, 65% reported experiencing some racism at baseline, and 36.5% had high depressive symptoms at follow-up. Those who experienced high frequency of racism before age 20 had an increased risk for high depressive symptoms (RR = 1.26, 95% CI: 1.07, 1.46) compared to participants in the low racism frequency group. We observed similar associations for high vs. low stress from racism (RR = 1.30, 95% CI : 1.06, 1.54) and high vs. low combination of racism frequency and stress (RR = 1.38, 95% CI: 1.13, 1.64). These findings did not hold or were weaker when assessing racism during the 20s. Among women who experienced high racism across the two time periods, the risk of high depressive symptoms was higher than those who experienced low racism during both periods (RR = 1.49, 95% CI: 1.14, 1.86). The slightly stronger associations between racism and depressive symptoms in childhood and adolescence than in young adulthood suggest that early life might be a sensitive period for experiencing racism.


Stressful life events, bipolar disorder, and the "kindling model".
A common misconception is that bipolar disorder is an endogenous process. However, previous research suggests a role for life events in the onset of and recovery from bipolar episodes. Yet, there remains some question as to whether the relationship between life events and onset changes over the course of the disorder as a result of the number of episodes an individual has experienced. Using a rigorous interview measure of stressful life events, the current study tested the kindling model (R. M. Post, 1992), which theorizes that major life events play a diminishing role over the course of illness in bipolar patients. Analyses revealed that the number of episodes experienced does not appear to have a significant effect on bipolar 1 patients' reactivity to external stressors. In addition, the results suggest that a more complex relationship exists among age, stress, and onset of new episodes than can be adequately explained by the kindling model.


Effect of a synthetic feline facial pheromone product on stress scores and incidence of upper respiratory tract infection in shelter cats.
OBJECTIVE To determine whether a synthetic feline facial pheromone product would decrease stress scores and upper respiratory tract infection (URI) incidence in shelter-housed cats. DESIGN Randomized controlled clinical trial. ANIMALS 336 stray, feral, owner-relinquished, or legally impounded cats at 2 animal shelters in northern California. PROCEDURES 5 cat holding rooms (3 at shelter A and 2 at shelter B) were used. A diffuser containing either synthetic pheromone or placebo was randomly assigned to each room, and cats were exposed for a 21-day period. Data collected on each cat included signalment, daily stress scores, and daily URI incidence. After 21 days, diffusers were removed for a 7-day washout period. The type of diffuser in each room was switched, and data were collected for another 21 days. Findings were statistically compared between exposure types and other groupings. RESULTS Cox proportional hazard analysis revealed no significant difference between exposure (pheromone or placebo) and URI incidence. Mixed-effects ordinal logistic regression revealed no significant relationship between exposure and daily stress scores. Three covariates had significant ORs: number of days in holding (OR, 0.80; 95% confidence interval [CI], 0.76 to 0.84), owner-relinquished versus stray (OR, 3.25; 95% CI, 1.18 to 8.94), and feral versus adult cat room at shelter A (OR, 11.10; 95% CI, 4.47 to 27.60). CONCLUSIONS AND CLINICAL RELEVANCE No evidence was found that the evaluated synthetic feline facial pheromone product had any effect on stress scores or URI incidence in shelter-housed cats. Therefore, other established methods for stress and URI reduction should be used in shelter settings.


Streptococcus ictaluri sp. nov., isolated from Channel Catfish Ictalurus punctatus broodstock.
A streptococcal-like organism was associated with diseased Channel Catfish Ictalurus punctatus broodstock on four commercial aquaculture operations in the Mississippi Delta. Conventional biochemical testing, 16S rRNA gene sequence analysis and DNA-DNA hybridization distinguished the isolates from these fish from previously published Streptococcus species. Comparative 16S rRNA gene sequencing studies revealed that the isolates were phylogenetically most similar to Streptococcus iniae, Streptococcus uberis and Streptococcus parauberis with divergence ranging from 2.0 to 2.3 %. Streptococcus pyogenes, Streptococcus urinalis, Streptococcus dysgalactiae subsp. dysgalactiae and Streptococcus canis were included in the analysis and showed even greater differences (2.5-3.2 % divergence). DNA relatedness was 22 % or less to the most phylogenetically related species at the optimal temperature. These data suggest that the isolates represent a novel species of Streptococcus for which the name Streptococcus ictaluri sp. nov. is proposed. The type strain is 707-05(T) (=SO2-1108(T)=ATCC BAA-1300(T)=CCUG 52536(T)).


