Silibinin modulates TNF-α and IFN-γ mediated signaling to regulate COX2 and iNOS expression in tumorigenic mouse lung epithelial LM2 cells.
Silibinin inhibits mouse lung tumorigenesis in part by targeting tumor microenvironment. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) can be pro- or anti-tumorigenic, but in lung cancer cell lines they induce pro-inflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). Accordingly, here we examined mechanism of silibinin action on TNF-α + IFN-γ (hereafter referred as cytokine mixture) elicited signaling in tumor-derived mouse lung epithelial LM2 cells. Both signal transducers and activators of the transcription (STAT)3 (tyr705 and ser727) and STAT1 (tyr701) were activated within 15 min of cytokine mixture exposure, while STAT1 (ser727) activated after 3 h. Cytokine mixture also activated Erk1/2 and caused an increase in both COX2 and iNOS levels. Pretreatment of cells with a MEK, NF-κB, and/or epidermal growth factor receptor (EGFR) inhibitor inhibited cytokine mixture-induced activation of Erk1/2, NF-κB, or EGFR, respectively, and strongly decreased phosphorylation of STAT3 and STAT1 and expression of COX2 and iNOS. Also, janus family kinases (JAK)1 and JAK2 inhibitors specifically decreased cytokine-induced iNOS expression, suggesting possible roles of JAK1, JAK2, Erk1/2, NF-κB, and EGFR in cytokine mixture-caused induction of COX2 and iNOS expression via STAT3/STAT1 activation in LM2 cells. Importantly, silibinin pretreatment inhibited cytokine mixture-induced phosphorylation of STAT3, STAT1, and Erk1/2, NF-κB-DNA binding, and expression of COX2, iNOS, matrix metalloproteinases (MMP)2, and MMP9, which was mediated through impairment of STAT3 and STAT1 nuclear localization. Silibinin also inhibited cytokine mixture-induced migration of LM2 cells. Together, we showed that STAT3 and STAT1 could be valuable chemopreventive and therapeutic targets within the lung tumor microenvironment in addition to being targets within tumor itself, and that silibinin inhibits their activation as a plausible mechanism of its efficacy against lung cancer.


Sung melody enhances verbal learning and recall after stroke.
Coupling novel verbal material with a musical melody can potentially aid in its learning and recall in healthy subjects, but this has never been systematically studied in stroke patients with cognitive deficits. In a counterbalanced design, we presented novel verbal material (short narrative stories) in both spoken and sung formats to stroke patients at the acute poststroke stage and 6 months poststroke. The task comprised three learning trials and a delayed recall trial. Memory performance on the spoken and sung tasks did not differ at the acute stage, whereas sung stories were learned and recalled significantly better compared with spoken stories at the 6 months poststroke stage. Interestingly, this pattern of results was evident especially in patients with mild aphasia, in whom the learning of sung versus spoken stories improved more from the acute to the 6-month stages compared with nonaphasic patients. Overall, these findings suggest that singing could be used as a mnemonic aid in the learning of novel verbal material in later stages of recovery after stroke.


Influence of Salmonella in pigs preharvest and during pork processing on human health costs and risks from pork.
Salmonellosis in humans is a costly disease traditionally assumed to be associated with exposure to contaminated food. We have developed a farm-to-fork model that allows estimation of the human health costs and risks associated with Salmonella in pork. This analysis focuses on the stages of the pork production chain up to the point of producing a chilled pork carcass. The model predicts the number of human cases of salmonellosis associated with pork (mean, 99,430; 90% confidence interval, 20,970 to 245,560) and the corresponding social costs (mean, $81.53 million; 90% confidence interval, $18.75 million to $197.44 million). Sensitivity and scenario analyses suggest that changes in Salmonella status during processing are more important for human health risk and have a higher benefit:cost ratio when compared with on-farm strategies for Salmonella control. Specifically, benefit:cost ratios are less than 1 (indicating they are not likely to be profitable from a social economic perspective) for the on-farm strategies of vaccination and meal feeding, whereas rinsing carcasses at various temperatures with and without sanitizer all have benefit:cost ratios greater than 1 (indicating they are profitable from a social economic perspective). This type of modeling is useful for evaluation of the relative cost effectiveness of interventions at different points in the food chain when allocating limited food safety dollars and is best used for examining trends and alternative strategies rather than for providing definitive dollar value estimates of risk. The dollar value estimates must be considered in the context of the wide confidence intervals.


The impact of cobalt-60 source age on biologically effective dose in high-dose functional Gamma Knife radiosurgery.
OBJECTIVE Functional Gamma Knife radiosurgery (GKRS) procedures have been increasingly used for treating patients with tremor, trigeminal neuralgia (TN), and refractory obsessive-compulsive disorder. Although its rates of toxicity are low, GKRS has been associated with some, if low, risks for serious sequelae, including hemiparesis and even death. Anecdotal reports have suggested that even with a standardized prescription dose, rates of functional GKRS toxicity increase after replacement of an old cobalt-60 source with a new source. Dose rate changes over the course of the useful lifespan of cobalt-60 are not routinely considered in the study of patients treated with functional GKRS, but these changes may be associated with significant variation in the biologically effective dose (BED) delivered to neural tissue. METHODS The authors constructed a linear-quadratic model of BED in functional GKRS with a dose-protraction factor to correct for intrafraction DNA-damage repair and used standard single-fraction doses for trigeminal nerve ablation for TN (85 Gy), thalamotomy for tremor (130 Gy), and capsulotomy for obsessive-compulsive disorder (180 Gy). Dose rate and treatment time for functional GKRS involving 4-mm collimators were derived from calibrations in the authors' department and from the cobalt-60 decay rate. Biologically plausible values for the ratio for radiosensitivity to fraction size (α/β) and double-strand break (DSB) DNA repair halftimes (τ) were estimated from published experimental data. The biphasic characteristics of DSB repair in normal tissue were accounted for in deriving an effective τ1 halftime (fast repair) and τ2 halftime (slow repair). A sensitivity analysis was performed with a range of plausible parameter values. RESULTS After replacement of the cobalt-60 source, the functional GKRS dose rate rose from 1.48 to 2.99 Gy/min, treatment time fell, and estimated BED increased. Assuming the most biologically plausible parameters, source replacement resulted in an immediate relative BED increase of 11.7% for GKRS-based TN management with 85 Gy, 15.6% for thalamotomy with 130 Gy, and 18.6% for capsulotomy with 180 Gy. Over the course of the 63-month lifespan of the cobalt-60 source, BED decreased annually by 2.2% for TN management, 3.0% for thalamotomy, and 3.5% for capsulotomy. CONCLUSIONS Use of a new cobalt-60 source after replacement of an old source substantially increases the predicted BED for functional GKRS treatments for the same physical dose prescription. Source age, dose rate, and treatment time should be considered in the study of outcomes after high-dose functional GKRS treatments. Animal and clinical studies are needed to determine how this potential change in BED contributes to GKRS toxicity and whether technical adjustments should be made to reduce dose rates or prescription doses with newer cobalt-60 sources.


Clinical outcomes following sublaminar decompression and instrumented fusion for lumbar degenerative spinal pathology.
Traditional treatment for lumbar stenosis with instability is laminectomy and posterolateral arthrodesis, with or without interbody fusion. However, laminectomies remove the posterior elements and decrease the available surface area for fusion. Therefore, a sublaminar decompression may be a preferred approach for adequate decompression while preserving bone surface area for fusion. A retrospective review of 71 patients who underwent sublaminar decompression in conjunction with instrumented fusion for degenerative spinal disorders at a single institution was performed. Data collected included demographics, preoperative symptoms, operative data, and radiographical measurements of the central canal, lateral recesses, and neural foramina, and fusion outcomes. Paired t-tests were used to test significance of the outcomes. Thirty-one males and 40 females with a median age 60years underwent sublaminar decompression and fusion. A median of two levels were fused. The mean Visual Analog Scale pain score improved from 6.7 preoperatively to 2.9 at last follow-up. The fusion rate was 88%, and the median time to fusion was 11months. Preoperative and postoperative mean thecal sac cross-sectional area, right lateral recess height, left lateral recess height, right foraminal diameter, and left foraminal diameter were 153 and 209mm(2) (p<0.001), 5.9 and 5.9mm (p=0.43), 5.8 and 6.3mm (p=0.027), 4.6 and 5.2mm (p=0.008), and 4.2 and 5.2mm (p<0.001), respectively. Sublaminar decompression provided adequate decompression, with significant increases in thecal sac cross-sectional area and bilateral foraminal diameter. It may be an effective alternative to laminectomy in treating central and foraminal stenosis in conjunction with instrumented fusion.


Scanning X-ray microanalysis of microcarrier cultured endothelial cells: elemental changes during the transition to confluency and the effect of ionophore A23187.
Porcine endothelial cells were grown on microcarrier beads and examined by scanning electron microscopy (SEM) at various times after initiation of culture. Total cell coverage on the bead surface varied from mean values of approximately 7% (3h) to 80% (96h). Beam penetration into the subcellular matrix presents a major problem with SEM X-ray microanalysis of microcarrier cultured cells and necessitates the use of an accelerating voltage not exceeding 10kV. At this voltage and below, X-ray contribution from elements present in the microcarrier bead has minimal effect on the determination of cell elemental levels. Washing the cells with 0.15M sucrose was the least perturbing of the rinsing techniques investigated, removing surface culture medium but not internal diffusible ions. X-ray microanalysis revealed detectable levels of Na, P, S, Cl, K and Ca in the cells, with well-marked changes from initial attachment to confluency. The level of K decreased from approximately 1.0% at 3h to 0.4% at 24h, with a corresponding decrease in the K/Na ratio. This unexpectedly low level of K was invariably observed after 24h, and is a genuine feature of established microcarrier culture. The effect of ionophore A23187 was determined at the 3h culture stage, and resulted in significant increases in the concentration of divalent cations (Mg2+, Ca2+), monovalent ions (Na+, Cl-) and a decrease in the level of K+.


