Effect of Source Animal Age upon Macrophage Response to Extracellular Matrix Biomaterials.
Extracellular matrix biomaterials have been shown to promote constructive remodeling in many preclinical and clinical applications. This response has been associated with the promotion of a timely switch from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages. A previous study has shown that this beneficial response is lost when these biomaterials are derived from aged animals. This study examined the impact of small intestine submucosa (SIS) derived from 12, 26 and 52 week old pigs on the phenotype and function of bone marrow macrophages derived either from 2 or 18 month old mice. Results showed that 52 week old SIS promoted less iNOS in 2 month macrophages and Fizz1 expression in 2 and 18 month compared to 12 week SIS. Pro-inflammatory cytokine exposure to 52 week SIS-treated macrophages resulted in higher iNOS in 18 month macrophages and reduced MHC-II expression in 2 month macrophages, as well as reduced nitric oxide production in comparison to 12 week SIS. These results indicate that ECM derived from aged animals promotes an altered macrophage phenotype compared to young controls. This suggests that sourcing of ECM from young donors is important to preserve constructive remodeling outcomes of ECM biomaterials. Alteration of macrophage phenotype by aged ECM also raises the hypothesis that alterations in aged ECM may play a role in immune dysfunction in aged individuals.


Platelets: an outlook from biology through evidence-based achievements in critical care.
Since the original observations by Bizzozero and Osler, we have seen tremendous advances in the understanding of platelets far beyond haemostasis and the restoration of injured endothelium. In this mini-review on platelets, we will briefly outline their historical description and the importance of their evolution, focusing on a 450 million years old living fossil of Limulus polyphemus, a marine chelicerate arthropod, which helped researchers explain the basis for the immunity role of platelets and make correlations with platelet ultrastructure and function. In addition, the impact of the Limulus Amoebocyte Lysate (LAL) test for modern medicine is highlighted. The role of platelets in cardiovascular diseases, their relevance in arterial and venous thrombosis, and the utilization of antithrombotic drugs as therapeutic agents are also reported. Furthermore, platelet receptors are crucial in aggravating or mitigating other diseases, such as cancer and infections, which can recruit cells and have numerous interactions in a process recently coined "NETosis formation", which is also briefly depicted.


Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy.
There is considerable evidence that pregnancy changes the disposition of drugs in an enzyme- and gestational stage-specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have been shown to be regulated by estradiol. Because estradiol concentrations increase by ∼50-fold during human pregnancy, it was hypothesized that the increasing estradiol concentrations during human pregnancy would result in induction of CYP2B6 activity. Hepatocytes from three female donors were treated with estradiol, and the EC(50) and E(max) were measured for CYP2B6 mRNA and bupropion hydroxylation activity. The measured values were used to predict the magnitude of CYP2B6 induction during human pregnancy. At 100 nM total estradiol, a concentration achievable during the third trimester of pregnancy, CYP2B6 activity was predicted to increase by 1.5-3-fold, based on increased CYP2B6 activity and mRNA. When the E(max) and EC(50) values were compared with those for carbamazepine and rifampin, estradiol was found to be as potent an inducer of CYP2B6 as rifampin and carbamazepine. These data suggest that, during human pregnancy, the increasing estradiol concentrations will result in increased clearance of drugs that have CYP2B6-mediated clearance pathways. This could in part explain the observed increase in methadone clearance during pregnancy.


The human visual cortex responds to gene therapy-mediated recovery of retinal function.
Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity.


Hypoglycemic and Hypolipidemic Effects of Seed Extract from Antidesma bunius (L.) Spreng in Streptozotocin-induced Diabetic Rats.
Antidesma bunius (L.) Spreng has been reported to possess various beneficial medicinal properties. Scientific information about this plant is limited. This study was therefore, designed to determine hypoglycaemic and hypolipidemic effects of ethanol seed extract from A. bunius (ABSE). Antioxidant activity and also acute toxicity were conducted. The hypoglycaemic and hypolipidemic effects were studied by oral giving ABSE at a dose of 250 mg kg -1 to streptozotocin-induced diabetic rats daily for 6 weeks. Antioxidant activity was studied using DPPH assay. The ABSE at the doses of 500, 1000, 1500 and 2000 mg kg -1 were employed in the acute toxicity study. The results revealed that ABSE significantly (p<0.05) reduced the blood glucose level and recovered the pathology of hematological values, but significantly (p<0.05) increased the body weight and slightly increased serum insulin of the diabetic rats. However, ABSE recovered pathology of hematological values, but affected renal and hepatic functions in the treated rats by producing an alteration of creatinine, albumin, total protein, BUN and ALP. Interestingly, ABSE increased WBC and HDL, but reduced CHOL, LDL and TG both in normal and diabetic ABSE treated rats. The ABSE possessed relatively low antioxidant activity with IC50 of 2174±14.24 mg mL -1 compared to vitamin C (1.48±0.07 μg mL -1). Fortunately, ABSE did not produce any symptoms of acute toxicity and mortality in the rats. The ethanol seed extract from A. bunius possesses hypoglycemic and hypolipidemic effects. The ABSE also recovered the pathology of the hematology but may cause renal dysfunction in the diabetic rats. The hypoglycemic and hypolipidemic effects are likely due to its antioxidant and insulin secretion activities.


Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: a double-blind placebo-controlled study.
Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics (SGAs) is imperative. In the present study, we sought to replicate our preliminary findings, which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Fifty-nine patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in this randomized double-blind study. Reboxetine (4 mg/day; 31 patients) or placebo (29 patients) was coadministered with olanzapine (10 mg/day) for 6 weeks. Analysis was by intention-to-treat. Nine patients in each group prematurely discontinued the trial. Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight (mean = 3.31 kg, SD = 2.73) than their olanzapine/placebo-treated counterparts (mean = 4.91 kg, SD = 2.45). Significantly fewer olanzapine/reboxetine-treated patients gained at least 7% of their initial weight, the cutoff for clinically significant weight gain (6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients). Seven (22.6%) olanzapine/reboxetine-treated patients compared to only one patient (3.6%) in the olanzapine/placebo group revealed no weight change or even modest weight loss. Appetite increase was significantly lower in the olanzapine/reboxetine than olanzapine/placebo group and was correlated with attenuation of weight gain. Reboxetine addition was safe and well tolerated. The results confirm that coadministration of reboxetine promotes a clinically meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients. If substantiated in long-term studies, along with behavioral management and diet counseling, reboxetine may have a clinical utility in controlling SGA-induced weight gain.


All-optical regenerative NRZ-to-RZ format conversion using coupled ring-resonator optical waveguide.
This paper proposes a scheme for format conversion from a distorted non-return-to-zero (NRZ) signal to a high-quality return-to-zero (RZ) signal, using the nonlinearity in a coupled ring-resonator optical waveguide (CROW) on a silicon chip. In this method, a distorted NRZ signal is amplified and fed into the CROW together with an RZ pulse train. The CROW performs as a nonlinear step gate for the RZ pulse train, which outputs amplitude-equalized RZ pulses inheriting the information from the NRZ signal. Clearly, the integration of the format conversion and regeneration simplifies the system. Our simulations performed at 10 Gb/s and 40 Gb/s verify the feasibility of our proposal.