Control of aldosterone secretion: a model for convergence in cellular signaling pathways.
Aldosterone secretion by glomerulosa cells is stimulated by angiotensin II (ANG II), extracellular K(+), corticotrophin, and several paracrine factors. Electrophysiological, fluorimetric, and molecular biological techniques have significantly clarified the molecular action of these stimuli. The steroidogenic effect of corticotrophin is mediated by adenylyl cyclase, whereas potassium activates voltage-operated Ca(2+) channels. ANG II, bound to AT(1) receptors, acts through the inositol 1,4,5-trisphosphate (IP(3))-Ca(2+)/calmodulin system. All three types of IP(3) receptors are coexpressed, rendering a complex control of Ca(2+) release possible. Ca(2+) release is followed by both capacitative and voltage-activated Ca(2+) influx. ANG II inhibits the background K(+) channel TASK and Na(+)-K(+)-ATPase, and the ensuing depolarization activates T-type (Ca(v)3.2) Ca(2+) channels. Activation of protein kinase C by diacylglycerol (DAG) inhibits aldosterone production, whereas the arachidonate released from DAG in ANG II-stimulated cells is converted by lipoxygenase to 12-hydroxyeicosatetraenoic acid, which may also induce Ca(2+) signaling. Feedback effects and cross-talk of signal-transducing pathways sensitize glomerulosa cells to low-intensity stimuli, such as physiological elevations of [K(+)] (< or =1 mM), ANG II, and ACTH. Ca(2+) signaling is also modified by cell swelling, as well as receptor desensitization, resensitization, and downregulation. Long-term regulation of glomerulosa cells involves cell growth and proliferation and induction of steroidogenic enzymes. Ca(2+), receptor, and nonreceptor tyrosine kinases and mitogen-activated kinases participate in these processes. Ca(2+)- and cAMP-dependent phosphorylation induce the transfer of the steroid precursor cholesterol from the cytoplasm to the inner mitochondrial membrane. Ca(2+) signaling, transferred into the mitochondria, stimulates the reduction of pyridine nucleotides.


Embryonic stem cell-specific miR302-367 cluster: human gene structure and functional characterization of its core promoter.
MicroRNAs (miRNAs) play a central role in the regulation of multiple biological processes including the maintenance of stem cell self-renewal and pluripotency. Recently, the miRNA cluster miR302-367 was shown to be differentially expressed in embryonic stem cells (ESCs). Unfortunately, very little is known about the genomic structure of miRNA-encoding genes and their transcriptional units. Here, we have characterized the structure of the gene coding for the human miR302-367 cluster. We identify the transcriptional start and functional core promoter region which specifically drives the expression of this miRNA cluster. The promoter activity depends on the ontogeny and hierarchical cellular stage. It is functional during embryonic development, but it is turned off later in development. From a hierarchical standpoint, its activity decays upon differentiation of ESCs, suggesting that its activity is restricted to the ESC compartment and that the ESC-specific expression of the miR302-367 cluster is fully conferred by its core promoter transcriptional activity. Furthermore, algorithmic prediction of transcription factor binding sites and knockdown studies suggest that ESC-associated transcription factors, including Nanog, Oct3/4, Sox2, and Rex1 may be upstream regulators of miR302-367 promoter. This study represents the first identification, characterization, and functional validation of a human miRNA promoter in stem cells. This study opens up new avenues to further investigate the upstream transcriptional regulation of the miR302-367 cluster and to dissect how these miRNAs integrate in the complex molecular network conferring stem cell properties to ESCs.


Comparative Efficacy of Bortezomib, Melphalan, and Prednisone (VMP) With or Without Daratumumab Versus VMP Alone in the Treatment of Newly Diagnosed Multiple Myeloma: Propensity Score Matching of ALCYONE and VISTA Phase III Studies.
Bortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates. The efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups. After matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching. This propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous).


Normalization of priming solution ionized calcium concentration improves hemodynamic stability of neonates receiving venovenous ECMO.
The authors' objectives in this investigation were: 1) to prospectively determine whether a normocalcemic priming solution would result in elimination of hypocalcemia after the initiation of extracorporeal membrane oxygenation (ECMO); 2) to investigate whether normocalcemia would result in improvements in the patient's hemodynamics during the initiation of ECMO; and 3) to further define the relationship between ionized calcium measurements and total calcium, serum total protein, serum albumin, and total magnesium. This was a prospective study done in our neonatal intensive care unit, and included nine neonatal patients placed on ECMO for cardiopulmonary support. The bypass circuit was primed in the standardized manner with 100 mg calcium chloride. Circuit ionized calcium measurements were performed, and additional calcium chloride was added to normalize the ionized calcium in the priming solution. Ionized calcium was measured from the circuit and the patient before the initiation of ECMO, and then again from the patient 5, 10, 15, 30, 60, 120, and 240 minutes after the initiation of ECMO. The patients' mean arterial pressure was measured simultaneously with each ionized calcium measurement. Ionized calcium, serum total calcium, total protein, serum albumin, and total magnesium were measured from blood samples simultaneously collected four times daily. There was no significant change in the ionized calcium measured in the patients after the initiation of ECMO. There was, however, a significant increase in blood pressure 5 min after the initiation of ECMO (62 +/- 7 mmHg vs 53 +/- 6 mmHg, p = 0.01). Thereafter, there was no difference in blood pressure measured when compared with pre ECMO values. A poor correlation was demonstrated between ionized calcium and total calcium (r2 = 0.35), serum total protein (r2 = 0.26), serum albumin (r2 = 0.27), and total magnesium (r2 = 0.05). On the basis of the authors' data, the initiation of ECMO with a normocalcemic prime results in a minimal change in patient ionized calcium and resolution of the hypotension previously observed. In addition, there was poor correction between ionized calcium, total calcium, and other indirect measures of ionized calcium. Ionized calcium measurements are critical for patient hemodynamic stability before bypass and should be normalized in both the patient and priming solution before the initiation of bypass.