Mast cell numbers in diffuse scleroderma.
Numbers of mast cells were quantitated in the lesions of diffuse scleroderma and morphea. Mast cells increased and then decreased in number in the papillary dermis of diffuse scleroderma. No significant change of mast cell numbers was noted in the reticular dermis. Mast cells increased in the papillary dermis with fine collagen bundles (grade 2 skin of scleroderma) and decreased in the papillary dermis with homogeneous collagen bundles (grade 3 skin of scleroderma). The total number of cells increased in the papillary dermis of grade 1 and 2 skin of scleroderma and decreased in the grade 3 skin of scleroderma. In morphea a reduced number of mast cells was noted in grade 3 lesions. It is suggested that mast cells play an important role in fibrotic process of scleroderma skin.


Evidence for incomplete replication of a penguin poxvirus in cells of mammalian origin.
The recent discovery of a novel poxvirus [penguin-pox virus (PPV)] from Jackass penguins offers the potential of a unique candidate vaccine vector for use in mammals. Infectivity studies were therefore undertaken using a number of mammalian cell lines and chick embryo fibroblasts (CEF). It was shown that the simian CV-1 cell line was able to support replication of the PPV DNA, but no infectious progeny virus could be recovered from the infected cells. Electron microscopy was used to establish the extent of virus morphogenesis in CV-1 cells as compared to that in both chorio-allantoic membranes (CAMs) of hens' eggs and CEF cells. It appears that CV-1 cells are able to support partial maturation of PPV, but that morphogenesis does not proceed to the stage of mature infectious particles. Vaccinia virus promoters were successful in achieving transient gene expression in PPV-infected cells.


Tyrosine phosphorylation of inducible nitric oxide synthase: implications for potential post-translational regulation.
The activation of cultured Raw 264.7 murine macrophages with interferon gamma and lipopolysaccharide results in the expression of inducible nitric oxide synthase (i_NOS) and the subsequent production of nitric oxide. In the present study, the i-NOS expressed in these activated cells was characterized for possible post-translational protein modification by endogenous tyrosine protein kinases. Western-blot analysis using phosphotyrosine antibodies revealed that i-NOS was phosphorylated on tyrosine residues and that this was an early event coinciding with the appearance of newly synthesized i-NOS. A brief exposure of activated cells to vanadate, a tyrosine phosphatase inhibitor, significantly increased the level of i-NOS tyrosine phosphorylation, suggesting that tyrosine phosphatases are dynamically involved in the regulation of this process. Vanadate treatment of activated cells also resulted in a rapid increase in enzyme activity, occurring within 5 min of exposure. Taken together, these results demonstrate that tyrosine kinases and phosphatases are involved in the post-translational modification of i-NOS and may potentially play a role in modulating the functional activity of the enzyme in macrophages.


Diagnosing and treating COPD: understanding the challenges and finding solutions.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that is not fully reversible; symptoms include chronic cough, sputum production, and dyspnea with exertion. An estimated 50% of the 24 million adults in the USA who have COPD are thought to be misdiagnosed or undiagnosed. Factors contributing to this include a low awareness of COPD and the initial symptoms of the disease among the general population, acceptance of these symptoms as a consequence of aging or smoking, some symptomatic similarity to asthma, and failure of health care personnel to use spirometry for diagnosis. Increased familiarization with COPD diagnosis and treatment guidelines, and proactive identification of patients with increased risk of developing COPD through occupational, environmental, or lifestyle exposures, will assist in a timely, accurate diagnosis and effective treatment, which will consequently improve patient outcomes. This review addresses the issues surrounding the diagnosis and misdiagnosis of COPD, their consequences, and how COPD can be better managed within primary care, including consideration of COPD care in patient-centered medical home and chronic care models.


Resistance to integrase inhibitors in children with vertically-transmitted human immunodeficiency virus: First cases in Uruguay.
Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.


Associations between reductions in routine care delivery and non-COVID-19-related mortality in people with diabetes in England during the COVID-19 pandemic: a population-based parallel cohort study.
The Office for Health Improvement and Disparities, part of the UK Government Department of Health and Social Care, highlighted an emerging signal of increased non-COVID-19-related deaths in England between July and October, 2021, with a potentially disproportionate higher increase in people with diabetes. We aimed to substantiate and quantify this apparent excess mortality, and to investigate the association between diabetes routine care delivery and non-COVID-19-related-mortality in people with diabetes before and after the onset of the pandemic. In this population-based parallel cohort study, we used the National Diabetes Audit (NDA) to identify people with diabetes in England. The primary outcome was non-COVID-19-related deaths between July 3, 2021, and Oct 15, 2021, in participants in the 2021 COVID-19 cohort (registered in the NDA in the periods Jan 1, 2019, to March 31, 2020, and Jan 1, 2020, to March 31, 2021) compared with deaths between June 29, 2019, and Oct 11, 2019 (the equivalent 15-week period in 2019) in the 2019 pre-COVID-19 comparator cohort (people registered in the NDA in the periods Jan 1, 2017, to March 31, 2018, and Jan 1, 2018 to March 31, 2019). In each cohort, multivariable logistic regression examined whether completion of eight diabetes care processes in each of the two years before the index mortality year was associated with non-COVID-19-related death, adjusting for diabetes type, age, sex, ethnicity, and socioeconomic deprivation. There were 3 218 570 people in the 2021 cohort and 2 973 645 people in the 2019 comparator cohort. In the 2021 cohort, there were 30 118 non-COVID-19-related deaths in people with diabetes, compared with 27 132 in the comparator cohort, representing an 11% increase (95% CI 9-13). The unadjusted incidence rate ratio (IRR) for mortality in the 2021 cohort compared to the 2019 cohort was 1·026 (1·009-1·043; p=0·003), which was unchanged after adjustment for age, sex, ethnicity, socioeconomic deprivation, and diabetes type (IRR 1·023 (1·006-1·040); p=0·007). In the 2021 cohort, 853 660 (26·5%) people received all eight care processes in 2020-21 compared with 1 547 240 (48·1%) people in 2019-20; a 44·8% (95% CI 44·7-45·0) relative reduction. In the pre-COVID-19 comparator cohort, 1 370 315 (46·1%) people with diabetes received all eight care processes in 2018-19 compared with 1 437 740 (48·3%) in 2017-18; a 4·7% (95% CI 4·5-4·9) relative decrease. Non-COVID-19-related mortality in the 2021 cohort was highest in people who did not receive all eight care processes in either of the two previous years (OR 2·67 [95% CI 2·56-2·77]; p<0·001) compared with those who received all eight care processes in both previous years. Mortality was also significantly higher in those who received all eight care processes in 2019-20 but not in 2020-21 (OR 1·66 [95% CI 1·59-1·73]; p<0·001) or not in 2019-20 but in 2020-21 (OR 1·27 [1·20-1·35]; p<0·001). This pattern of association was similar in the 2019 pre-COVID-19 cohort. Our results show an increased risk of mortality in those who did not receive all eight care processes in one or both of the previous two years. Our results provide evidence that the increased rate of non-COVID-19-related mortality in people with diabetes in England observed between July 3, and Oct 15 of 2021 is associated with a reduction in completion of routine diabetes care processes following the pandemic onset in 2020. None.


Electrooptical remote sensing methods as nondestructive testing and measuring techniques in agriculture.
Characteristics of plants that influence reflectance and emission of electromagnetic energy are discussed. Four main spectral regions are influenced by plants. These wavelength bands include the visible region of chlorophyll absorption, very near ir wavelengths, where plant structure is of major importance, the near and middle ir wavelengths, where water and CO(2) absorption predominate, and the far ir region of thermal ir emission. Soil characteristics that influence reflectance and emission of energy are discussed. Nondestructive testing techniques described include laboratory spectrophotometry, field spectrometry, color photography, radiometry, and generation of line scan imagery. Spectrophotometer and spectrometer reflectance data obtained in the laboratory and field are related to interpretation of remote sensing imagery. Model studies that permit predictions of reflectance from plant canopies are described. The principle of multispectral sensing which permits utilization of multiple wavelength channels for establishing unique plant and soil signature is reviewed.


Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY study.
We assessed the role of low aBMD and impaired architecture-assessed by an HR-pQCT system-in a case-control study of postmenopausal women with fractures. Vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone, independent of aBMD assessed by DXA. Alterations of bone architecture and low BMD both contribute to skeletal fragility, but the contribution of cortical and trabecular architecture, independently of areal BMD (aBMD), to the risk of fracture in postmenopausal women has not been thoroughly evaluated. We assessed the role of impaired architecture and low BMD in postmenopausal women with fractures. A matched case-control study in women from the OFELY cohort was performed after 13 years of follow-up. One hundred one women (mean, 73.7+/-8 years) who sustained a fragility fracture during the follow-up of the study were age-matched with one control who never had a fracture. Density and architecture at the distal radius and tibia were measured with high-resolution pQCT (HR-pQCT) using an XTreme CT (Scanco Medical AG, Bassersdorf, Switzerland). aBMD at the total hip and ultradistal radius was measured by DXA. There were 80 peripheral fractures in 72 women, 44 vertebral fractures in 34 women, and both types of fractures in 5 women over the 14 years of follow-up. At the distal radius, women with fractures had lower volumetric total (D tot) and trabecular (D trab) BMDs, BV/TV, cortical thickness (Cort Th), trabecular number (TbN), and trabecular thickness (TbTh) and higher trabecular separation (TbSp) and distribution of trabecular separation (TbSpSd) than controls without fractures. In a logistic model, each SD decrease of volumetric total and trabecular densities was associated with a significantly increased risk of fracture at both sites (ORs ranged from 2.00 to 2.47). After adjusting for aBMD measured by DXA at the ultradistal radius, differences between cases and controls remained significant for D trab, and there was a similar trend for TbN, TbSp, and TbSpSd, with adjusted ORs ranging from 1.32 to 1.50. At the distal tibia, before and after adjusting for total hip aBMD, differences between cases and controls remained significant for D tot, D trab, Cort Th, and TbTh, with adjusted ORs ranging from 1.80 to 2.09. In postmenopausal women, vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone that can be assessed noninvasively and that are partially independent of aBMD assessed by DXA.


Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus.
Astrocytes in the hippocampus express high-affinity glutamate transporters that are important for lowering the concentration of extracellular glutamate after release at excitatory synapses. These transporters exhibit a permeability to chaotropic anions that is associated with transport, allowing their activity to be monitored in cell-fee patches when highly permeant anions are present. Astrocyte glutamate transporters are highly temperature sensitive, because L-glutamate-activated, anion-potentiated transporter currents in outside-out patches from these cells exhibited larger amplitudes and faster kinetics at 36 degreesC than at 24 degreesC. The cycling rate of these transporters was estimated by using paired applications of either L-glutamate or D-aspartate to measure the time necessary for the peak of the transporter current to recover from the steady-state level. Transporter currents in patches recovered with a time constant of 11.6 msec at 36 degreesC, suggesting that either the turnover rate of native transporters is much faster than previously reported for expressed EAAT2 transporters or the efficiency of these transporters is very low. Synaptically activated transporter currents persisted in astrocytes at physiological temperatures, although no evidence of these currents was found in CA1 pyramidal neurons in response to afferent stimulation. L-glutamate-gated transporter currents were also not detected in outside-out patches from pyramidal neurons. These results are consistent with the hypothesis that astrocyte transporters are responsible for taking up the majority of glutamate released at Schaffer collateral-commissural synapses in the hippocampus.


Exploring political influences on evidence-based non-communicable disease prevention across four countries.
Implementation of evidence-based practices can improve efficiency and effectiveness of public health efforts. Few studies have explored the political contextual factors that impact implementation of evidence-based non-communicable disease prevention (EBNCDP). This study aimed to do so in Australia, Brazil, China and the United States. Investigators conducted 10-13 qualitative, semi-structured interviews of public health practitioners working in functionally similar public health organizations in each country (total N = 50). Study participants were identified through purposive sampling and interviews were structured around an interview guide covering six domains related to EBNCDP. Interviewees from all four countries identified funding as the primary politically-influenced barrier to implementing EBNCDP. Similarly widespread barriers included government funding priorities that shift based on who is in power and the difficulty of convincing policy-makers and funders that non-communicable disease prevention is a wise investment of political capital. Policymakers who are not evidence-driven was another common barrier even in the United States and Australia, where EBNCDP is more established. Findings suggest that political contextual factors influence EBNCDP and vary to an extent by country, though certain factors seem to be universal. This can aid public health practitioners, political leaders, and policymakers in advocating for conditions and policies that encourage evidence-based practice.


["E" rosette formation in "active" T lymphocytes: phenomenon modulated by intracellular level of cyclic AMP and GMP (author's transl)].
The rosette formation envolving the binding of sheep red blood cells (SRBC) with active T lymphocytes was activated when the lymphocytes were incubated with levamisole, acetylcholine or carbamylcholine. Similar activation was seen when to the incubation medium was added substances of glucose metabolism (lactate, fumarate or succinate) or triphosphate de adenosina--ATP. The lymphocytes incubation with aminophyline, isoproterenol or 2-4-dinitrofenol--DNP--inhibited the rosette formation. The inhibition promoted by aminophyline was reversed by levamisole, acetylcholine or carbamylcholine, but not when lactate or ATP was used. When the rosette formation inhibition was caused by DNP, the reversion was only possible by ATP and no affect occurred if guanil cyclase activators were added to the incubation medium.


Public Health Service study of Reye's syndrome and medications. Report of the main study.
Between January 1985 and May 1986, following completion of a pilot study, a main study concerning the possible association between Reye's syndrome and salicylates was conducted. Twenty-seven patients with stage II or deeper Reye's syndrome whose diagnoses were confirmed by an expert panel and who had appropriate antecedent illnesses (chickenpox, respiratory illness, or gastrointestinal illness) prior to the onset of Reye's syndrome were compared with 140 controls matched for age, race (black or not black), and type and timing of onset of antecedent illness. Controls were selected from the same hospital, emergency room, or school as case-patients or were identified by random-digit telephone dialing. As in the pilot study, a strong statistical association with ingestion of salicylates during the antecedent illness and prior to the onset of Reye's syndrome was observed (odds ratio, 40; lower 95% confidence limit, 5.8). Analysis of the independent risk of aspirin and nonaspirin salicylates revealed a significant association with aspirin (odds ratio, 26; lower 95% confidence limit, 6.4); the independent risk of nonaspirin salicylates could not be assessed because only two cases were not exposed to aspirin. Assessment of epidemiologic issues of concern, including case-control differences in the severity of the antecedent illness, did not explain the high odds ratios that were observed. The high percentage of patients with Reye's syndrome exposed to salicylates (greater than or equal to 90%) in this and prior studies suggests that, though the reported incidence of Reye's syndrome has declined in recent years, concomitant with a decline in salicylate use among children, a majority of Reye's syndrome cases may be attributable to salicylate use.


Intraductal papillary mucinous neoplasms of the pancreas: clinical surveillance and malignant progression, multifocality and implications of a field-defect.
Intraductal papillary mucinous neoplasms (IPMNs) are a heterogeneous group of mucin producing cystic tumors that involve the main pancreatic duct and/or branch ducts and may be associated with invasive carcinoma. Predicting the risk of malignant transformation of an IPMN lesion can be challenging. The Sendai criteria, based in large part on radiographic imaging features, help guide surgical intervention based on the stratification of cysts into high and low risk lesions for malignancy. Invasive carcinoma may develop in the index IPMN lesion or in a separate site within the pancreas, supporting the concept of a field defect in IPMN tumorigenesis. This stresses the importance of evaluation of the entire pancreas upon diagnosis of IPMN and continued surveillance of the residual pancreas following resection. Herein, the authors summarize the data presented at the 2012 ASCO Gastrointestinal Cancers Symposium regarding prevalence and site of invasive carcinoma detected in patients undergoing surveillance for IPMN (Abstract #152).


Parental self-efficacy in childhood overweight: validation of the Lifestyle Behavior Checklist in the Netherlands.
Evaluating whether parental challenges and self-efficacy toward managing children's lifestyle behaviors are successfully addressed by interventions requires valid instruments. The Lifestyle Behavior Checklist (LBC) has recently been developed in the Australian context. It consists of two subscales: the Problem scale, which measures parental perceptions of children's behavioral problems related to overweight and obesity, and the Confidence scale, measuring parental self-efficacy in dealing with these problems. The aim of the current study was to systematically translate the questionnaire into Dutch and to evaluate its internal consistency, construct validity and test-retest reliability. The LBC was systematically translated by four experts at Maastricht University. In total, 392 parents of 3-to13-year-old children were invited to fill out two successive online questionnaires with a two-week interval. Of these, 273 parents responded to the first questionnaire (test, response rate = 69.6%), and of the 202 who could be invited for the second questionnaire (retest), 100 responded (response rate = 49.5%). We assessed the questionnaire's internal consistency (Cronbach's α), construct validity (Spearman's Rho correlation tests, using the criterion measures: restrictiveness, nurturance, and psychological control), and test-retest reliability (Spearman's Rho correlation tests). Both scales had high internal consistency (Cronbach's α ≥ 0.90). Spearman correlation coefficients indicated acceptable test-retest reliability for both the Problem scale (rs = 0.74) and the Confidence scale (rs = 0.70). The LBC Problem scale was significantly correlated to all criterion scales (nurturance, restrictiveness, psychological control) in the hypothesized direction, and the LBC Confidence scale was significantly correlated with nurturance and psychological control in the hypothesized direction, but not with restrictiveness. The Dutch translation of the LBC was found to be a reliable and reasonably valid questionnaire to measure parental perceptions of children's weight-related problem behavior and the extent to which parents feel confident to manage these problems.


Blasticidin S deaminase gene (BSD): a new selection marker gene for transformation of Arabidopsis thaliana and Nicotiana tabacum.
Arabidopsis thaliana and Nicotiana tabacum were transformed to blasticidin S (BS) resistance with BSD (the BS deaminase gene from Aspergillus terreus) using the Agrobacterium-mediated transformation method. Expression of BSD allowed direct selection of transformants by the fungicide, and both kinds of transgenic plants showed high level of resistance phenotype at 100 ppm of BS sprayed on the leaves. Using Botrytis cinerea, the causal fungus of gray mold disease, it was exemplified that application of BS could control the disease in transgenic tobacco with negligible phytotoxicity.


Characterization of autostimulatory and transforming growth factors from human melanoma cells.
Serum-free growth of the human malignant melanoma cell line Hs0294 is associated with production of transforming growth factor-alpha and an autostimulatory melanoma mitogen (melanoma growth-stimulatory activity, MGSA). The transforming activity is characterized by stimulation of anchorage-independent growth of normal rat kidney fibroblasts and competition with 125I-epidermal growth factor for binding to normal rat kidney cells. The second activity, MGSA, stimulates the anchorage-dependent growth of human melanoma cells in serum-free culture medium. When acetic acid extracts of Hs0294 conditioned medium are subjected to Bio-Gel P-30 chromatography followed by reverse-phase high-pressure liquid chromatography, the majority of the transforming growth factor-alpha elutes at 30 +/- 4% acetonitrile, while the major peak of MGSA elutes at 35 +/- 3% acetonitrile. These data indicate that the anchorage-dependent serum-free growth of the Hs0294 human melanoma cell line is apparently dependent upon the autostimulatory melanoma mitogen, MGSA, which is separable from the 125I-epidermal growth factor competing activity produced by these cells.