Covid-19 Opens up domestic market for Indian shrimp.
COVID-19 pandemic presents both a challenge and an opportunity to the Indian shrimp sector. With revitalizing the institutional arrangements and redirecting the focus, the Indian shrimp industry can flourish just by adapting to the needs of the local demand, even when the export prospects are uncertain. This paper takes a historical perspective of Indian shrimp farming and exports and suggests a domestic alternative/supplementary market for Indian farmed shrimp, resulting from COVID-19.


Analysis of surface receptor expression on bacteria isolated from patients with endocarditis.
Fifteen bacterial isolates (12 streptococcal and 3 staphylococcal strains) from patients with bacterial endocarditis were screened for a variety of surface receptors, in an attempt to identify a common feature that might contribute to their ability to attach to and colonize damaged heart tissue. The bacterial receptors screened for, using a dot-blot autoradiographic procedure, included those for the Fc region of human IgG, fibrinogen, fibronectin and human C1q. Bacteria with receptors for each of the probes used could be identified, but no common receptor was present on all endocarditis-causing strains.


Certification and credentialing to define competency-based practice.
One of the challenges that healthcare organizations face today is how to effectively establish, document, and evaluate competency in intravenous practice. The process used to define practice parameters based on national certification and credentialing versus organizational policies is described. Key attributes, the role of mentoring, and adverse outcomes are addressed.


[Encrusted pyelitis in patients with urinary diversion].
This is a case of Encrusted Pyelitis (EP) caused by Corynebacterium urealyticum (CU) in a patient who had undergone a cystectomy and Bricker type urinary diversion 28 months beforehand. After the immediate post-operative period no urinary catheterisation or any other urological procedure was performed on the patient. Before surgery, the patient presented non functional of the right kidney, secondary to a lithiasic obstructive uropathy. Clinical symptoms were deteriorated renal function, anuria, haematuria, pyrexia and left lumbar pain. It was suspected that the patient had this pathology and this was fundamental in diagnosis. Helicoid CT was the principal method used to show calcification plaques on the wall of the left renal pelvis, and selective culture of CU confirmed the diagnosis. Early commencement of treatment with vancomycin at an initial dosage of 500 mg/12 hours, and subsequent adjustment of dosage according to blood drug levels, achieved negative urine culture within a fortnight. Oral acidification was effected using acetohidroxamic acid 125 mg/12 hours, and it was continued until CT confirmed the disappearance or considerable reduction of the pyelic calcification plaques. The presence of EP in patients with urinary diversion is a matter worthy of consideration, even in patients who have not undergone recent urological procedures. Awareness of risk factors and early commencement of effective treatment may improve the prognosis of these patients.


Characterization and chromatin distribution of the H1 histones and high-mobility-group non-histone chromosomal proteins of trout liver and hepatocellular carcinoma.
The H1 histones serve as general repressors of gene expression by inducing the formation of a compact chromatin structure, whereas the high-mobility-group (HMG) non-histone chromosomal proteins have roles in maintaining the structure and function of transcriptionally active chromatin. The distribution of the H1 histone subtypes and HMG proteins among various trout tissues (liver, hepatocellular carcinoma, testis and erythrocyte) was determined. Histone H1b was present in the chromatin of liver, but not in the chromatin of hepatocellular carcinoma, testis or erythrocyte. Nuclease-resistant regions of liver chromatin had elevated levels of histone H1b. Histone H1b was isolated, and the N-terminal amino acid sequence of histone H1b was found to be highly similar to that of mammalian histone H1(0) and duck H5. HMG proteins T1, T2, T3, H6, C, D and F were associated with liver and hepatocellular-carcinoma chromatin, with hepatocellular carcinoma containing higher levels of HMG T1 and F. Testis and erythrocyte had HMG T2 and H6 as their predominant HMG proteins. Most of the HMG H6 of hepatocellular carcinoma, but not of liver, was located in a chromatin fraction that was soluble at physiological ionic strength and enriched in transcriptionally active DNA. These alterations in the chromatin distribution and content of hepatocyte HMG proteins and H1 histone subtypes may contribute to aberrant hepatocyte gene expression in the hepatocellular carcinoma.


Community medicine teaching and evaluation: scope of betterment.
There have been rapid and extensive changes in the way assessment is conducted in medical education. Assessment brings about standardization of the manner in which the syllabus is to be implemented and also gives guidelines regarding the teaching pattern, especially when the student is going to rotate through various departments in a medical college. Community Medicine is an important branch of medicine concerned with the health of populations. Existing forms of assessment of community medicine education mainly consists of internal [formative] assessment and final (summative) examination. Advantages of the present system is the similarity of the methods used for internal assessments and final examinations and is relatively easily done since only the knowledge application and recall ability of the student in theory and practical are assessed. Disadvantages in the current evaluation system are neglecting the assessment of psychomotor, affective and communication skills. Evaluation systems can be improved by implementing techniques to assess psychomotor skills, presentation and communication skills, organizational skills and the student's ability to work in a team. Regular feedback from students should be taken periodically for the betterment of Community Medicine education. This article is meant to sensitise the academic experts in medical education to plan better need based methods of assessment in the subject of Community Medicine, in relation to the new MCI 2012 Regulations, in order to make it a better learning experience for the students.


The single molecule probe: nanoscale vectorial mapping of photonic mode density in a metal nanocavity.
We use superresolution single-molecule polarization and lifetime imaging to probe the local density of states (LDOS) in a metal nanocavity. Determination of the orientation of the molecular transition dipole allows us to retrieve the different LDOS behavior for parallel and perpendicular orientations with respect to the metal interfaces. For the perpendicular orientation, a strong lifetime reduction is observed for distances up to 150 nm from the cavity edge due to coupling to surface plasmon polariton modes in the metal. Contrarily, for the parallel orientation we observe lifetime variations resulting from coupling to characteristic lambda/2 cavity modes. Our results are in good agreement with calculations of the nanoscale variations of the projected LDOS, which demonstrates the potential of single molecules as nonperturbative, nanoscale vectorial point probes in photonic and biological nanostructures.


Health Insurance Trajectories and Long-Term Survival After Heart Transplantation.
Health insurance status at heart transplantation influences recipient survival, but implications of change in insurance for long-term outcomes are unclear. Adults aged 18 to 64 receiving first-time orthotopic heart transplants between July 2006 and December 2013 were identified in the United Network for Organ Sharing registry. Patients surviving >1 year were categorized according to trajectory of insurance status (private compared with public) at wait listing, transplantation, and 1-year follow-up. The most common insurance trajectories were continuous private coverage (44%), continuous public coverage (27%), and transition from private to public coverage (11%). Among patients who survived to 1 year (n=9088), continuous public insurance (hazard ratio =1.36; 95% confidence interval 1.19, 1.56; P<0.001) and transition from private to public insurance (hazard ratio =1.25; 95% confidence interval 1.04, 1.50; P=0.017) were associated with increased mortality hazard relative to continuous private insurance. Supplementary analyses of 11 247 patients included all durations of post-transplant survival and examined post-transplant private-to-public and public-to-private transitions as time-varying covariates. In these analyses, transition from private to public insurance was associated with increased mortality hazard (hazard ratio =1.25; 95% confidence interval 1.07, 1.47; P=0.005), whereas transition from public to private insurance was associated with lower mortality hazard (hazard ratio =0.78; 95% confidence interval 0.62, 0.97; P=0.024). Transition from private to public insurance after heart transplantation is associated with worse long-term outcomes, compounding disparities in post-transplant survival attributed to insurance status at transplantation. By contrast, post-transplant gain of private insurance among patients receiving publicly funded heart transplants was associated with improved outcomes.