Evaluation of scatter contribution from shielding materials used in scatter measurements for calibration range characterization.
The contribution of scatter from the shielding material used in scatter measurements at the Ohio Emergency Management Agency was evaluated. This was accomplished by comparing physical measurements with results generated by detectors modeled in the Monte Carlo shielding code, MCNP4B. The high purity germanium (HPGe) detector model was improved by using radiographs to more accurately represent the detector geometry, including a model of the lithium-contact transition region, and considering the effects of the non-uniform electric field in the germanium crystal. Photons scattered from the shielding material were found to contribute 4.25% of the total scatter recorded by the HPGe detector (thus contributing only 0.26% of the total dose) at a point 5 m from a 1.35 GBq (36.4 mCi) 137Cs source.


TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS.
Amyotrophic lateral sclerosis (ALS) was initially thought to be associated with oxidative stress when it was first linked to mutant superoxide dismutase 1 (SOD1). The subsequent discovery of ALS-linked genes functioning in RNA processing and proteostasis raised the question of how different biological pathways converge to cause the disease. Both familial and sporadic ALS are characterized by the aggregation of the essential DNA- and RNA-binding protein TDP-43, suggesting a central role in ALS etiology. Here we report that TDP-43 aggregation in neuronal cells of mouse and human origin causes sensitivity to oxidative stress. Aggregated TDP-43 sequesters specific microRNAs (miRNAs) and proteins, leading to increased levels of some proteins while functionally depleting others. Many of those functionally perturbed gene products are nuclear-genome-encoded mitochondrial proteins, and their dysregulation causes a global mitochondrial imbalance that augments oxidative stress. We propose that this stress-aggregation cycle may underlie ALS onset and progression.


New developments in the treatment of squamous cell lung cancer.
To highlight the recent developments in the molecular characterization of lung squamous cell carcinoma (SQCC) and to summarize the current clinical trials of targeted agents. Lung SQCC is the second-largest histological subtype of nonsmall-cell lung cancer after lung adenocarcinoma and is closely associated with tobacco smoking. Targeted therapies have been successfully used for the treatment of lung adenocarcinoma but have not been implemented in the treatment of lung SQCC to date. Both lung adenocarcinomas and SQCCs are characterized by specific somatic DNA modifications such as exonic mutations, copy-number alterations, and genomic rearrangements which are substantially different between the two subtypes. Progress in genomic characterization using next-generation sequencing (NGS) technologies makes it possible to investigate these somatic DNA modifications at the whole-genome level and to generate comprehensive profiles of genetic alterations. Application of NGS in lung SQCC led to a more detailed understanding of the possible targets and will identify new targeted therapeutic approaches in the near future. In this review, we highlight the current knowledge of molecular targets, clinical trials of targeted agents, and druggable aberrations in lung SQCCs.


Ursolic Acid Derivative UA232 Promotes Tumor Cell Apoptosis by Inducing Endoplasmic Reticulum Stress and Lysosomal Dysfunction.
Due to increased drug and radiation tolerance, there is an urgent need to develop novel anticancer agents. In our previous study, we performed a series of structural modifications of ursolic acid (UA), a natural product of pentacyclic triterpenes, and found UA232, a derivative with stronger anti-tumor activity. In vitro experiments showed that UA232 inhibited proliferation, induced G0/G1 arrest, and promoted apoptosis in human breast cancer and cervical cancer cells. Mechanistic studies revealed that UA232 promoted apoptosis and induced protective autophagy via the protein kinase R-like endoplasmic reticulum kinase/activating transcription factor 4/C/EBP homologous protein-mediated endoplasmic reticulum stress. In addition, we also found that UA232 induced lysosomal biogenesis, increased lysosomal membrane permeability, promoted lysosomal protease release, and led to lysosome-dependent cell death. Furthermore, UA232 suppressed tumor growth in a mouse xenograft model. In conclusion, our study revealed that UA232 exerts multiple pharmacological effects against breast and cervical cancers by simultaneously triggering endoplasmic reticulum stress and lysosomal dysfunction. Thus, UA232 may be a promising drug candidate for cancer treatment.


The induction of long-term potentiation at amygdalo-hippocampal synapses in vivo.
Electrical stimulation of the basolateral amygdala (BLA) evoked synaptic potentials in the dentate gyrus (DG) of the hippocampus in anesthetized rats. To determine if this pathway possesses synaptic plasticity, we investigated the impact of several conditions of high-frequency stimulation on BLA-DG synaptic potentials in these rats. Application of two trains of 100-pulse, 100-Hz stimulation or theta-burst stimulation to the BLA reproducibly induced long-term potentiation (LTP) of BLA-DG synaptic potentials. Paired-pulse facilitation was unchanged during LTP, suggesting that postsynaptic mechanisms are involved in the expression of LTP. In addition, the induction of LTP was not affected by the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate, suggesting that activation of NMDA receptors is not required. This novel form of LTP should be a valuable model for elucidating neural mechanisms underlying the formation of emotional memory.


Proteomic-based stratification of intermediate-risk prostate cancer patients.
Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in the Gleason grade group (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or overtreatment of a significant number of patients. Here, we performed proteomic, differential expression, machine learning, and survival analyses for 1,348 matched tumour and benign sample runs from 278 patients. Three proteins (F5, TMEM126B, and EARS2) were identified as candidate biomarkers in patients with biochemical recurrence. Multivariate Cox regression yielded 18 proteins, from which a risk score was constructed to dichotomize prostate cancer patients into low- and high-risk groups. This 18-protein signature is prognostic for the risk of biochemical recurrence and completely independent of the intermediate GG. Our results suggest that markers generated by computational proteomic profiling have the potential for clinical applications including integration into prostate cancer management.