Brain White Matter Microstructure as a Risk Factor for Cognitive Decline After Chemotherapy for Breast Cancer.
Cognitive decline is frequently observed after chemotherapy. As chemotherapy is associated with changes in brain white matter microstructure, we investigated whether white matter microstructure before chemotherapy is a risk factor for cognitive decline after chemotherapy. Neuropsychologic tests were administered before and 6 months (n = 49), 2 years (n = 32), and 3 years (n = 32) after chemotherapy in patients with breast cancer receiving anthracycline-based chemotherapy (BC + CT group), at matched intervals to patients with BC who did not receive systemic therapy (BC - CT group: n = 39, 23, and 19, respectively) and to no-cancer controls (NC group: n = 37, 29, and 28, respectively). Using multivariate normative comparison, we evaluated to what extent the cognitive profiles of patients deviated from those of controls. Fractional anisotropy (FA), derived from magnetic resonance diffusion tensor imaging, was used to measure white matter microstructure before treatment. FA was evaluated as a risk factor for cognitive decline, in addition to baseline age, fatigue, cognitive complaints, and premorbid intelligence quotient. We subsequently ran voxel-wise diffusion tensor imaging analyses to investigate white matter microstructure in specific nerve tracts. Low FA independently predicted cognitive decline early (6 months, P = .013) and late (3 years, P < .001) after chemotherapy. FA did not predict cognitive decline in the BC - CT and NC groups. Voxel-wise analysis indicated involvement of white matter tracts essential for cognitive functioning. Low FA may reflect low white matter reserve. This may be a risk factor for cognitive decline after chemotherapy for BC. If validated in future trials, identification of patients with low white matter reserve could improve patient care, for example, by facilitating targeted, early interventions or even by influencing choices of patients and doctors for receiving chemotherapy.


Induction of gamma-glutamyl transpeptidase mRNA by platinum complexes in a human ovarian carcinoma cell line.
Elevation of glutathione (GSH) is widely observed in cellular resistance to platinum agents. Our previous studies have shown that sublines of human ovarian carcinoma cell line A2780, which exhibited low levels of resistance to oxaliplatin, showed elevated steady state levels of mRNA and activity of gamma-glutamyl transpeptidase (gamma-GT, EC 220.127.116.11), but not of gamma-glutamylcysteine synthetase (gamma-GCS, EC 22.214.171.124) [El-akawi et al., Cancer Lett. 105:5-14; 1966]. To understand this phenomenon better, we have studied the effect of single exposures of oxaliplatin or cisplatin on the mRNA expression of gamma-GT and gamma-GCS in A2780 cells. The mRNAs of gamma-GT and gamma-GCS were measured by reverse transcriptase PCR, with quantitation of the PCR product by HPLC; mRNA levels are expressed as ratios to beta-actin mRNA, used as an endogenous standard. GSH was measured by HPLC. The gamma-GT activity was measured by a colorimetric assay. Single exposures of cells to oxaliplatin induced a time- and concentration-dependent increase in the mRNA of gamma-GT, but not of gamma-GCS. Cisplatin also induced an elevation in gamma-GT mRNA, but to a lower degree. The gamma-GT enzyme activity increased corresponding to the elevation in mRNA expression. The gamma-GT-induced cells showed an increase in cellular GSH when incubated in medium containing GSH. The data suggest that a) single, brief exposures to pharmacologically relevant concentrations of platinum complexes induce elevation in mRNA of gamma-GT, b) elevation in gamma-GT mRNA translates into elevated gamma-GT activity and increase in GSH salvage, and c) the degree of induction of gamma-GT mRNA differs between platinum complexes.


Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas.
The role of antibiotic treatment in early stage gastric mucosa associated lymphoid tissue (MALT) lymphoma not associated with Helicobacter pylori infection has not been investigated. Six patients with localised gastric MALT lymphoma underwent antibiotic treatment with clarithromycin, metronidazole, and pantoprazole. Staging, including endosonography plus gastroscopy, computed tomography of the thorax and abdomen, colonoscopy, magnetic resonance imaging of the salivary glands, and bone marrow biopsy were performed to rule out distant spread of the disease. In addition, MALT specific genetic changes, including reverse transcriptase-polymerase chain reaction for t(11;18)(q21;q21), were tested in all patients. H pylori infection was ruled out by histology, urease breath test, serology, and stool antigen testing. All six patients had MALT lymphoma restricted to the stomach, and no evidence of infection with H pylori was found. Only one patient tested positive for t(11;18)(q21;q21) while the remaining five displayed no genetic aberrations. Following antibiotic treatment, endoscopic controls were performed every three months. Five patients responded with lymphoma regression between three and nine months following antibiotic treatment (one partial remission and four complete responses). One patient had stable disease for 12 months and was then referred for chemotherapy. Patients with early stage gastric MALT lymphoma negative for H pylori might still benefit from antibiotic treatment as the sole treatment modality.


Antimicrobial use and antimicrobial resistance: a population perspective.
The need to stem the growing problem of antimicrobial resistance has prompted multiple, sometimes conflicting, calls for changes in the use of antimicrobial agents. One source of disagreement concerns the major mechanisms by which antibiotics select resistant strains. For infections like tuberculosis, in which resistance can emerge in treated hosts through mutation, prevention of antimicrobial resistance in individual hosts is a primary method of preventing the spread of resistant organisms in the community. By contrast, for many other important resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium resistance is mediated by the acquisition of genes or gene fragments by horizontal transfer; resistance in the treated host is a relatively rare event. For these organisms, indirect, population-level mechanisms of selection account for the increase in the prevalence of resistance. These mechanisms can operate even when treatment has a modest, or even negative, effect on an individual host's colonization with resistant organisms.


Phosphate transporters of the SLC20 and SLC34 families.
Transport of inorganic phosphate (Pi) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na(+)-dependent, secondary-active cotransporters to transport Pi across cell membranes. The SLC34 proteins are expressed in specific organs important for Pi homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in Pi reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates Pi absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity, regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarizes our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiology and pharmacology.


Modulation of secretory leukoprotease inhibitor gene expression in human bronchial epithelial cells by phorbol ester.
Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease, helps to protect the epithelial surface of the airways from the destructive capacity of neutrophil elastase. Based on the recognition that SLPI levels can increase in the presence of airway inflammation, we hypothesized that inflammatory stimuli should modulate the expression of the SLPI gene in airway epithelial cells. To evaluate this, the modulation of SLPI gene expression with various inflammatory stimuli was evaluated in the HS-24 human bronchial epithelial cell line. After preliminary studies showed that several inflammatory mediators enhanced SLPI messenger RNA (mRNA) levels, PMA was used as a model inflammatory stimulus. PMA significantly increased the level of 0.7-kb SLPI mRNA transcripts in HS-24 cells in a dose- and time-dependent fashion and increased the amount of SLPI protein in the culture supernatant. Nuclear run-on analyses showed that the SLPI gene transcription rate increased approximately twofold after PMA stimulation. Transfection studies using fusion genes composed of fragments of up to 1.2 kb of the 5' flanking sequence of the SLPI gene and a luciferase reporter gene demonstrated potent promoter activity in the 131-bp segment (-115 to +16 relative to the transcription start site), and all longer segments up to 1.2 kb, whereas smaller segments showed low promoter activity. An 18-bp element (-98 to -115), in a region with homology to PMA-responsive regions in the Moloney murine leukemia virus enhancer and the IL-8 gene, was shown to be of importance in the level of transcription of the SLPI gene. However, this element was not responsible for the upregulation of SLPI gene expression by PMA. Evaluation of HS-24 cells in the presence of actinomycin D demonstrated that SLPI mRNA transcripts were very stable and became more so in the presence of PMA. Thus, SLPI gene expression in airway epithelial cells can be upregulated by an inflammatory stimulus, and this modulation is regulated at both the transcriptional and posttranscriptional levels. These mechanisms of SLPI upregulation likely play a role in defending the epithelial surface in the local milieu of inflammatory lung diseases.


Alstrom syndrome: a case report.
Alstrom syndrome is a rare disorder characterized by early obesity, loss of central vision, diabetes mellitus, hearing loss and short stature. Previous studies, have reported no information regarding oral findings. This article describes oral findings in two cases of Alstrom syndrome. In both cases, gingivitis was present and also light yellow-brown discolored enamel bands were observed on the anterior teeth. This staining may have resulted from discoloration of the preexisting slight band-like enamel hypoplasia. The gingiva was examined histologically by light and transmission electron microscopy. Irregular thickness of the basal lamina and delamination of the myelin sheath were detected by transmission electron microscopy. There is no information about pathological odontogenesis in Alstrom syndrome in previous reports. Oral present findings may contribute further information about the clinical manifestations of Alstrom syndrome.


Coaggregation occurs between microorganisms isolated from different environments.
Coaggregation, the specific recognition and adherence of different microbial species, is thought to enhance biofilm formation. To date, no studies have focused on the ability of microorganisms isolated from a broad range of environments to coaggregate with each other and it is unclear whether coaggregation promotes the transmission of microorganisms between environmental niches. We aimed to evaluate the coaggregation ability of 29 bacteria and one fungus, isolated from a range of different environments, and to characterize the cell-surface polymers that mediate coaggregation between selected pairs. Strains were categorized as belonging to one of the four microbial archetypes: aquatic, broad environment, human opportunistic pathogen or human oral. A total of 23 of the 30 strains (77%) coaggregated with at least one other and 21/30 (70%) coaggregated with strains belonging to other archetypes. Nasopharyngeal bacteria belonging to the human opportunistic pathogen archetype showed the least number of coaggregations, and five Haemophilus influenzae strains did not coaggregate. Protease and sugar treatments indicated that coaggregation between strains of different archetypes was often mediated by lectin-saccharide interactions (9 of 15 evaluated pairs). In conclusion, coaggregation can occur between taxonomically disparate species isolated from discrete environments. We propose that these organisms be labeled as 'cross-environment coaggregating organisms'. The ability to coaggregate may aid species to colonize non-indigenous biofilms.