Estimating the impact of structural directionality: How reliable are undirected connectomes?
Directionality is a fundamental feature of network connections. Most structural brain networks are intrinsically directed because of the nature of chemical synapses, which comprise most neuronal connections. Because of the limitations of noninvasive imaging techniques, the directionality of connections between structurally connected regions of the human brain cannot be confirmed. Hence, connections are represented as undirected, and it is still unknown how this lack of directionality affects brain network topology. Using six directed brain networks from different species and parcellations (cat, mouse, C. elegans, and three macaque networks), we estimate the inaccuracies in network measures (degree, betweenness, clustering coefficient, path length, global efficiency, participation index, and small-worldness) associated with the removal of the directionality of connections. We employ three different methods to render directed brain networks undirected: (a) remove unidirectional connections, (b) add reciprocal connections, and (c) combine equal numbers of removed and added unidirectional connections. We quantify the extent of inaccuracy in network measures introduced through neglecting connection directionality for individual nodes and across the network. We find that the coarse division between core and peripheral nodes remains accurate for undirected networks. However, hub nodes differ considerably when directionality is neglected. Comparing the different methods to generate undirected networks from directed ones, we generally find that the addition of reciprocal connections (false positives) causes larger errors in graph-theoretic measures than the removal of the same number of directed connections (false negatives). These findings suggest that directionality plays an essential role in shaping brain networks and highlight some limitations of undirected connectomes.


Determinants of Utility Based on the EuroQol Five-Dimensional Questionnaire in Patients with Chronic Heart Failure and Their Change Over Time: Results from the Swedish Heart Failure Registry.
There is limited information on drivers of utilities in patients with chronic heart failure (CHF). To analyze determinants of utility in CHF and drivers of change over 1 year in a large sample from clinical practice. We included 5334 patients from the Swedish Heart Failure Registry with EuroQol five-dimensional questionnaire information available following inpatient or outpatient care during 2008 to 2010; 3495 had 1-year follow-up data. Utilities based on Swedish and UK value sets were derived. We applied ordinary least squares (OLS) and two-part models for utility at inclusion and OLS regression for change over 1 year, all with robust standard errors. We assessed the predictive accuracy of both models using cross-validation. Patients' mean age was 73 years, 65% were men, 19% had a left ventricular ejection fraction of 50% or more, 23% had 40% to 49%, 27% had 30% to 39%, and 31% had less than 30%. For both models and value sets, utility at inclusion was affected by sex, age, New York Heart Association class, ejection fraction, hemoglobin, blood pressure, lung disease, diabetes, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, nitrates, antiplatelets, and diuretics. The OLS model performed slightly better than did the two-part model on a population level and for capturing utility ranges. Change in utility over 1 year was influenced by age, sex, and (measured at inclusion) disease duration, New York Heart Association class, blood pressure, ischemic heart disease, lung disease, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and antiplatelets. Utilities in CHF and their change over time are influenced by diverse demographic and clinical factors. Our findings can be used to target clinical interventions and for economic evaluations of new therapies.


Biphasic adaptation to osmotic stress in the C. elegans germ line.
Cells respond to environmental stress in multiple ways. In the germ line, heat shock and nutritive stress trigger the assembly of large ribonucleoprotein (RNP) granules via liquid-liquid phase separation (LLPS). The RNP granules are hypothesized to maintain the quality of oocytes during stress. The goal of this study was to investigate the cellular response to glucose in the germ line and determine if it is an osmotic stress response. We found that exposure to 500 mM glucose induces the assembly of RNP granules in the germ line within 1 h. Interestingly, the RNP granules are maintained for up to 3 h; however, they dissociate after longer periods of stress. The RNP granules include processing body and stress granule proteins, suggesting shared functions. Based on several lines of evidence, the germ line response to glucose largely appears to be an osmotic stress response, thus identifying osmotic stress as a trigger of LLPS. Although RNP granules are not maintained beyond 3 h of osmotic stress, the quality of oocytes does not appear to decrease after longer periods of stress, suggesting a secondary adaptation in the germ line. We used an indirect marker of glycerol and observed high levels after 5 and 20 h of glucose exposure. Moreover, in gpdh-1;gpdh-2 germ lines, glycerol levels are reduced concomitant with RNP granules being maintained for an extended period. We speculate that increased glycerol levels may function as a secondary osmoregulatory adaptive response in the germ line, following a primary response of RNP granule assembly.


Concentration gradients of monoamine metabolites in human cerebrospinal fluid.
The monamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), vanillylmandelic acid (VMA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were analysed in CSF from different regions of the CSF system to study the caudocranial concentration gradient of the metabolites. Four consecutive 10 ml fractions of CSF were withdrawn in 17 patients during the course of four minutes. The CSF pressure was monitored through a lumbar cannula because of suspected adult hydrocephalus. A pronounced gradient of the HVA concentration was found with a ratio between the last and the first fraction of 1,7. 5-HIAA showed a slight increase while HMPG and VMA showed no increase at higher levels of the CSF system. The results suggest that lumbar HVA reflects dopaminergic activity in the brain, whereas lumbar 5-HIAA and HMPG/VMA reflect the activity of 5-hydroxytryptamine and noradrenaline secreting neurones in both the brain and the spinal cord.


The Pyramiding of Three Key Root Traits Aid Breeding of Flood-Tolerant Rice.
Flooding is constantly threatening the growth and yield of crops worldwide. When flooding kicks in, the soil becomes water-saturated and, therefore, the roots are the first organs to be exposed to excess water. Soon after flooding, the soil turns anoxic and the roots can no longer obtain molecular oxygen for respiration from the rhizosphere, rendering the roots dysfunctional. Rice, however, is a semi-aquatic plant and therefore relatively tolerant to flooding due to adaptive traits developed during evolution. In the present review, we have identified three key root traits, viz. cortical aerenchyma formation, a barrier to radial oxygen loss and adventitious root growth. The understanding of the physiological function, the molecular mechanisms, and the genetic regulation of these three traits has grown substantially and therefore forms the backbone of this review. Our synthesis of the recent literature shows each of the three key root traits contributes to flood tolerance in rice. One trait, however, is generally insufficient to enhance plant tolerance to flooding. Consequently, we suggest comprehensive use of all three adaptive traits in a pyramiding approach in order to improve tolerance to flooding in our major crops, in general, and in rice, in particular.


Plant fatty acyl reductases: enzymes generating fatty alcohols for protective layers with potential for industrial applications.
Primary fatty alcohols are found throughout the biological world, either in free form or in a combined state. They are common components of plant surface lipids (i.e. cutin, suberin, sporopollenin, and associated waxes) and their absence can significantly perturb these essential barriers. Fatty alcohols and/or derived compounds are also likely to have direct functions in plant biotic and abiotic interactions. An evolutionarily related set of alcohol-forming fatty acyl reductases (FARs) is present in all kingdoms of life. Plant microsomal and plastid-associated FAR enzymes have been characterized, acting on acyl-coenzymeA (acyl-CoA) or acyl-acyl carrier protein (acyl-ACP) substrates, respectively. FARs have distinct substrate specificities both with regard to chain length and chain saturation. Fatty alcohols and wax esters, which are a combination of fatty alcohol and fatty acid, have a variety of commercial applications. The expression of FARs with desired specificities in transgenic microbes or oilseed crops would provide a novel means of obtaining these valuable compounds. In the present review, we report on recent progress in characterizing plant FAR enzymes and in understanding the biological roles of primary fatty alcohols, as well as describe the biotechnological production and industrial uses of fatty alcohols.