Phenotype and envelope gene diversity of nef-deleted HIV-1 isolated from long-term survivors infected from a single source.
The Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with attenuated, nef-deleted variants of human immunodeficiency virus type 1 (HIV-1) acquired from a single source. Long-term prospective studies have demonstrated that the SBBC now comprises slow progressors (SP) as well as long-term nonprogressors (LTNP). Convergent evolution of nef sequences in SBBC SP and LTNP indicates the in vivo pathogenicity of HIV-1 in SBBC members is dictated by factors other than nef. To better understand mechanisms underlying the pathogenicity of nef-deleted HIV-1, we examined the phenotype and env sequence diversity of sequentially isolated viruses (n = 2) from 3 SBBC members. The viruses characterized here were isolated from two SP spanning a three or six year period during progressive HIV-1 infection (subjects D36 and C98, respectively) and from a LTNP spanning a two year period during asymptomatic, nonprogressive infection (subject C18). Both isolates from D36 were R5X4 phenotype and, compared to control HIV-1 strains, replicated to low levels in peripheral blood mononuclear cells (PBMC). In contrast, both isolates from C98 and C18 were CCR5-restricted. Both viruses isolated from C98 replicated to barely detectable levels in PBMC, whereas both viruses isolated from C18 replicated to low levels, similar to those isolated from D36. Analysis of env by V1V2 and V3 heteroduplex tracking assay, V1V2 length polymorphisms, sequencing and phylogenetic analysis showed distinct intra- and inter-patient env evolution. Independent evolution of env despite convergent evolution of nef may contribute to the in vivo pathogenicity of nef-deleted HIV-1 in SBBC members, which may not necessarily be associated with changes in replication capacity or viral coreceptor specificity.


Leaf optical properties in higher plants: linking spectral characteristics to stress and chlorophyll concentration.
A number of studies have linked responses in leaf spectral reflectance, transmittance, or absorptance to physiological stress. A variety of stressors including dehydration, flooding, freezing, ozone, herbicides, competition, disease, insects, and deficiencies in ectomycorrhizal development and N fertilization have been imposed on species ranging from grasses to conifers and deciduous trees. In all cases, the maximum difference in reflectance within the 400-850 nm wavelength range between control and stressed states occurred as a reflectance increase at wavelengths near 700 nm. In studies that included transmittance and absorptance as well as reflectance, maximum differences occurred as increases and decreases, respectively, near 700 nm. This common optical response to stress could be simulated closely by varying the chlorophyll concentration of model leaves (fiberglass filter pads) and by the natural variability in leaf chlorophyll concentrations in senescent leaves of five species. The optical response to stress near 700 nm, as well as corresponding changes in reflectance that occur in the green-yellow spectrum, can be explained by the general tendency of stress to reduce leaf chlorophyll concentration.


Comparison of Electropolishing of Aluminum in a Deep Eutectic Medium and Acidic Electrolyte.
Research advances in electropolishing, with respect to the field of metalworking, have afforded significant improvements in the surface roughness and conductivity properties of aluminum polished surfaces in ways that machine polishing and simple chemical polishing cannot. The effects of a deep eutectic medium as an acid-free electrolyte were tested to determine the potential energy thresholds during electropolishing treatments based upon temperature, experiment duration, current, and voltage. Using voltammetry and chronoamperometry tests during electropolishing to supplement representative recordings via atomic force microscopy (AFM), surface morphology comparisons were performed regarding the electropolishing efficiency of phosphoric acid and acid-free ionic liquid treatments for aluminum. This eco-friendly solution produced polished surfaces superior to those surfaces treated with industry standard acid electrochemistry treatments of 1 M phosphoric acid. The roughness average of the as-received sample became 6.11 times smoother, improving from 159 nm to 26 nm when electropolished with the deep eutectic solvent. This result was accompanied by a mass loss of 0.039 g and a 7.2 µm change in step height along the edge of the electropolishing interface, whereas the acid treatment resulted in a slight improvement in surface roughness, becoming 1.63 times smoother with an average post-electropolishing roughness of 97.7 nm, yielding a mass loss of 0.0458 g and a step height of 8.1 µm.


Exposure to contaminants and nutritional intakes in a French vegetarian population.
The NutriNet Santé study collected, on a voluntary basis, the dietary consumption of French vegetarian populations (N = 1766, including 188 vegan individuals) from 18 to 81 years (18-77 years for the vegan). Taking advantage of the availability of contamination data generated in the context of the second French total diet study, dietary exposures of French vegetarian populations to several contaminants were estimated. Results showed that exposures to persistent organic pollutants (PCBs, PCDD/Fs for instance) was dramatically lower than those of the general French population due to the non consumption of food of animal origins. On the other hand, exposures to phytoestrogens, some mycotoxins (T2 and HT2 toxins) and some trace elements (Cd, Al, Sn, Ni) were higher in the vegetarian population compared to those of the general population. Despite some limitations of this approach (both the consumption study and the total diet study were not aimed to estimate dietary exposure of the vegetarian populations), this study showed that dietary habits can dramatically influence the exposure of some contaminants.