You shouldn't have: your brain on others' crimes.
Our legal system requires assigning responsibility for crimes and deciding on appropriate punishments. A new fMRI study by Buckholtz et al. in this issue of Neuron reveals that the right dorsolateral prefrontal cortex (rDLPFC) plays a key role in these cognitive processes. This finding sheds light on the neural mechanisms underlying moral judgment from a third-party perspective.


Effect of functional feeds on fatty acid and eicosanoid metabolism in liver and head kidney of Atlantic salmon (Salmo salar L.) with experimentally induced heart and skeletal muscle inflammation.
Heart and Skeletal Muscle Inflammation (HSMI) is an emerging viral disease caused by a novel Atlantic salmon reovirus (ASRV) affecting farmed fish. Primary symptoms associated with HSMI include myocardial and skeletal muscle necrosis indicating a severe inflammatory process. Recently, we applied the concept of clinical nutrition to moderate the long-term inflammatory process associated with HSMI in salmon subjected to experimental ASRV challenge. The use of functional feeds with lower lipid (hence energy) content reduced the inflammatory response to ASRV infection and the severity of associated heart lesions. The aim of the present study was to elucidate possible mechanisms underpinning the observed effects of the functional feeds, focussing on eicosanoid and fatty acid metabolism in liver and head kidney. Here we show that liver was also a site for histopathological lesions in HSMI showing steatosis reflecting impaired lipid metabolism. This study is also the first to evaluate the expression of a suite of key genes involved in pathways relating diet and membrane phospholipid fatty acid compositions, and the inflammatory response after ASRV infection. The expression of hepatic Δ6 and Δ5 desaturases was higher in fish fed the functional feeds, potentially increasing their capacity for endogenous production and availability of anti-inflammatory EPA. Effects on mobilization of lipids and changes in the LC-PUFA composition of membrane phospholipids, along with significant changes in the expression of the genes related to eicosanoid pathways, showed the important role of the head kidney in inflammatory diseases caused by viral infections. The results from the present study suggest that clinical nutrition through functional feeding could be an effective complementary therapy for emerging salmon viral diseases associated with long-term inflammation.


Characterization of the Xenopus Hox 2.4 gene and identification of control elements in its intron.
We report on the Xenopus homolog of the Hox 2.4 gene. This gene occupies the next to 5'-most position in the Xenopus Hox2 complex. Hox 2.4 RNA is first detected at the early neurula stage, reaching a peak at the early tailbud stage, and is localized in the middle and posterior portions of the embryos. Antibodies raised against a fusion protein show expression of Hox 2.4 protein in Xenopus embryos in a band located in the mid spinal cord. Thus, the protein is expressed in a narrower domain than that of Hox 2.4 mRNA. The Xenopus Hox 2.4 antibody cross-reacts readily with mouse embryonic tissue, where the protein is detected in migrating neural crest cells, the dorsal portion of the spinal cord, somites, lateral plate mesoderm, and in the forelimb bud. The Xenopus Hox 2.4 intron shares considerable sequence identity with the intron in the mouse homolog. A reporter gene containing an element from this intron which can bind homeodomain proteins is activated following microinjection into Xenopus embryos. The short distance between the end of the Hox 2.4 cDNA and the start site of the neighboring gene in the complex raises the possibility that this transcriptional element might be shared by two Hox genes.


Large-Scale Functional Group Symmetry-Adapted Perturbation Theory on Graphical Processing Units.
Symmetry-adapted perturbation theory (SAPT) is a valuable method for analyzing intermolecular interactions. The functional group SAPT partition (F-SAPT) has been introduced to provide additional insight into the origins of noncovalent interactions. Until now, SAPT analysis has been too costly for large ligand-protein complexes where it could provide key insights for chemical modifications that might improve ligand binding. In this paper, we present a large-scale implementation of a variant of F-SAPT. Two pragmatic choices are made from the outset to render the problem tractable: (1) Ab initio computation of dispersion and exchange-dispersion is replaced with Grimme's empirical dispersion correction. (2) Basis sets with augmented functions are avoided to allow for efficient integral screening. These choices allow the F-SAPT analysis to be written largely in terms of Coulomb and exchange matrix builds which have been implemented efficiently on graphical processing units (GPUs). Our formulation of F-SAPT is routinely applicable to molecules with well over 3000 atoms and 25,000 basis functions and is particularly optimized for the case where one monomer is significantly larger than the other. This is demonstrated explicitly with results from F-SAPT analysis of the full indinavir @ HIV-II protease complex (PDB ID 1HSG ) in a polarized double-ζ basis.


Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms.
Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII-induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.


Chryseobacterium indologenes infection: a case report.
A case of Chryseobacterium indologenes infection is reported, identified in an invasive mechanic ventilation patient's tracheal aspiration material. Epidemiological, microbiological, and intensive care unit therapy aspects are discussed. The patient was a 30 years-old male, admitted with idiopathic medullary aplasia and febrile neutropenia, referred to the intensive care unit with severe bronchopneumonia and sepsis of pulmonary origin. Most of the previously reported Chryseobacterium indologenes infection cases were associated with severe diseases and polymicrobial infections which could make difficult interpreting antimicrobial therapy options against this agent.


Plasma fibronectin during myocardial ischemia-reperfusion: effects of magnesium, diltiazem, and a novel Mac-1 inhibitor.
The important role of fibronectin (Fn) has been recognized in patients with ischemic heart disease. However, serial changes of Fn during both brief and prolonged ischemia-reperfusion are poorly known. Plasma Fn was measured during acute myocardial infarction (AMI) and myocardial stunning (MS), and in the absence of myocardial injury. The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on the level of Fn were elucidated. Forty-nine swine underwent prolonged (50 min) or brief (8 min) coronary artery occlusion followed by reperfusion, while six control animals were free of ischemia. During the AMI experiments, plasma Fn underwent a significant progressive increase. Mg or diltiazem similarly affects the plasma Fn, reducing its release during the entire reperfusion period, and did not influence the plasma Fn in the absence of myocardial injury. Contrarily, Mac-1 inhibition resulted in the Fn elevation in controls, and during the occlusion phase, with no significant effect during reperfusion. There were no changes in the plasma Fn during MS, while inhibition of Mac-1 was associated with the significant increase of Fn during ischemia-reperfusion. Ability of Mg, diltiazem, and leumedins to modulate plasma Fn level may have direct clinical implications for the use of these agents in patients with coronary artery disease.


Discussion of Trial Designs for Biomarker Identification and Validation Through the Use of Case Studies.
With the launch of the National Cancer Institute's Precision Medicine Initiative in 2015, there has been a shift to trial designs that tailor health care solutions to individual patients by using a screening platform and by moving away from the one-trial/one-biomarker-at-a-time approach. To make precision medicine a reality, it is critical to identify and validate potential biomarkers to help select patients who will truly benefit from a targeted therapy. In this article, we discuss five trial designs: enrichment, umbrella, basket, subgroup, and window of opportunity. For each trial design, we describe the design characteristics, use ongoing or completed trials as case studies, provide any recent advances to the trial design, and discuss advantages and disadvantages of each design.


HPLC -DAD analysis, anti-inflammatory and anti-arthritic potentials of Coronopus didymus (L.) Sm. extracts: effects on pro- and anti-inflammatory cytokines, COX-2, I-κβ, NF-κβ and oxidative stress biomarkers.
Coronopus didymus (L.) Sm. (CD) has been traditionally used to treat pain, rheumatism, and inflammation. This study was planned to appraise the anti-oxidant, anti-inflammatory and anti-arthritic potentials of CD (whole plant) aqueous ethanolic (CDAEE) and aqueous extracts (CDAE) and chemical characterization by high-performance liquid chromatography-diode array detector. In vivo anti-inflammatory (Carrageenan induced paw edema, and Xylene induced ear edema assays) and anti-arthritic potentials were evaluated in Wistar rats. Both extracts showed significant (p < 0.0001) in vitro free radical scavenging and in vitro anti-arthritic potentials by inhibition of protein denaturation and stabilization of the HRBC membrane and anti-oedematogenic potential, whereas more activity was expressed by CDAEE. In complete Freund's adjuvant-induced arthritic model, the CDAEE at 200, 400, and 800 mg kg-1 and methotrexate (1 mg kg-1) profoundly (p < 0.05) reduced the arthritic score and paw edema, restored body and immune organ weight, and altered blood parameters and oxidative stress biomarkers. The qRT-PCR analysis revealed that CDAEE at 400 mg kg-1 significantly (p < 0.0001) downregulated TNF-α (2.22 ± 0.16 fold), IL-6 (2.29 ± 0.05 fold), IL-1β (2.10 ± 0.01 fold), COX-2 (2.45 ± 0.02 fold), and NF-ĸβ (2.72 ± 0.06 fold) and considerably upregulated IL-10 (58.84 ± 0.67%), IL-4 (76.16 ± 2.79%) and I-kβ (75.45 ± 0.17%) in arthritic rats in contrast to disease control and methotrexate as evidenced from the joint histology. These findings suggested the antioxidant, anti-inflammatory and anti-arthritic activities of C. didymus, which might be due to the presence of quercetin, ferulic acid, dihydromyricetin, apigenin, vitexin, and kaempferol in CDAEE.