Role of treatment on the development of secondary malignancies in patients with essential thrombocythemia.
Aim of this study is to explore the role of different treatments on the development of secondary malignancies (SMs) in a large cohort of essential thrombocythemia (ET) patients. We report the experience of a regional cooperative group in a real-life cohort of 1026 patients with ET. We divided our population into five different groups: group 0, no treatment; group 1, hydroxyurea (HU); group 2, alkylating agents (ALK); group 3, ALK + HU sequentially or in combination; and group 4, anagrelide (ANA) and/or α-interferon (IFN) only. Patients from groups 1, 2, and 3 could also have been treated either with ANA and/or IFN in their medical history, considering these drugs not to have an additional cytotoxic potential. In all, 63 of the 1026 patients (6%) developed 64 SM during the follow-up, after a median time of 50 months (range: 2-158) from diagnosis. In univariate analysis, a statistically significant difference was found only for gender (P = 0.035) and age (P = 0.0001). In multivariate analysis, a statistically significant difference was maintained for both gender and age (gender HR1.7 [CI 95% 1.037-2.818] P = 0.035; age HR 4.190 [CI 95% 2.308-7.607] P = 0.0001). The impact of different treatments on SMs development was not statistically significant. In our series of 1026 ET patients, diagnosed and followed during a 30-year period, the different therapies administered, comprising HU and ALK, do not appear to have impacted on the development of SM. A similar rate of SMs was observed also in untreated patients. The only two variables which showed a statistical significance were male gender and age >60 years.


What Is the Key to Improving Renal Transplant Recipients' Awareness of Skin Cancer Risk?
Previous studies have shown poor compliance rates regarding sun protection among organ transplant recipients. The main objective of the present study was to assess the awareness among renal transplant recipients (RTRs) of their risk of non-melanoma skin cancer (NMSC) development and their sunscreen use. The influence of several potentially relevant variables was also assessed in order to identify possible weak points on which to concentrate efforts in this respect. A total of 132 RTRs (92 males and 40 females) were included. The following information was collected and elaborated: (a) demographics; (b) skin phototype; (c) educational level; (d) time elapsed since transplantation; (e) immunosuppressive treatments; (f) previous dermatological visits; (g) patients' awareness of their NMSC risk; (h) use of sunscreen; and (i) previous documented NMSCs or NMSCs found during the study visit. Overall, 65 patients (49.2%) expressed awareness of their susceptibility to skin cancers. A high educational level was the main factor associated with patients' awareness. Thirty-six RTRs (27.3%) reported using sunscreen regularly. High educational level and awareness of personal susceptibility to NMSC development were the most relevant factors associated with sun protection habits. The present study showed the low level of sunscreen use among RTRs and their scanty awareness of personal skin cancer risk. Since educational level has been found to be highly related to both awareness of cancer risk and adequate use of sunscreen among RTRs, it is necessary to improve the way education is delivered by dermatologists and nephrologists, especially to subjects with a low educational level.


Synergistic enhancement of antitumor immunity with adoptively transferred tumor-specific CD4+ and CD8+ T cells and intratumoral lymphotactin transgene expression.
The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have shown that transplanted SP2/0 myeloma tumors that have been engineered to express lymphotactin (Lptn) invariably regress under the influence of infiltrating XCR1+T cells and neutrophils. Herein, we characterize these T cells and investigate their therapeutic efficacy, either alone or with Lptn gene therapy. After stimulation with SP2/0 cells, these T cells were CD25+FasL+L-selectin-, expressed XCR-1, and were chemoattracted by Lptn in vitro. They comprised 66% CD4+ Th1 and 33% CD8+ Tc1 cells, both of which expressed significant amounts of IFN-gamma, perforin, and tumor necrosis factor-alpha, but not interleukin-4. The CD4+ Th1 and CD8+ Tc1 cells, which were inhibited and stimulated, respectively, for proliferation with Lptn signaling, displayed 38 and 84% specific killing, respectively, for Ia(d)/H-2K(d)-expressing SP2/0 tumor cells (E:T ratio, 100). In vivo, combined intratumoral Lptn gene transfer and adoptive immunotherapy with these CD4+ and CD8+ T cells eradicated well-established SP2/0 tumors in six of eight mice, and dramatically slowed tumor growth in the other two mice. Cell tracking using labeled T cells confirmed that these cells infiltrated better into the Lptn-expressing tumors than non-Lptn-expressing ones. Control or Lptn adenoviral treatments by themselves did not alter the lethal outcome for tumor-bearing mice, nor did T-cell therapy by itself, although the latter two treatments did slow its time frame. Combined Lptn gene transfer and adoptive CD4+ or CD8+ cell transfers were not nearly as efficacious as the combined Lptn gene and unfractionated T-cell transfers. Taken together, our data provide solid evidence of a potent synergy between adoptive CD4+ and CD8+ T-cell therapy and Lptn gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.


Impact of Flipped Classroom Design on Student Performance and Perceptions in a Pharmacotherapy Course.
Objective. To determine whether a flipped classroom design would improve student performance and perceptions of the learning experience compared to traditional lecture course design in a required pharmacotherapy course for second-year pharmacy students. Design. Students viewed short online videos about the foundational concepts and answered self-assessment questions prior to face-to-face sessions involving patient case discussions. Assessment. Pretest/posttest and precourse/postcourse surveys evaluated students' short-term knowledge retention and perceptions before and after the redesigned course. The final grades improved after the redesign. Mean scores on the posttest improved from the pretest. Postcourse survey showed 88% of students were satisfied with the redesign. Students reported that they appreciated the flexibility of video viewing and knowledge application during case discussions but some also struggled with time requirements of the course. Conclusion. The redesigned course improved student test performance and perceptions of the learning experience during the first year of implementation.


Generation of Aromatic N-Heterocyclic Radicals for Functionalization of Unactivated Alkenes.
Nitrogen-centered radicals (NCRs) have been widely recognized as versatile synthetic intermediates for the construction of nitrogen containing molecules of high value. As such, there has been a long-standing interest in the field of organic synthesis to develop novel nitrogen-based radicals and explore their inherent reactivity. In this study, we present the generation of aromatic N-heterocyclic radicals and their application in a novel and diverse functionalization of unactivated alkenes. Bench-stable aromatic N-heterocyclic pyridinium salts were employed as crucial NCR precursors, which enabled the efficient conversion of various unactivated alkenes into medicinally relevant alkylated N-heterocyclic amines. This approach offers an unexplored retrosynthetic disconnection for the synthesis of related molecules that commonly possess therapeutic value. Furthermore, this platform can be extended to the synthesis of densely functionalized heterocyclic amines by utilizing disulfides and diethyl bromomalonate as radical quenchers. Mechanistic investigations indicate an energy transfer (EnT) pathway involving the formation of a transient aromatic N-heterocyclic radical, radical addition to unactivated alkenes, and subsequent generation of the amination product through either hydrogen atom transfer (HAT) or radical addition processes.