Conventional influenza vaccination is not associated with complications in working-age patients with asthma or chronic obstructive pulmonary disease.
By using a nested case-control design, the authors studied the effectiveness of the influenza vaccine in reducing severe and fatal complications in 4,241 and 5,966 primary care, working-age patients aged 18-64 years who had asthma or chronic obstructive pulmonary disease during the 1998-1999 and 1999-2000 influenza epidemics in the Netherlands. Patients developing fatal or nonfatal exacerbations of lung disease, pneumonia, congestive heart failure, or myocardial infarction during either epidemic were considered cases. For each case, four age- and sex-matched controls were randomly sampled, and patient records were reviewed. Conditional logistic regression and propensity scores were used to assess vaccine effectiveness after adjustment for confounding factors. In seasons one and two, respectively, 87% (47/54) and 85% (171/202) of the cases and 74% (155/210) and 75% (575/766) of the controls had been vaccinated. After adjustments, vaccination was not associated with reductions in complications (season one: odds ratio = 0.95, 95% confidence interval (CI): 0.26, 3.48; season two: odds ratio = 1.07, 95% CI: 0.59, 1.96; pooled odds ratio = 1.07, 95% CI: 0.63, 1.80). Because influenza vaccination appeared not to be associated with a clinically relevant reduction in severe morbidity, other measures need to be explored.


[Chrysin promotes SMMC-7721 cell apoptosis by regulating MAPKs signaling pathway].
To study the effect of chrysin in inducing apoptosis of human hepatic carcinoma cells and explore the possible mechanism. Human hepatic carcinoma SMMC-7721 cells treated with DMSO or chrysin at different concentrations (5-200 μg/mL) were examined for changes in the cell proliferation using CCK-8 assay. The morphological changes of SMMC-7721 cells were observed in response to treatment with 5, 10, or 20 μg/mL chrysin, and the changes in the cell nuclei were observed using DAPI nuclear staining. Annexin Ⅴ-FITC/PI flow cytometry was used to determine the cell apoptosis rate. The changes in the apoptosis-related proteins (PARP and caspase-3) and MAPKs signal pathway were detected with Western blotting. Chrysin treatment obviously suppressed the proliferation of SMMC-7721 cells in a dose-dependent manner below the concentration of 60 μg/mL. Chrysin (20 μg/mL) also caused significantly increased cell apoptosis and significant cleavage of PARP and caspase-3. Chrysin significantly activated MAPKs signaling pathway in a time-and dose-dependent manner, with the peak activation level occurring at 15 min. Pretreatment of the cells with specific inhibitors of the MAPKs pathway obviously inhibited the effect of chrysin in inducing cell apoptosis. Chrysin inhibits the proliferation and promotes apoptosis of SMMC-7721 cells by regulating the activation of MAPKs signaling.


Studies on in vitro antioxidant and antistaphylococcal activities of some important medicinal plants.
Oxidative stress is initiated by free radicals, which seek stability through electron pairing with biological macromolecules in healthy human cells and cause protein and DNA damage along with lipid peroxidation. Many phytochemicals have been found to play as potential antioxidants and antimicrobials. In the present study antioxidant and antistaphylococcal activities of Bauhinia variegata, Tinospora cardifolia and Piper longum have been determined. Total phenolic contents in plant extracts were estimated and different amounts of phenolic contents were found in B. variegata, T. cardifolia and P. longum extracts. The antioxidant activity of the extracts was compared with standard antioxidants such as, BHA, BHT, quercetin, ascorbic acid and propyl gallate. The % scavenging activity gradually increased with increasing concentrations of the test extracts in DPPH radical scavenging assay. Dose dependent antioxidant activity pattern was also observed in phosphomolybdate assay. Antioxidant activity was directly correlated with the amount of total phenolic contents in the extracts. As compared to B. variegata, the extracts from other two plants exhibited higher antioxidant activity. In disc diffusion assays several solvent extracts derived from test plants inhibited the growth of Staphylococcus aureus. Maximum inhibitory efficacy was observed in T. cardifolia extracts. However, the lowest minimum bactericidal concentration (MBC) (0.43 mg/ml) was recorded for ethyl acetate and acetone extracts of P. longum. This study demonstrates notable antioxidant and anti-staphylococcal roles assigned to some plant extracts tested.


Prognostic Factors of Extramammary Paget's Disease.
Most patients with extramammary Paget's disease (EMPD) show a good prognosis; however, some patients develop fatal metastases. Early detection is important for improving prognosis, due to the difficulties associated with the treatment of distant EMPD metastases. Several studies have emphasized the importance of the invasion level of the primary lesion for predicting the presence of metastasis, and deeper invasion or increased thickness is correlated with poorer prognosis. Vascular tumor invasion of the primary lesion can also predict the risk of metastasis. Lymph node metastasis is a strong indicator for poor prognosis, and the number of lymph node metastases affects patient outcome, in that there is a significant difference in survival between patients with zero or one lymph node metastasis and those with more than two lymph node metastases. Serum markers may be able to predict the presence of systemic metastases, and carcinoembryonic antigen and cytokeratin 19 fragment 21-1 reflect disease progression and may be clinically valuable. Although several genetic alterations have been determined for EMPD, factors determining prognosis should be further explored.