Transplantation for metastatic liver disease.
The liver is a common site of metastases from many cancers, particularly those originating in the gastrointestinal tract. Liver transplantation is an uncommonly used but promising and at times controversial treatment option for neuroendocrine and colorectal liver metastases. Transplantation with meticulous patient selection has been associated with excellent long-term outcomes in individuals with neuroendocrine liver metastases, but questions remain regarding the role of transplantation in those who could also be eligible for hepatectomy, the role of neoadjuvant/adjuvant treatments in minimising recurrence, and the optimal timing of the procedure. A prospective pilot study of liver transplantation for unresectable colorectal liver metastases that reported a 5-year overall survival rate of 60% reinvigorated interest in this area following initially dismal outcomes. This has been followed by larger studies, and prospective trials are ongoing to quantify the potential benefits of liver transplantation over palliative chemotherapy. This review provides a critical summary of currently available knowledge on liver transplantation for neuroendocrine and colorectal liver metastases, and highlights avenues for further study to address gaps in the evidence base.


The impact of antibacterial peptides on bacterial lipid membranes depends on stage of growth.
The impact of maculatin 1.1 (Mac1) on the mechanical properties of supported lipid membranes derived from exponential growth phase (EGP) and stationary growth phase (SGP) E. coli lipid extracts was analysed by surface plasmon resonance and atomic force microscopy. Each membrane was analysed by quantitative nanomechanical mapping to derive measurements of the modulus, adhesion and deformation in addition to bilayer height. Image analysis revealed the presence of two domains in the EGP membrane differing in height by 0.4 nm. Three distinct domains were observed in the SGP membrane corresponding to 4.2, 4.7 and 5.4 nm in height. Using surface plasmon resonance, Mac1 was observed to bind strongly to both membranes and then disrupt the membranes as evidenced by a sharp drop in baseline. Atomic force microscopy (AFM) topographic analysis revealed the formation of domains of different height and confirmed that membrane destruction was much faster for the SGP derived bilayer. Moreover, Mac1 selectively disrupted the domain with the lowest thickness, which may correspond to a liquid ordered domain. Overall, the results provide insight into the role of lipid domains in the response of bacteria to antimicrobial peptides.


Surface modification of surface sol-gel derived titanium oxide films by self-assembled monolayers (SAMs) and non-specific protein adsorption studies.
Biological events occurring at the implant-host interface, including protein adsorption are mainly influenced by surface properties of the implant. Titanium alloys, one of the most widely used implants, has shown good biocompatibility primarily through its surface oxide. In this study, a surface sol-gel process based on the surface reaction of metal alkoxides with a hydroxylated surface was used to prepare ultrathin titanium oxide (TiOx) coatings on silicon wafers. The oxide deposited on the surface was then modified by self-assembled monolayers (SAMs) of silanes with different functional groups. Interesting surface morphology trends and protein adhesion properties of the modified titanium oxide surfaces were observed as studied by non-specific protein binding of serum albumin. The surface properties were investigated systematically using water contact angle, ellipsometry, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) measurements. Results showed that the surface sol-gel process predominantly formed homogeneous, but rough and porous titanium oxide layers. The protein adsorption was dependent primarily on the silane chemistry, packing of the alkyl chains (extent of van der Waals interaction), morphology (porosity and roughness), and wettability of the sol-gel oxide. Comparison was made with a thermally evaporated TiOx-Ti/Si-wafer substrate (control). This method further extends the functionalization of surface sol-gel derived TiOx layers for possible titanium alloy bioimplant surface modification.


Effects of injection--drug injury on ankle mobility and chronic venous disorders.
To identify potential confounders and test a causal model of injection-site risk, chronic venous disorders (CVD), and ankle mobility. The reliability and validity of goniometry measurements of ankle mobility were also of interest because they are seldom performed in people with a history of injection-drug use. The study was a test-retest design, consisting of 104 participants from a methadone maintenance treatment center. Each participant provided demographic information, health and drug histories, and underwent bilateral ankle goniometric measures of dorsiflexion, plantar flexion, inversion, and eversion. The clinical portion of the Clinical-Etiology-Anatomy-Pathophysiology (CEAP)was used to classify CVD severity. Reliability of goniometry measurements ranged from .70 to .90. Causal modeling supported hypotheses of increased risk from leg injection and reciprocal effects involving ankle mobility and disease progression. Ankle inversion mobility was the strongest indicator of ankle mobility. Injury to the lower extremities from IDU affected CVD and mobility. Further research should include assessment of comorbidity and other potential confounders. Ankle inversion should remain part of the goniometry assessment.


Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury.
Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.


Ca(2+) signaling in arterioles and small arteries of conscious, restrained, optical biosensor mice.
Two-photon fluorescence microscopy and conscious, restrained optical biosensor mice were used to study smooth muscle Ca(2+) signaling in ear arterioles. Conscious mice were used in order to preserve normal mean arterial blood pressure (MAP) and sympathetic nerve activity (SNA). ExMLCK mice, which express a genetically-encoded smooth muscle-specific FRET-based Ca(2+) indicator, were equipped with blood pressure telemetry and immobilized for imaging. MAP was 101 ± 4 mmHg in conscious restrained mice, similar to the freely mobile state (107 ± 3 mmHg). Oscillatory vasomotion or irregular contractions were observed in most arterioles (71%), with the greatest oscillatory frequency observed at 0.25 s(-1). In a typical arteriole with an average diameter of ~35 μm, oscillatory vasomotion of a 5-6 μm magnitude was accompanied by nearly uniform [Ca(2+)] oscillations from ~0.1 to 0.5 μM, with maximum [Ca(2+)] occurring immediately before the rapid decrease in diameter. Very rapid, spatially uniform "Ca(2+) flashes" were also observed but not asynchronous propagating Ca(2+) waves. In contrast, vasomotion and dynamic Ca(2+) signals were rarely observed in ear arterioles of anesthetized exMLCK biosensor mice. Hexamethonium (30 μg/g BW, i.p.) caused a fall in MAP to 74 ± 4 mmHg, arteriolar vasodilation, and abolition of vasomotion and synchronous Ca(2+) transients. MAP and heart rate (HR) were normal during high-resolution Ca(2+) imaging of conscious, restrained mice. SNA induced continuous vasomotion and irregular vasoconstrictions via spatially uniform Ca(2+) signaling within the arterial wall. FRET-based biosensor mice and two-photon imaging provided the first measurements of [Ca(2+)] in vascular smooth muscle cells in arterioles of conscious animals.


The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin beta subunits to the cytoskeleton.
Talin1 is a large cytoskeletal protein that links integrins to actin filaments through two distinct integrin binding sites, one present in the talin head domain (IBS1) necessary for integrin activation and a second (IBS2) that we have previously mapped to talin residues 1984-2113 (fragment J) of the talin rod domain (1 Tremuth, L., Kreis, S., Melchior, C., Hoebeke, J., Ronde, P., Plancon, S., Takeda, K., and Kieffer, N. (2004) J. Biol. Chem. 279, 22258-22266), but whose functional role is still elusive. Using a bioinformatics and cell biology approach, we have determined the minimal structure of IBS2 and show that this integrin binding site corresponds to 23 residues located in alpha helix 50 of the talin rod domain (residues 2077-2099). Alanine mutation of 2 highly conserved residues (L2094A/I2095A) within this alpha helix, which disrupted the alpha-helical structure of IBS2 as demonstrated by infrared spectroscopy and limited trypsin proteolysis, was sufficient to prevent in vivo talin fragment J targeting to alphaIIbbeta3 integrin in focal adhesions and to inhibit in vitro this association as shown by an alphaIIbbeta3 pulldown assay. Moreover, expression of a full-length mouse green fluorescent protein-talin LI/AA mutant in mouse talin1(-/-) cells was unable to rescue the inability of these cells to assemble focal adhesions (in contrast to green fluorescent protein-talin wild type) despite the presence of IBS1. Our data provide the first direct evidence that IBS2 in the talin rod is essential to link integrins to the cytoskeleton.


Regional coronary blood flow at rest and during high sustained +Gz in a miniature swine with subclinical, ischemic, coronary heart disease due to coronary stenosis.
New-generation high-performance aircraft can produce levels of high sustained +Gz which may exceed man's physiological capacity to withstand such stress. The severity of this stress has led to concern that sudden incapacitation due to coronary heart disease could occur during sustained +Gz. This report presents results obtained from an apparently asymptomatic miniature swine with a severe stenosis of the left anterior descending branch of the left coronary artery. Regional coronary blood flow was measured with the radiolabeled microsphere technique using 9 +/- 0.8 microgram diameter microspheres. Under resting conditions, myocardial blood flow was marginally depressed in the areas distal to the coronary stenosis. When the animal was exposed to +7 Gz, a large portion of the heart became acutely ischemic due to a redistribution of coronary blood flow. After 49 x of exposure to +7 Gz, the animal developed fatal ventricular fibrillation. Histologically, the areas of myocardium supplied by the stenosed vessel showed a variety of ischemia-induced lesions, including infarction and patchy myocardial fibrosis.


Maintaining Epigenetic Inheritance During DNA Replication in Plants.
Biotic and abiotic stresses alter the pattern of gene expression in plants. Depending on the frequency and duration of stress events, the effects on the transcriptional state of genes are "remembered" temporally or transmitted to daughter cells and, in some instances, even to offspring (transgenerational epigenetic inheritance). This "memory" effect, which can be found even in the absence of the original stress, has an epigenetic basis, through molecular mechanisms that take place at the chromatin and DNA level but do not imply changes in the DNA sequence. Many epigenetic mechanisms have been described and involve covalent modifications on the DNA and histones, such as DNA methylation, histone acetylation and methylation, and RNAi dependent silencing mechanisms. Some of these chromatin modifications need to be stable through cell division in order to be truly epigenetic. During DNA replication, histones are recycled during the formation of the new nucleosomes and this process is tightly regulated. Perturbations to the DNA replication process and/or the recycling of histones lead to epigenetic changes. In this mini-review, we discuss recent evidence aimed at linking DNA replication process to epigenetic inheritance in plants.


van der Waals Layered Materials: Opportunities and Challenges.
Since graphene became available by a scotch tape technique, a vast class of two-dimensional (2D) van der Waals (vdW) layered materials has been researched intensively. What is more intriguing is that the well-known physics and chemistry of three-dimensional (3D) bulk materials are often irrelevant, revealing exotic phenomena in 2D vdW materials. By further constructing heterostructures of these materials in the planar and vertical directions, which can be easily achieved via simple exfoliation techniques, numerous quantum mechanical devices have been demonstrated for fundamental research and technological applications. It is, therefore, necessary to review the special features in 2D vdW materials and to discuss the remaining issues and challenges. Here, we review the vdW materials library, technology relevance, and specialties of vdW materials covering the vdW interaction, strong Coulomb interaction, layer dependence, dielectric screening engineering, work function modulation, phase engineering, heterostructures, stability, growth issues, and the remaining challenges.