Use of mitomycin C in the treatment of conjunctival primary acquired melanosis with atypia.
A patient who had primary acquired melanosis with marked atypia shown on histological studies received topical 0.02% mitomycin C for 2 weeks and 0.04% mitomycin C for an additional 2 weeks. Conjunctival biopsy specimens were obtained to evaluate the efficacy of the treatment. After the first course of mitomycin C administration, some decrease of conjunctival pigmentation was seen, and histological studies disclosed a lower degree of atypia. After the second application of mitomycin C, the pigmentation disappeared except for one small spot that contained only a few typical melanocytes on histological study. The clinical findings did not change during 7 months of follow-up. No adverse reactions to topical mitomycin C occurred except for mild conjunctival hyperemia at the end of the courses of treatment. Administration of topical mitomycin C may be an effective medical treatment for primary acquired melanosis with atypia.


Early experience with in situ saphenous vein bypass for distal arterial reconstruction.
During a 36-month period 74 patients underwent infrainguinal in situ saphenous vein bypass to the popliteal or tibial vessels. The first 54 operations were performed with standard valvulotomes and valve-cutting scissors, while in the last 20 operations a new intraluminal valve-cutting device was used to incise the valves. Ninety-four percent of bypasses were performed for limb salvage, 80% of all operations were done to the tibial vessels, and 31% of bypasses were done to the ankle vessels. The operation was attempted in 81 patients and completed in 74 patients, for a vein utilization rate of 91%. Fifty-five percent of all veins had a distal diameter of less than 4 mm (average 3.6 mm). The patency rates were 92% at 3 months and 90% at 12 and 36 months for all grafts. There were six failed grafts, all within the first 6 months, and eight diabetic patients required reoperation, two for missed valve leaflets, and three needed revision of the distal anastomosis; however, all these grafts were patent at the time of reexploration. There were four perioperative deaths and two patients had nonfatal postoperative myocardial infarctions. This study demonstrates that in situ saphenous vein grafting provides for a high vein utilization rate and suggests that the technique provides for higher graft patency and limb salvage rates than do more traditional types of procedures.


GyneScan: an improved online paradigm for screening of ovarian cancer via tissue characterization.
Ovarian cancer is the fifth highest cause of cancer in women and the leading cause of death from gynecological cancers. Accurate diagnosis of ovarian cancer from acquired images is dependent on the expertise and experience of ultrasonographers or physicians, and is therefore, associated with inter observer variabilities. Computer Aided Diagnostic (CAD) techniques use a number of different data mining techniques to automatically predict the presence or absence of cancer, and therefore, are more reliable and accurate. A review of published literature in the field of CAD based ovarian cancer detection indicates that many studies use ultrasound images as the base for analysis. The key objective of this work is to propose an effective adjunct CAD technique called GyneScan for ovarian tumor detection in ultrasound images. In our proposed data mining framework, we extract several texture features based on first order statistics, Gray Level Co-occurrence Matrix and run length matrix. The significant features selected using t-test are then used to train and test several supervised learning based classifiers such as Probabilistic Neural Networks (PNN), Support Vector Machine (SVM), Decision Tree (DT), k-Nearest Neighbor (KNN), and Naive Bayes (NB). We evaluated the developed framework using 1300 benign and 1300 malignant images. Using 11 significant features in KNN/PNN classifiers, we were able to achieve 100% classification accuracy, sensitivity, specificity, and positive predictive value in detecting ovarian tumor. Even though more validation using larger databases would better establish the robustness of our technique, the preliminary results are promising. This technique could be used as a reliable adjunct method to existing imaging modalities to provide a more confident second opinion on the presence/absence of ovarian tumor.


Sensitivity change in cornea and tear layer due to incision difference on cataract surgery with either manual small-incision cataract surgery or phacoemulsification.
To describe corneal sensitivity changes caused by different incision methods-manual small-incision cataract surgery (manual SICS) and phacoemulsification-and their influence on tear film quantity and quality. This was a prospective observational study conducted in 30 subjects undergoing manual SICS or phacoemulsification. Corneal sensitivity was assessed before and 1, 7, and 15 days after surgery by Cochet-Bonnet esthesiometer. Tear meniscus, noninvasive breakup time, lipid pattern, and Schirmer test results were evaluated. Patient symptoms were reviewed based on the Ocular Surface Disease Index. In the group undergoing phacoemulsification, corneal sensitivity decreased at the incision site and at other sites on days 1, 7, and 15 after surgery, whereas in the group undergoing manual SICS, no change in corneal sensitivity was noted. Between-group difference in corneal sensitivity was significant on days 1, 7, and 15. Aqueous production significantly (P = 0.016) increased on the first day in both groups and returned to presurgery level on day 15. Tear film quality decreased on day 1 only in the group undergoing manual SICS (P = 0.035). Tear meniscus and tear lipid profile showed no change in either group. Patient symptoms significantly increased on day 1 in both groups, and the difference between the 2 groups was significant on day 15 (P = 0.044). Compared with manual SICS, temporal-side incision in phacoemulsification decreased corneal sensitivity in the incision site and other sites until day 15 and changes in tear film quantity and patient symptoms only on day 1.


Rhodium-Catalyzed Allylic Addition as an Atom-Efficient Approach in Total Synthesis.
ConspectusFinding efficient synthetic methods for the asymmetric synthesis of complex molecules has always been of interest to organic chemists. Creating and controlling the stereochemistry of stereogenic centers bearing branched allylic moieties in organic molecules using a catalytic process is an attractive and successful method for the synthesis of several natural products and medicinally important compounds. Remarkable progress toward their synthesis has been achieved via transition-metal catalysis, especially in the case of allylic substitution and allylic C-H oxidation chemistry. However, for allylic substitution the preinstallation of a leaving group is essential, and for allylic C-H oxidation, stoichiometric amounts of oxidant are required. Besides that, the control of regioselectivity with these methods is often problematic because the linear product can be produced as a major isomer. Our research group has developed a regioselective, enantioselective, and atom economic route toward the more valuable branched product via a Rh-catalyzed coupling of easily accessible alkynes or the double-bond isomeric allenes with pronucleophiles. It was demonstrated that, using this new approach, it is possible to add different pronucleophiles to alkynes or allenes to form branched allylic moieties through C-C and C-heteroatom bond formation. Since new organic reactions offer new opportunities in chemical synthesis and the benchmark for new synthetic methods is their application in target-oriented synthesis, we have demonstrated several successful syntheses of natural products and medicinally relevant targets. For example, in the total syntheses of Quercuslactones, Helicascolides A-C, Epothilone D, Homolargazole, and Thailandepsin B, the Rh-catalyzed hydro-oxycarbonylation of allenes was used as key step via C-O bond formation. Remarkably, the Rh-catalyzed C2-symmetric dimerization strategy was used to synthesize the complex molecules Clavosolide A and Vermiculine, leading to an extreme increase in structural complexity within a single step. For the total syntheses of Centrolobine, Pitavastatin, and Rosuvastatin, C-O bond formation was achieved through the addition of a hydroxy function to the allene moiety. The potential of the addition of nitrogen pronucleophiles to allenes was demonstrated in the total syntheses of Cusparein, Angusterein, Cermicin C, Senepodin G, Homoproline, Pipecolinol, Coniceine, Coniine, Ruxolitinib, Sitagliptin, Abacavir, Glucokinase activators, and Chaetominine. All of these examples testify to the wide applicability of the Rh-catalyzed addition of pronucleophiles to allenes or alkynes in target-oriented synthesis, and in this Account we summarize our contribution.