Renoprotective effects of combination treatment with sodium-glucose cotransporter inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus according to preceding medication.
Combination therapy with sodium-glucose cotransporter inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1Ras) is now of interest in clinical practice. The present study evaluated the effects of the preceding drug type on the renal outcome in clinical practice. We retrospectively extracted type 2 diabetes mellitus patients who had received both SGLT2i and GLP1Ra treatment for at least 1 year. A total of 331 patients in the GLP1Ra-preceding group and 312 patients in the SGLT2i-preceding group were ultimately analyzed. Either progression of the albuminuria status and/or a ≥30% decrease in the eGFR was set as the primary renal composite outcome. The analysis using propensity score with inverse probability weighting was performed for the outcome. The incidences of the renal composite outcome in the SGLT2i- and GLP1Ra-preceding groups were 28% and 25%, respectively, with an odds ratio [95% confidence interval] of 1.14 [0.75, 1.73] (p = .54). A logistic regression analysis showed that the mean arterial pressure (MAP) at baseline, the logarithmic value of the urine albumin-to-creatinine ratio at baseline, and the change in MAP were independent factors influencing the renal composite outcome. With combination therapy of SGLT2i and GLP1Ra, the preceding drug did not affect the renal outcome.


Error-enhancing robot therapy to induce motor control improvement in childhood onset primary dystonia.
Robot-generated deviating forces during multijoint reaching movements have been applied to investigate motor control and to tune neuromotor adaptation. Can the application of force to limbs improve motor learning? In this framework, the response to altered dynamic environments of children affected by primary dystonia has never been studied. As preliminary pilot study, eleven children with primary dystonia and eleven age-matched healthy control subjects were asked to perform upper limb movements, triangle-reaching (three directions) and circle-writing, using a haptic robot interacting with ad-hoc developed task-specific visual interfaces. Three dynamic conditions were provided, null additive external force (A), constant disturbing force (B) and deactivation of the additive external force again (C). The path length for each trial was computed, from the recorded position data and interaction events. The results show that the disturbing force affects significantly the movement outcomes in healthy but not in dystonic subjects, already compromised in the reference condition: the external alteration uncalibrates the healthy sensorimotor system, while the dystonic one is already strongly uncalibrated. The lack of systematic compensation for perturbation effects during B condition is reflected into the absence of after-effects in C condition, which would be the evidence that CNS generates a prediction of the perturbing forces using an internal model of the environment.The most promising finding is that in dystonic population the altered dynamic exposure seems to induce a subsequent improvement, i.e. a beneficial after-effect in terms of optimal path control, compared with the correspondent reference movement outcome. The short-time error-enhancing training in dystonia could represent an effective approach for motor performance improvement, since the exposure to controlled dynamic alterations induces a refining of the existing but strongly imprecise motor scheme and sensorimotor patterns.


Maxed Out: Optimizing Accuracy, Precision, and Power for Field Measures of Maximum Metabolic Rate in Fishes.
Both laboratory and field respirometry are rapidly growing techniques to determine animal performance thresholds. However, replicating protocols to estimate maximum metabolic rate (MMR) between species, populations, and individuals can be difficult, especially in the field. We therefore evaluated seven different exercise treatments-four laboratory methods involving a swim tunnel (critical swim speed [Ucrit], Ucrit postswim fatigue, maximum swim speed [Umax], and Umax postswim fatigue) and three field-based chasing methods (3-min chase with 1-min air exposure, 3-min chase with no air exposure, and chase to exhaustion)-in adult coho salmon (Oncorhynchus kisutch) as a case study to determine best general practices for measuring and quantifying MMR in fish. We found that all seven methods were highly comparable and that chase treatments represent a valuable field alternative to swim tunnels. Moreover, we caution that the type of test and duration of measurement windows used to calculate MMR can have significant effects on estimates of MMR and statistical power for each approach.


Endoscopic decompression for the treatment of lumbar spinal stenosis: an updated systematic review and meta-analysis.
Lumbar stenosis treatment has evolved with the introduction of minimally invasive surgery (MIS) techniques. Endoscopic methods take the concepts applied to MIS a step further, with multiple studies showing that endoscopic techniques have outcomes that are similar to those of more traditional approaches. The aim of this study was to perform an updated meta-analysis and systematic review of studies comparing the outcomes between endoscopic (uni- and biportal) and microscopic techniques for the treatment of lumbar stenosis. Following PRISMA guidelines, a systematic search was performed using the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Ovid Embase, and PubMed databases from their dates of inception to December 14, 2020. All identified articles were then systematically screened against the following inclusion criteria: 1) studies comparing endoscopic (either uniportal or biportal) with minimally invasive approaches, 2) patient age ≥ 18 years, and 3) diagnosis of lumbar spinal stenosis. Bias was assessed using quality assessment criteria and funnel plots. Meta-analysis using a random-effects model was used to synthesize the metadata. From a total of 470 studies, 14 underwent full-text assessment. Of these 14 studies, 13 comparative studies were included for quantitative analysis, totaling 1406 procedures satisfying all criteria for selection. Regarding postoperative back pain, 9 studies showed that endoscopic methods resulted in significantly lower pain scores compared with MIS (mean difference [MD] -1.0, 95% CI -1.6 to -0.4, p < 0.01). The length of stay data were reported by 7 studies, with endoscopic methods associated with a significantly shorter length of stay versus the MIS technique (MD -2.1 days, 95% CI -2.7 to -1.4, p < 0.01). There was no significant difference with respect to leg visual analog scale scores, Oswestry Disability Index scores, blood loss, surgical time, and complications, and there were not any significant quality or bias concerns. Both endoscopic and MIS techniques are safe and effective methods for treating patients with symptomatic lumbar stenosis. Patients who undergo endoscopic surgery seem to report less postoperative low-back pain and significantly reduced hospital stay with a trend toward less perioperative blood loss. Future large prospective randomized trials are needed to confirm the findings in this study.