[Ultrasonic retrograde urethrography. Technique. Comparison with radiologic retrograde urethrography].
Using ultrasound scan urethrography (U.S.U.) and radiological retrograde urethrography (R.U.), the anterior urethra has been studied in 61 males in an attempt to establish the best technique to perform U.S.U. and to compare it, from the technical point of view, with R.U. U.S.U. should be made retrogradely filling the urethra with a saline solution, under direct ultrasound guidance, which allows to see the anterior urethra, from the syringe come introduced into the glandular urethra up to the urogenital diaphragm and the beginning of the membranous urethra. Overall, U.S.U. is faster to perform than R.U., nine times cheaper, more comfortable for the patient, and there is no risk of exposure to irradiation or radiological markers.


[Biogenic amine metabolism in severe brain trauma during various techniques of brain protection from hypoxia].
Biogenic amine metabolism in severe brain trauma has been analysed in 165 patients whose brain was protected from hypoxia with GOBA and thiobarbiturates in subnarcotic doses (116 cases) and the combination of the above agents with an early course of HBO (49 cases). The peculiarities of biogenic amine metabolism have been established in patients recovered and those who died later. As any activation of biogenic amine systems realizing stress enhances disadaptation processes, it is recommended to begin a course of HBO upon their stabilization.


Have "formal investigations" into fishing vessel losses ceased?
Systematic studies of 618 fishing vessel losses between January 1961 and December 1982 have shown a significantly increased incidence of total losses from 1972 onwards. Comparison of mean pre- and post-1972 rates indicated an increase of 120% from 2.54 to 5.58 losses per 1000 vessels at risk. Parallel examination of the mortality of fishermen from all occupational accidents showed no improvement. For deaths arising from vessel losses alone, the mean crude death rate, for the same periods, increased by 13%. Despite these findings, formal investigations (courts of inquiry) into fishing losses, ordered by the Department of Transport according to specified criteria, decreased in number from about 1975 onwards. The mean number fell by 61% from 3.1 (1961-71) to 1.2 a year (1972-82). Furthermore, the reduction in the rate of formal investigations into fishing vessel losses (-84%; p less than 0.0001) was greater than the corresponding reduction (-61%; p less than 0.001) in United Kingdom merchant vessel investigations and this difference was statistically significant (p less than 0.01). During 1972-82 there were 61 fewer fishing investigations than predicted from the rate at which these were ordered during 1961-71. The last took place in 1979. None of the 141 fishing vessel losses between January 1980 and December 1982 proceeded to formal investigation. The possibility that the criteria for ordering formal investigations have not been fulfilled by the circumstances of fishing vessel losses from 1975 onwards is assessed as one explanation for this paradoxical finding of an inverse relation between losses and investigations. The accident investigation and public reporting procedures for aviation accidents should be adobted for marine accidents in general and fishing vessel losses in particular.


Case management community care for people living with HIV/AIDS (PLHAs).
A case management approach to support services was developed in a Toronto-based AIDS service organization (ASO) in Canada to support people living with HIV/AIDS (PLHAs) whose needs could not be addressed through usual self-directed access to services. It was therefore important to determine which PLHAs would benefit most from case management. New clients and those who had been receiving support services from an ASO were randomized to receive either self-directed use of support services or self-directed care plus strengths-based case management for a six-month period. Results indicated that those who benefited most from case management were very depressed at baseline. Strengths-based case management compared to usual self-directed care markedly improved the physical, social and mental health function of very depressed PLHAs, and reduced their risk behaviours. In addition, the case management participants' use of community services was associated with an economically important, though not statistically significant, $3,300 per person per annum lower expenditure for the use of all direct health and social services. Although more research is warranted, this research demonstrates that ASOs and funders ought to seriously consider implementing a case management approach to practical assistance for PLHAs with depression.


Practical needs and considerations for refugees and other forcibly displaced persons with neurological disorders: Recommendations using a modified Delphi approach.
Background: There are >70 million forcibly displaced people worldwide, including refugees, internally displaced persons, and asylum seekers. While the health needs of forcibly displaced people have been characterized in the literature, more still needs to be done globally to translate this knowledge into effective policies and actions, particularly in neurology. Methods: In 2020, a global network of published experts on neurological disease and refugees was convened. Nine physician experts from nine countries (2 low, 1 lower-middle income, 5 upper-middle, 1 high income) with experience treating displaced people originating from 18 countries participated in three survey and two discussion rounds in accordance with the Delphi method. Results: A consensus list of priority interventions for treating neurological conditions in displaced people was created, agnostic to cost considerations, with the ten highest ranking tests or treatments ranked as: computerized tomography scans, magnetic resonance imaging scans, levetiracetam, acetylsalicylic acid, carbamazepine, paracetamol, sodium valproate, basic blood tests, steroids and anti-tuberculous medication. The most important contextual considerations (100% consensus) were all economic and political, including the economic status of the displaced person's country of origin, the host country, and the stage in the asylum seeking process. The annual cost to purchase the ten priority neurological interventions for the entire displaced population was estimated to be 220 million USD for medications and 4.2 billion USD for imaging and tests. Conclusions: A need for neuroimaging and anti-seizure medications for forcibly displaced people was emphasized. These recommendations could guide future research and investment in neurological care for forcibly displaced people.


hsa-miR-34a-5p Ameliorates Hepatic Ischemia/Reperfusion Injury Via Targeting HNF4α.
To investigate the relationship between the expression level of hsa-miR-34a-5p and liver injury and to further explore its regulatory signaling pathways Methods: Liver tissue and blood were collected from 60 patients undergoing hepatectomy. We constructed a rat HIRI model and treated it with an intraperitoneal injection of agomir-miR-34a-5p or agomir-normal control (NC) for 7 days after the surgery. The pathological changes of agomir-miR-34a-5p or agomir-normal control (NC) groups were compared. 7702 and AML12 cells were transfected with mimics NC or miR-34a-5p mimics and then treated with H2O2 for 6 hours. Cell apoptosis was detected by flow cytometry, Western blot, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, respectively. Furthermore, the target genes of miR- 34a-5p were identified by luciferase reporter gene assay and were verified in vitro. The relatively high miR-34a-5p expression group revealed a lower level of alanine aminotransferase and aspartate aminotrans- ferase compared with the relatively low miR-34a-5p expression group. HIRI+agomir-miR-34a-5p rats exhibited significantly higher miR-34a-5p expression, lower serum alanine aminotransferase, aspartate aminotransferase, alleviated hepatic necrosis, reduced hepa- tocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI+agomir-NC rats (P < .05). After hydrogen peroxide treatment, alpha mouse liver-12 cell (AML-12) and normal liver cell line LO2 (LO2) cells transfected with miR-34a-5p mimics had significantly lower apoptosis rate compared with miR-34a-5p mimics NC group (P < .05). Hepatocyte nuclear factor 4α was identified as a miR-34a-5p target gene. Hepatocyte nuclear factor 4α expression was significantly downregulated in AML12 and HL-7702 (7702) cells transfected with miR-34a-5p (P < .05). Moreover, AML12 and 7702 cells transfected with miR-34a-5p signifi- cantly showed higher c-Jun N-terminal kinase (JNK), P38, cleavage cas-3, and BCL2 associated X (Bax) protein levels compared with AML12 and 7702 cells transfected with agomir-NC. miR-34a-5p possibly protected the liver from I/R injury through downregulating Hepatocyte nuclear factor 4α to inhibit the JNK/P38 signaling pathway.


[Progress toward molecular determinants of the pathogenesis of disease due to nontypeable Haemophilus influenzae].
Haemophilus influenzae (Hi) is a pathogen exclusively found in humans. It causes a wide range of infections from the upper respiratory tract to serious invasive diseases. Such as pneumonia, septicemia and meningitis. Strains of Hi are usually classified into six serotypes a to f and nontypeable H. influenzae (NTHI) according to the antigenicities and compositions of their polysaccharide capsules. Hib was a common cause of serious infections in younger children. The polysaccharide-protein conjugate vaccines against Hib had almost eliminated H. influenzae as a cause of pediatric meningitis. However, NTHI remains an important pathogen, particularly in children and the elderly. Efforts to understand and control NTHI disease have been hampered by the diversity of these bacteria. This review introduced the study progress about pathogenic mechanism of NTHI. In order to provide the help for development of vaccine, clinic treatment and prevent the occurrence of diseases causing by NTHI.


Trauma among female veterans: a critical review.
This article reviews the literature documenting the nature and prevalence of traumatic experiences, trauma-related mental and physical health problems, and service use among female veterans. Existing research indicates that female veterans experience higher rates of trauma exposure in comparison to the general population. Emerging data also suggest that female veterans may be as likely to be exposed to combat as male veterans, although not as directly or as frequently. Female veterans also report high rates of posttraumatic stress disorder, which has been associated with poor psychiatric and physical functioning. Although sexual assault history has been related to increased medical service use, further research is needed to understand relationships between trauma history and patterns of medical and mental health service use. Researchers also are encouraged to employ standardized definitions of trauma and to investigate new areas, such as treatment outcomes and mediators of trauma and health. Policy and practice implications are discussed.