Puzzle Imaging: Using Large-Scale Dimensionality Reduction Algorithms for Localization.
Current high-resolution imaging techniques require an intact sample that preserves spatial relationships. We here present a novel approach, "puzzle imaging," that allows imaging a spatially scrambled sample. This technique takes many spatially disordered samples, and then pieces them back together using local properties embedded within the sample. We show that puzzle imaging can efficiently produce high-resolution images using dimensionality reduction algorithms. We demonstrate the theoretical capabilities of puzzle imaging in three biological scenarios, showing that (1) relatively precise 3-dimensional brain imaging is possible; (2) the physical structure of a neural network can often be recovered based only on the neural connectivity matrix; and (3) a chemical map could be reproduced using bacteria with chemosensitive DNA and conjugative transfer. The ability to reconstruct scrambled images promises to enable imaging based on DNA sequencing of homogenized tissue samples.


Management of home care by family caregivers to elderly after hospital discharge.
To understand the management of home care by family caregivers of dependent elderly people after hospital discharge. Qualitative research guided by hermeneutics-dialectic, anchored in the theory of communicative action. Data collection took place using a semi-structured interview with 11 participants. Two categories were constructed: Management of the many types of care by the caregiver and the relationship between family caregiver and health care network. Care and management actions carried out routinely cause major changes in the family caregiver's life. He/she does not recognize planning, home care periodicity or support in required procedures. The management of home care for dependent elderly people after hospital discharge is complex, involving physical and emotional overloads, as well as difficulties in getting support from health services. The planning shared between the health team and the family since the discharge is required, and the better visibility of the role of primary care when the patient is assisted by a home care service.


Persisting while wanting to change: women's lived experiences.
This article presents an inquiry into a common lived experience, which the author named persisting while wanting to change to signify the struggle of trying to change health patterns. Parse's phenomenological-hermeneutic methodology was used to investigate the phenomenon, as it is lived by women in an abusive relationship. Through dialogical engagement with the researcher, eight women described their experiences of persisting while wanting to change. The generated structure and central finding contained three core concepts: wavering in abiding with the burdensome-cherished, engaging-distancing with ameliorating intentions, and anticipating the possibilities of the new. The core concepts are illustrated with excerpts from the dialogues and are discussed in relation to Parse's human becoming theory and related literature. Findings are consistent with those of other studies in which leaving an abusive relationship was described as a process. Implications for practice and further research also are discussed.


Emotion in action: When emotions meet motor circuits.
The brain is a remarkably complex organ responsible for a wide range of functions, including the modulation of emotional states and movement. Neuronal circuits are believed to play a crucial role in integrating sensory, cognitive, and emotional information to ultimately guide motor behavior. Over the years, numerous studies employing diverse techniques such as electrophysiology, imaging, and optogenetics have revealed a complex network of neural circuits involved in the regulation of emotional or motor processes. Emotions can exert a substantial influence on motor performance, encompassing both everyday activities and pathological conditions. The aim of this review is to explore how emotional states can shape movements by connecting the neural circuits for emotional processing to motor neural circuits. We first provide a comprehensive overview of the impact of different emotional states on motor control in humans and rodents. In line with behavioral studies, we set out to identify emotion-related structures capable of modulating motor output, behaviorally and anatomically. Neuronal circuits involved in emotional processing are extensively connected to the motor system. These circuits can drive emotional behavior, essential for survival, but can also continuously shape ongoing movement. In summary, the investigation of the intricate relationship between emotion and movement offers valuable insights into human behavior, including opportunities to enhance performance, and holds promise for improving mental and physical health. This review integrates findings from multiple scientific approaches, including anatomical tracing, circuit-based dissection, and behavioral studies, conducted in both animal and human subjects. By incorporating these different methodologies, we aim to present a comprehensive overview of the current understanding of the emotional modulation of movement in both physiological and pathological conditions.


Evaluation of impact of major causes of death on life expectancy changes in China, 1990-2005.
To evaluate the impact of major causes of death on changes of life expectancy in China. Life expectancy was calculated by standard life table techniques using mortality data from the national censuses in 1990 and 2000 and the 1% National Population Sampling Surveys in 1995 and 2005. Mortality data about the major causes of death from VR-MOH were used as reference values to estimate their death proportions of the specific age groups by sex and regions, as well as all-cause mortality and age-specific mortality rates of major causes of death. Decomposition method was used to quantitatively evaluate the impact. Three key findings were identified in our study. First, China's health challenge was shifted from diseases related to living conditions to those related to behavior and lifestyle, with rural areas relatively lagged behind urban areas. Second, the impacts of cardiovascular diseases and neoplasm on the middle aged and elderly population were stressed. Third, compared to the urban population, the rural population tended to have increasing mortality of neoplasm and cardiovascular diseases, especially in adults at the age of 15-39 years. Further efforts should be made to reduce the incidence of neoplasm and cardiovascular diseases, especially in rural areas, by promoting healthy behavior and lifestyle and providing appropriate therapies for all patients in need.


Oligomerization of the Sec7 domain Arf guanine nucleotide exchange factor GBF1 is dispensable for Golgi localization and function but regulates degradation.
Members of the large Sec7 domain-containing Arf guanine nucleotide exchange factor (GEF) family have been shown to dimerize through their NH2-terminal dimerization and cyclophilin binding (DCB) and homology upstream of Sec7 (HUS) domains. However, the importance of dimerization in GEF localization and function has not been assessed. We generated a GBF1 mutant (91/130) in which two residues required for oligomerization (K91 and E130 within the DCB domain) were replaced with A and assessed the effects of these mutations on GBF1 localization and cellular functions. We show that 91/130 is compromised in oligomerization but that it targets to the Golgi in a manner indistinguishable from wild-type GBF1 and that it rapidly exchanges between the cytosolic and membrane-bound pools. The 91/130 mutant appears active as it integrates within the functional network at the Golgi, supports Arf activation and COPI recruitment, and sustains Golgi homeostasis and cargo secretion when provided as a sole copy of functional GBF1 in cells. In addition, like wild-type GBF1, the 91/130 mutant supports poliovirus RNA replication, a process requiring GBF1 but believed to be independent of GBF1 catalytic activity. However, oligomerization appears to stabilize GBF1 in cells, and the 91/130 mutant is degraded faster than the wild-type GBF1. Our data support a model in which oligomerization is not a key regulator of GBF1 activity but impacts its function by regulating the cellular levels of GBF1.