[Prognosis of the syndrome of mild cognitive impairment: the data of the biennial follow-up study].
Structure and prognostic significance of the syndrome of mild cognitive impairment (MCI) were studied in a prospective biennial study of a randomized cohort of elderly people meeting current MCI criteria. The study comprised 40 patients aged from 50 to 80 years. Clinical follow up study included psychopathological, psychometric, neuropsychological, neuroimaging and molecular genetic (ApoE genotyping) examinations were made. Psychopathological structure and psychometric characteristics of the MCI syndrome are described, and clinical and genetic factors of prognostic value are singled out.


Efficacy and tolerability of AFPep, a cyclic peptide with anti-breast cancer properties.
The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials. AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts. AFPep arrests the growth of human MCF-7 breast cancer xenografts, inhibits the estrogen-induced growth of mouse uteri, and does not affect liver growth nor stimulate growth of human hepatocellular carcinoma cell lines when growing in vitro or as xenografts in vivo. AFPep is well tolerated in mice, rats, dogs, and primates. AFPep is effective for the treatment of ER-positive breast cancer and exhibits a therapeutic index that is substantially wider than that for drugs currently in clinical use. The data emphasize the importance of pursuing pre-clinical toxicology studies with the intent to enter clinical trials.


Fully Optical in Operando Investigation of Ambient Condition Electrical Switching in MoS2 Nanodevices.
MoS2 nanoswitches have shown superb ultralow switching energies without excessive leakage currents. However, the debate about the origin and volatility of electrical switching is unresolved due to the lack of adequate nanoimaging of devices in operando. Here, three optical techniques are combined to perform the first noninvasive in situ characterization of nanosized MoS2 devices. This study reveals volatile threshold resistive switching due to the intercalation of metallic atoms from electrodes directly between Mo and S atoms, without the assistance of sulfur vacancies. A "semi-memristive" effect driven by an organic adlayer adjacent to MoS2 is observed, which suggests that nonvolatility can be achieved by careful interface engineering. These findings provide a crucial understanding of nanoprocess in vertically biased MoS2 nanosheets, which opens new routes to conscious engineering and optimization of 2D electronics.


Ion-Specific Assembly of Strong, Tough, and Stiff Biofibers.
Designing engineering materials with high stiffness and high toughness is challenging as stiff materials tend to be brittle. Many biological materials realize this objective through multiscale (i.e., atomic- to macroscale) mechanisms that are extremely difficult to replicate in synthetic materials. Inspired from the architecture of such biological structures, we here present flow-assisted organization and assembly of renewable native cellulose nanofibrils (CNFs), which yields highly anisotropic biofibers characterized by a unique combination of high strength (1010 MPa), high toughness (62 MJ m-3 ) and high stiffness (57 GPa). We observed that properties of the fibers are primarily governed by specific ion characteristics such as hydration enthalpy and polarizability. A fundamental facet of this study is thus to elucidate the role of specific anion binding following the Hofmeister series on the mechanical properties of wet fibrillar networks, and link this to the differences in properties of dry nanostructured fibers. This knowledge is useful for rational design of nanomaterials and is critical for validation of specific ion effect theories. The bioinspired assembly demonstrated here is relevant example for designing high-performance materials with absolute structural control.


Generation of transmissible hepatitis C virions from a molecular clone in chimpanzees.
Multiple alignments of hepatitis C virus (HCV) polyproteins from six different genotypes identified a total of 22 nonconsensus mutations in a clone derived from the Hutchinson (H77) isolate. These mutations, collectively, may have contributed to the failure in generating a "functionally correct" or "infectious" clone in earlier attempts. A consensus clone was constructed after systematic repair of these mutations, which yielded infectious virions in a chimpanzee after direct intrahepatic inoculation of in vitro transcribed RNAs. This RNA-infected chimpanzee has developed hepatitis and remained HCV positive for more than 11 months. To further verify this RNA-derived infectivity, a second naive chimpanzee was injected intravenously with serum collected from the first chimpanzee. Infectivity analysis of the second chimpanzee demonstrated that the HCV infection was successfully transmitted, which validated unequivocally the infectivity of our repaired molecular clone. Amino acid sequence comparisons revealed that our repaired infectious clone had 4 mismatches with the isogenic clone reported by Kolykhalov et al. (1997, Science 277, 570-574) and 8 mismatches with that reported by Yanagi et al. (1997, Proc. Natl. Acad. Sci. USA 94, 8738-8743). At the RNA level, more mismatches (43 and 67, respectively) were identified; most of them were synonymous substitutions. Further comparisons with 16 isolates from different genotypes demonstrated that our repaired clone shares greater consensus than the reported isogenic clones. This approach of generating infectious HCV RNA validates the importance of amino acid sequence consensus in relation to the biology of HCV.