Inhibition of lipopolysaccharide-induced suppression of luteal function in isolated perfused bovine ovaries.
Recently, we observed that lipopolysaccharide (LPS) suppresses corpus luteum (CL) function in isolated perfused ovaries. It remained unclear if this suppression was due to increased luteal PGF2α secretion or LPS-induced apoptosis. Therefore, possible impacts of PGF2α and LPS were inhibited by a non-steroidal anti-inflammatory drug (flunixin) and an endotoxin-binding agent (polymyxin B), respectively. Bovine ovaries with a mid-cycle CL were collected immediately after slaughter and perfused for 240 min. After 50 min of equilibration, either flunixin or polymyxin B (5 μg/ml of each) were added to the perfusion medium of six ovaries, respectively. All ovaries (n = 12) were treated with E. coli LPS (0.5 μg/ml) 60 min after the onset of perfusion, and received 500 I.U. of hCG after 210 min of perfusion. Progesterone and PGF2α were measured in the effluent perfusate every 10 and 30 min, respectively. Biopsies of the CL were collected every 60 min to determine the mRNA expression of the cytokine TNFA and factors of apoptosis (CASP3, -8). Flunixin-treatment inhibited the increase of PGF2α after LPS-challenge that was observed in the polymyxin B-treated (PX-LPS) ovaries. After hCG-stimulation, progesterone secretion increased (P < 0.05) in group PX-LPS but not in the flunixin-treated (F-LPS) ovaries. Compared to initial values before LPS-challenge, luteal mRNA expression of TNFA and CASP3 was increased (P < 0.05) in group F-LPS at 120 and 180 min, respectively, and those of CASP8 was decreased (P < 0.05) in PX-LPS at 60 and 120 min after LPS-treatment. In conclusion, although flunixin managed to inhibit PGF2α, it did not suffice to successfully prevent LPS-induced apoptosis. However, endotoxin-binding polymyxin B resulted in luteal responsiveness to hCG after LPS-challenge.


Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage.
Hyperglycemia-induced oxidative stress has been concerned in the development of diabetic nephropathy (DN), which may cause kidney damage associated with inflammation and fibrosis. This study has been conducted to investigate the role of genistein supplementation in an acute DN state. Mice with FBG levels more than 250 mg/dL after alloxan injection (single i.p., 150 mg/kg) were considered as diabetic. Diabetic mice (DM) were further subdivided according to their FBG levels, medium-high FBG (DMMH < 450 mg/dL) and high FBG (DMH; 450 mg/dL) and were administrated by an AIG-93G diet supplemented with different doses of genistein (0, 0.025 or 0.1%). After 2 weeks' treatment, the levels of kidney malondialdehyde (MDA), blood urea nitrogen (BUN), and plasma creatinine and lipid profiles, as well as oxidative stress and inflammation-related markers, were measured (P < 0.05). Genistein supplementation improved levels of FBG in the DMMH groups, but not in the DMH group, regardless of the treatment dose. Moreover, the supplementation attenuated kidney oxidative stress indicated by MDA, BUN, and plasma creatinine. In addition, genistein treatment decreased inflammatory markers such as nuclear factor kappa B (p65), phosphorylated inhibitory kappa B alpha, C-reactive protein, monocyte chemotactic protein-1, cyclooxygenase-2, and tumor necrosis factor-alpha and improved oxidative stress markers (nuclear-related factor E2, heme oxygenase-1, glutathione peroxidase, and superoxide dismutase isoforms) in treatment groups, regardless of the genistein treatment dose. Furthermore, genistein supplementation inhibited the fibrosis-related markers (protein kinase C, protein kinase C-beta II, and transforming growth factor-beta I) in the DN state. However, 0.1% genistein supplementation in diabetes with high FBG levels selectively showed a preventive effect on kidney damage. These results suggest that genistein might be a good protective substance for DN through regulation of oxidative stress and inflammation. In particular, genistein is more efficient in diabetes patients with medium-high blood glucose levels. Finally, it is required to establish the beneficial dosage of genistein according to blood glucose levels.


[An effective method for site-directed mutagenesis in plasmids and cloning single-stranded DNA fragments].
A three primer variant of the earlier devised oligonucleotide-directed mutagenesis in plasmids is described, useful also for the fast cloning of single-stranded DNA products of the asymmetric polymerase chain reaction (PCR). Using this method for plasmid pHD-001-14-11, a 59 b. p. deletion and a 7 b. p. insertion were simultaneously introduced at 81% frequency, and the PCR-copied phage fd transcription terminator (26 b. p.) was inserted with the yield of 67%.


A research on asymptomatic bacteriuria in 14- to 17-year-old female students.
Urinary tract infections, which are more common in women than in men, are especially seen in young asymptomatic females who don't obey the general rules of hygiene. This research has been carried out on 14- to 17-year-old young females from several high schools, 966 specimens in total. 3.3% of them had bacteriuria and 75% of the isolated bacteria was Escherichia coli.


Information sharing may impede the success of environmental projects.
A major challenge in ecosystem management is to promote cooperation among the multiple agents that manage the ecosystem. In particular, sharing information among the agents is often essential for reaching a desirable collective treatment. However, it is unclear how the sharing of information affects the incentives of selfish agents to cooperate and contribute to the common environmental project. Here, we consider a harmful species population that migrates across lands and causes damages to multiple agents, each of which aims to minimize her/his own costs due to both treatment and damages over time. We use game-theoretical models and compare the resulting collective treatment in three scenarios that differ in the information that agents have about (1) the true contribution of their neighbors to the treatment and (2) the true damages inflicted on their neighbors by the harmful species. We demonstrate that sharing such social information may incentivize the agents to free ride on their neighbors' contributions, thereby reducing the efficiency of the collective treatment. This implies that monitoring and sharing information may have negative consequences, and the extent to which information should be shared in joint projects necessitates a careful examination.


Rare Case of Olmesartan Induced Enteropathy.
Olmesartan (brand name Benicar) is an antihypertensive drug clinicians commonly use to treat high blood pressure. Olmesartan induced enteropathy (OSE) is a rare entity that authors first identified in 2012. The etiological basis of OSE remains unclear, although authors have suggested that this condition could be due to alternations in cell mediated immune responses induced by the drug. The objective of the case report is to describe a patient who presented with diarrhea and was eventually diagnosed with OSE. A female patient in her later 60s presented to an emergency room after two recent hospitalizations with profound diarrhea, generalized weakness and weight loss. She underwent a diagnostic workup including endoscopy and colonoscopy. The patient's endoscopy with duodenal biopsy revealed villous atrophy with attenuated and blunted villi with intraepithelial CD3 positive T lymphocytes, suggestive of gluten-induced enteropathy. When the patient's symptoms did not improve after the authors placed her on a gluten free diet for a few days, they further investigated her for secretory diarrhea, including Gastrin, Somatostatin and Vasoactive Intestinal Peptide lab values that they found to be within normal limits. Due to the patient's lack of improvement with initial treatment, the authors suspected OSE and stopped her olmesartan and the patients' symptoms gradually improved in three weeks.


Frequency of occurrence of antibodies to tissues in the sera of various groups of population.
A new method of detecting antibodies to tissues (ATA) in the sera of humans has been developed. The method is based on special treatment of human erythrocytes of the first group (rhesus-negative) with glutaric aldehyde rendering them capable of reacting with antibodies to tissues. Positive reaction is recorded in the form of haemagglutination. The reaction is easy to perform and open to mass examination of sera of children and adult population. The incidence of antibodies to tissues in the sera of sick and healthy children and adults was investigated. A total of 723 sera including 160 sera obtained from sick adults, 255 from healthy adults, 110 from sick children and 198 from healthy children were examined in the haemagglutination reaction using a microtechnique. It has been established that no antibodies to tissues were present in the sera of most healthy subjects (79.2%), children or adults. In 19.4% ATA were detected in titres 1:2-1:4, while an increased level (ATA titres 1:8 and higher) was found in only 1.4% of the sera. The subjects whose sera contained ATA predominated in the group of sick adults and children. In 52.9% of cases, ATA titres were 1:2-1:4. In 30.8% they were higher (1:8 and higher). The method can be recommended for mass examinations with the purpose of evaluating the immune state of the population.


Pharmacokinetics of the neuroprotective glutamate antagonist NBQX (6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione) in mice, rats, and dogs. Interactions with probenecid.
NBQX [6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione] has proven effective in protecting against cerebral ischemic insult in rodents. The preclinical development included pharmacokinetic and toxicological investigations in mice, rats, and dogs. For these purposes, NBQX was given as an intravenous bolus dose (in mice, rats, and dogs) or as a constant infusion for up to 4 weeks in rats and dogs. In NMRI mice t1/2, CL, and V2 were 1-4 hr, 0.6-1 liter/kg/hr, and 1-4 liters/kg following 3, 10, or 30 mg/kg. In Wistar and Sprague-Dawley rats, the mean +/- SD values of t1/2, CL, and Vz were 0.8 +/- 0.35 hr, 3.2 +/- 1.0 liters/kg/hr, and 4.0 +/- 1.1 liters/kg, respectively. About 33 +/- 5.2% of the dose was excreted unchanged in urine. The CLR was 0.90 +/- 0.20 liter/kg/hr. The pH of the urine samples ranged from pH 6.2 to 8.8, with a mean of 7.9 +/- 0.72. The plasma concentrations were proportional to the dose rate in the dose range 0.3-10 mg/kg/hr, independent of sex, and did not change during 4 weeks of infusion. CL and CLR were decreased to half their value when NBQX was administered in combination with probenecid. In beagle dogs, t1/2 and Vz were 1-3 hr and 1-3 liters/kg, respectively. The CL was determined to be 1.5 +/- 0.4 liters/kg/hr (N = 18) following 2 days of infusion (0.2-1 mg/kg/hr), but after 1 month CL had decreased significantly (p < 0.0001) to 1.0 +/- 0.1 liter/kg/hr.(ABSTRACT TRUNCATED AT 250 WORDS)