Funicular myelosis in a butcher: it was the cream cans.
Background. Funicular myelosis is a known consequence of exposure to nitrous oxide. Nevertheless, there are only a few clinical trials assessing its long-term effects and there is no literature about the role of nutritional vitamin B12 supplementation in the context of nitrous oxide abuse. Case Descriptions. We diagnosed funicular myelosis in a young butcher, who consumed high amounts of meat regularly. Since the diagnostic process did not reveal any metabolic causes, reinterrogation of the patient uncovered recreational abuse of nitrous oxide out of whipped cream can gas cartridges. After stopping abuse and supplementation of vitamin B12, the patient recovered almost completely. Conclusions. In our case, even high nutritional vitamin B12 uptake could not compensate the noxious effects of nitrous oxide. Since there are emerging reports of increasing misuse, this should be considered in the diagnostic and therapeutic care of patients with nitrous oxide abuse. Furthermore, our case emphasizes that patients with vitamin B12 deficiency should be assessed for nitrous oxide abuse.


An elastomer with ultrahigh strain-induced crystallization.
Strain-induced crystallization (SIC) prevalently strengthens, toughens, and enables an elastocaloric effect in elastomers. However, the crystallinity induced by mechanical stretching in common elastomers (e.g., natural rubber) is typically below 20%, and the stretchability plateaus due to trapped entanglements. We report a class of elastomers formed by end-linking and then deswelling star polymers with low defects and no trapped entanglements, which achieve strain-induced crystallinity of up to 50%. The deswollen end-linked star elastomer (DELSE) reaches an ultrahigh stretchability of 12.4 to 33.3, scaling beyond the saturated limit of common elastomers. The DELSE also exhibits a high fracture energy of 4.2 to 4.5 kJ m-2 while maintaining low hysteresis. The heightened SIC and stretchability synergistically promote a high elastocaloric effect with an adiabatic temperature change of 9.3°C.


A novel mutant-enriched liquidchip technology for the qualitative detection of somatic mutations in KRAS gene from both serum and tissue samples.
Somatic mutations in the KRAS gene have been reported to confer drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors and some monoclonal antibodies. However, current DNA mutation detection technologies are primarily DNA sequencing-based and not high throughput, nor sensitive enough to meet clinical needs. A mutant-enriched PCR method was designed by introducing a unique restriction enzyme site to the PCR product. This allowed the wild-type KRAS sequence to be selectively removed by restriction enzyme digestion before application to the Luminex liquidchip system. A total of 100 copies of mutant KRAS DNA fragment mixed with 1x10(5) copies of the wild-type KRAS DNA could be detected to achieve a sensitivity of 0.1%. This technology is currently used for clinical testing of KRAS somatic mutations for the purpose of pharmacogenomic evaluation. Serum samples from 109 patients with non-small cell lung cancer were tested and 34 mutations were detected (34/109). The formalin-fixed and paraffin-embedded samples from 60 patients with colorectal cancer were tested and 19 mutations were detected (19/60). A novel, qualitative, sensitive, reliable and high throughput liquidchip technology has been developed for detecting KRAS mutations using clinical serum and formalin-fixed and paraffin-embedded samples.


[Mechanism of the anti-inflammatory action of immunodepressants].
The effectiveness of immunodepressants in lingering exudative processes, their inhibitory action in the proliferative phase of inflammation, depression of the phagocytic activity of leucocytes, as well as suppressive influence on the development of a toxic pulmonary edema and upon generalized anaphylaction reaction was demonstrated in tests staged on rats and mice. The antiphlogistic action of immunodepressants was not abolished during the first hours after their administration by specific metabolites, but was suppressed at the peak of the cytostatic effect together with the latter. The phlogolytic effect was not mediated through the hypophysis-adrenal system and did not include the lienic factor.


"What do they want me to say?" The hidden curriculum at work in the medical school selection process: a qualitative study.
There has been little study of the role of the essay question in selection for medical school. The purpose of this study was to obtain a better understanding of how applicants approached the essay questions used in selection at our medical school in 2007. The authors conducted a qualitative analysis of 210 essays written as part of the medical school admissions process, and developed a conceptual framework to describe the relationships, ideas and concepts observed in the data. Findings of this analysis were confirmed in interviews with applicants and assessors. Analysis revealed a tension between "genuine" and "expected" responses that we believe applicants experience when choosing how to answer questions in the admissions process. A theory named "What do they want me to say?" was developed to describe the ways in which applicants modulate their responses to conform to their expectations of the selection process; the elements of this theory were confirmed in interviews with applicants and assessors. This work suggests the existence of a "hidden curriculum of admissions" and demonstrates that the process of selection has a strong influence on applicant response. This paper suggests ways that selection might be modified to address this effect. Studies such as this can help us to appreciate the unintended consequences of admissions processes and can identify ways to make the selection process more consistent, transparent and fair.


Symptoms and signs of temporomandibular disorders before, during and after orthodontic treatment.
The relationship between orthodontic treatment and symptoms and signs of temporomandibular disorders (TMD) was studied prospectively and longitudinally in 65 adolescent girls with Class II malocclusion. The subjects received orthodontic fixed appliance treatment with the straight-wire technique combined with or without extractions and were examined for symptoms and signs of TMD before, during, after, and finally one year post-treatment. Both symptoms and signs of TMD showed considerable fluctuations over the three-year period within the individuals. The general tendency was a decreased prevalence of symptoms of TMD over the three years. The prevalence of pain on mandibular movement and tenderness to palpation of the masticatory muscles was significantly less common during and after orthodontic treatment than before. Clinically registered TMJ clicking increased slightly over the three year period. One orthodontic treatment effect when normalizing Class II malocclusions with fixed appliances was a decreased prevalence of functional occlusal interferences. We concluded that the orthodontic treatment either with or without tooth extractions did not increase the risk for TMD or worsen pre-treatment signs of TMD. Subjects with Class II malocclusion and pre-treatment signs of TMD of muscular origin seemed rather to benefit functionally from orthodontic treatment in a three-year perspective.


TAp73 alpha increases p53 tumor suppressor activity in thyroid cancer cells via the inhibition of Mdm2-mediated degradation.
p53 family proteins include p53 tumor suppressor, p63, and p73. Despite the high similarity in structure and function with p53, p63, and p73 function in tumor suppression is still controversial. Here, we show that TAp73alpha, a transcriptionally active p73 isoform, is able to synergize p53 tumor suppressor function in thyroid cancer cells. Indeed, depletion of p73 by small interfering RNA in thyroid cancer cells resulted in a reduced transcriptional activity of p53. Ectopic coexpression of both p53 and TAp73alpha in thyroid cancer cells resulted in increased transcription and tumor suppressor function compared with p53 or TAp73alpha alone, as well as in increased p53 protein levels. The enhancing effect of TAp73alpha on p53 activity is Mdm2 dependent because it is prevented by Mdm2 depletion by small interfering RNA. At least two mechanisms may explain the interference of TAp73alpha with p53 function. First, in thyroid cancer cells, TAp73alpha inhibits the effect of p53 on Mdm2 induction by antagonizing p53 at the Mdm2 promoter level. Second, a TAp73alpha mutant (G264W), which is devoid of DNA binding capability, is still able to increase p53 protein levels by competing with p53 for Mdm2 protein binding. Taken together, these results indicate that in thyroid cancer cells, TAp73alpha is able to increase p53 protein level and function by interfering with Mdm2-mediated p53 degradation. These results may be useful for designing gene therapies aimed at restoring a normal p53 function in thyroid cancer cells.