Long-term outcomes of deep pediatric arteriovenous malformations.
Multimodality treatment has been shown to be the optimal management strategy for pediatric arteriovenous malformations (AVMs). Deep AVMs represent a subset of AVMs for which optimal management may be achieved with a combination of radiosurgery and highly selective embolization, in the absence of compelling features requiring operative intervention. The objective of this study was to identify predictors of good functional outcomes in pediatric patients with deep AVMs. A retrospective cohort study of the outcomes of 79 patients with deep AVMs from January 1988 through December 2021 was performed. Deep AVMs were defined as those with the majority of the nidus centered in the basal ganglia, thalamus, or brainstem. Collected data included patient demographics and presenting symptoms, presenting modified Rankin Scale (mRS) score, radiographic findings and outcomes, management strategy, complications, and clinical outcomes as indicated by follow-up mRS score. A good outcome was defined as a follow-up mRS score ≤ 2, while a poor outcome was defined as a follow-up mRS score ≥ 3. Statistical analysis was performed to identify factors associated with functional outcomes. With a mean follow-up duration of 85.6 months, there was a 72.2% angiographic obliteration rate, with 75.9% of patients having a good clinical outcome (mRS score ≤ 2). Presenting symptoms and radiographic characteristics were not significantly associated with long-term functional outcomes. There was a significantly higher rate of posttreatment hemorrhage in patients with a poor versus good outcome (11.8% vs 0%, p = 0.010). On multivariate logistic regression analysis, poor long-term functional outcome was only associated with poor presenting mRS score (p = 0.002). Satisfactory angiographic obliteration rates and good long-term functional outcomes can be achieved for deep AVMs, with stereotactic radiosurgery as the cornerstone of multimodality treatment.


Orientation dependence of ionization edges in EELS.
Anisotropy in the density of unoccupied states can be detected in the fine structure of ionization edges in angle-resolved EELS. It is shown that in a crystal an interference term occurs in the inelastic signal, and how it relates to electron channeling and site selection. The combination of orientation and site selection induces subtle variations in the ELNES. It is shown how this technique can be used to analyze local anisotropy related to the point group of the target atom. A second example shows how to extract non-dipole transitions at small scattering angles.


Transgenic tobacco expressing the hrpN(EP) gene from Erwinia pyrifoliae triggers defense responses against botrytis cinerea.
HrpN(EP), from the gram-negative pathogen, Erwinia pyrifoliae, is a member of the harpin group of proteins, inducing pathogen resistance and hypersensitive cell death in plants. When the hrpN(EP) gene driven by the OsCc1 promoter was introduced into tobacco plants via Agrobacterium-mediated transformation, their resistance to the necrotrophic fungal pathogen, Botrytis cinerea, increased. Resistance to B. cinerea was correlated with enhanced induction of SA-dependent genes such as PR-1a, PR2, PR3 and Chia5, of JA-dependent genes such as PR-1b, and of genes related to ethylene production, such as NT-EFE26, NT-1A1C, DS321, NT-ACS1 and NT-ACS2. However the expression of NPR1, which is thought to be essential for multiple-resistance, did not increase. Since the pattern of expression of defense-related genes in hrpN(EP)-expressing tobacco differed from that in plants expressing hpaG(Xoo) from Xanthomonas oryzae pv. Oryzae, these results suggest that different harpins can affect the expression of different defense-related genes, as well as resistance to different plant pathogens.


Characterization of the lipopolysaccharide from Actinobacillus actinomycetemcomitans Y4 and N27.
The lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans strains Y4 and N27 was isolated by the phenol-water procedure. Morphologically, the molecule consisted of ribbon and branched filaments which comprised 3% of the cellular dry weight. Chemical analysis of the isolated and purified LPSs of both strains showed them to consist of carbohydrate, lipid, 2-keto-3-deoxyoctonate, heptose, hexosamine, and phosphate. The major fatty acids of the lipid A moiety were saturated C14 and beta-OH C14 compounds. Rhamnose, fucose, galactose, glucose, heptose, glucosamine, and galactosamine comprised the monosaccharide portion of the LPS. Biological activity studies revealed both LPS molecules to be active in the Schwartzman reaction and in in vitro 45Ca bone resorption, as well as in macrophage activation and lethality and in platelet aggregation.


Catalytic microcontact printing on chemically functionalized H-terminated silicon.
We report a novel inkless soft lithographic fabrication protocol that permits uniform parallel patterning of hydrogen-terminated silicon surfaces using catalytic elastomeric stamps. Pattern transfer is achieved catalytically via reaction between sulfonic acid moieties covalently bound to an elastomeric stamp and a Boc-functionalized SAM grafted to passivated silicon. The approach represents the first example of a soft lithographic printing technique that creates patterns of chemically distinctive SAMs on oxide-free silicon substrates.


[Sublingual specific immunotherapy for rhinoconjunctivitis caused by grass pollens].
Fifty eight patients with rhino-conjunctivitis caused by grass pollen were included in a double-blind study in which they received, by the sub-lingual route over 5 months, either a solution of purified and standardised allergen or a placebo. Assessment of the effect of this immunotherapy, which was done with drops of Stallergenes "5-grass pollen" was by clinical symptoms and the use of authorized drugs and treatments. Compared with the placebo group, the patients on active treatment showed significantly less (P = 0.05 to P = 0.01) rhinitis symptoms (sneezing and rhinorrhea) and conjunctivitis (reddening and tears) during the pollen season. Consumption of nasal cromoglycate solution, of betamethasone and dexchlorpheniramine was significantly lower (p = 0.01) in the desensitised group. Secondary effects were negligible. From this study, it can be concluded that immunotherapy with grass pollen extract, by the sub-lingual route, of patients with rhino-conjunctivitis who were sensitive to these allergens, is efficacious, easy to do, economic and sure.