Origin and evolution of the chicken leukocyte receptor complex.
In mammals, the cell surface receptors encoded by the leukocyte receptor complex (LRC) regulate the activity of T lymphocytes and B lymphocytes, as well as that of natural killer cells, and thus provide protection against pathogens and parasites. The chicken genome encodes many Ig-like receptors that are homologous to the LRC receptors. The chicken Ig-like receptor (CHIR) genes are members of a large monophyletic gene family and are organized into genomic clusters, which are in conserved synteny with the mammalian LRC. One-third of CHIR genes encode polypeptide molecules that contain both activating and inhibitory motifs. These genes are present in different phylogenetic groups, suggesting that the primordial CHIR gene could have encoded both types of motifs in a single molecule. In contrast to the mammalian LRC genes, the CHIR genes with similar function (inhibition or activation) are evolutionarily closely related. We propose that, in addition to recombination, single nucleotide substitutions played an important role in the generation of receptors with different functions. Structural models and amino acid analyses of the CHIR proteins reveal the presence of different types of Ig-like domains in the same phylogenetic groups, as well as sharing of conserved residues and conserved changes of residues between different CHIR groups and between CHIRs and LRCs. Our data support the notion that the CHIR gene clusters are regions homologous to the mammalian LRC gene cluster and favor a model of evolution by repeated processes of birth and death (expansion-contraction) of the Ig-like receptor genes.


Inhaled gold nanoparticles cause cerebral edema and upregulate endothelial aquaporin 1 expression, involving caveolin 1 dependent repression of extracellular regulated protein kinase activity.
Gold nanoparticles (Au-NPs) have extensive applications in electronics and biomedicine, resulting in increased exposure and prompting safety concerns for human health. After absorption, nanoparticles enter circulation and effect endothelial cells. We previously showed that exposure to Au-NPs (40-50 nm) collapsed endothelial tight junctions and increased their paracellular permeability. Inhaled nanoparticles have gained significant attention due to their biodistribution in the brain; however, little is known regarding their role in cerebral edema. The present study investigated the expression of aquaporin 1 (AQP1) in the cerebral endothelial cell line, bEnd.3, stimulated by Au-NPs. We found that treatment with Au-NPs induced AQP1 expression and increased endothelial permeability to water. Au-NP exposure rapidly boosted the phosphorylation levels of focal adhesion kinase (FAK) and AKT, increased the accumulation of caveolin 1 (Cav1), and reduced the activity of extracellular regulated protein kinases (ERK). The inhibition of AKT (GDC-0068) or FAK (PF-573228) not only rescued ERK activity but also prevented AQP1 induction, whereas Au-NP-mediated Cav1 accumulation remained unaltered. Neither these signaling molecules nor AQP1 expression responded to Au-NPs while Cav1 was silenced. Inhibition of ERK activity (U0126) remarkably enhanced Cav1 and AQP1 expression in bEnd.3 cells. These data demonstrate that Au-NP-mediated AQP1 induction is Cav1 dependent, but requires the repression on ERK activity. Mice receiving intranasally administered Au-NPs displayed cerebral edema, significantly augmented AQP1 protein levels; furthermore, mild focal lesions were observed in the cerebral parenchyma. These data suggest that the subacute exposure of nanoparticles might induce cerebral edema, involving the Cav1 dependent accumulation on endothelial AQP1.


Measuring participatory strategies: instrument development for worksite populations.
A participatory strategies approach which involves employees in the planning and delivery of worksite health promotion programs was utilized in the 55 experimental worksites included in the national, NCI-funded Working Well Trial. According to study protocol, Employee Advisory Boards (EABs) were organized in each experimental worksite. This paper describes two substudies designed to develop and measure participatory strategies associated with the EABs in the Working Well Trial. Study 1 determined characteristics of the EABs, developed subscales and assessed the internal consistency of the scales. Study 2 used a confirmatory factor analysis to examine the structure of the developed questionnaire. The four subscales include: Autonomy/Independence, Management Involvement, Institutionalization/Commitment and Others Involvement. Results from Study 1 indicate that the four subscales of the 24-item instrument demonstrated strong internal consistency and three were sensitive enough to register differences by Study Center at the baseline. Study 2 results found that the EAB subscales again demonstrated good internal consistency, structural stability and acceptable sensitivity. An initial validity analysis was performed and yielded results which supported some but not all of the hypothesized associations. Implications for further refinement and application of this new instrument in worksite settings are explored.


Assessment of multicoefficient correlation methods, second-order Møller-Plesset perturbation theory, and density functional theory for H3O(+)(H2O)n (n = 1-5) and OH(-)(H2O)n (n = 1-4).
We have assessed the ability of 52 methods including 15 multicoefficient correlation methods (MCCMs), two complete basis set (CBS) methods, second-order Møller-Plesset perturbation theory (MP2) with 5 basis sets, the popular B3LYP hybrid functional with 6 basis sets, and 24 combinations of local density functional and basis set to accurately reproduce reaction energies obtained at the Weizmann-1 level of theory for hydronium, hydroxide, and pure water clusters. The three best methods overall are BMC-CCSD, G3SX(MP3), and M06-L/aug-cc-pVTZ. If only microsolvated ion data is included, M06-L/aug-cc-pVTZ is the best method; it has errors only half as large as the other density functionals. The deviations between the three best performing methods are larger for the larger hydronium- and hydroxide-containing clusters, despite a decrease in the average reaction energy, making it impossible to determine which of the three methods is overall the best, so they might be ranked in order of increasing cost, with BMC-CCSD least expensive, followed by M06-L/aug-cc-pVTZ. However, the cost for M06-L will increase more slowly as cluster size increases. This study shows that the M06-L functional is very promising for condensed-phase simulations of the transport of hydronium and hydroxide ions in aqueous solution.


AQP2 as a target of lycopene protects against atrazine-induced renal ionic homeostasis disturbance.
Atrazine (ATR), a ubiquitous environmental contaminant in water and soil, causes environmental nephrosis. To reveal the toxic effect of ATR on the kidney and the potential chemical nephroprotective effect of lycopene (LYC), Kun-Ming mice of specific pathogen-free (SPF) grade were treated with LYC (5 mg kg-1) and/or ATR (50 mg kg-1 or 200 mg kg-1) for 21 days. The degree of renal injury was evaluated by measuring the ion concentration, ATPase activities and the mRNA expressions/levels of associated ATPase subunits. In addition, the expression of renal aquaporins (AQPs) was analyzed. The results showed that the renal tubular epithelial cells of ATR-exposed mice were swollen, the glomeruli were significantly atrophied, and the ion concentrations were obviously changed. The activity of Na+-K+-ATPase and the transcription of its subunits were downregulated. The activity of Ca2+-Mg2+-ATPase and the transcription of its subunits were upregulated. The expression of AQPs, especially the critical AQP2, was affected. Notably, ATR-induced nephrotoxicity was significantly improved by LYC supplementation. Therefore, LYC could protect the kidney against ATR-induced nephrotoxicity via maintaining ionic homeostasis, reversing the changes in ATPase activity and controlling the expression of AQPs on the cell membrane. These results suggested that AQP2 was a target of LYC and protected against ATR-induced renal ionic homeostasis disturbance.


New targets for the immunotherapy of colon cancer-does reactive disease hold the answer?
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in both men and women, posing a serious demographic and economic burden worldwide. In the United Kingdom, CRC affects 1 in every 20 people and it is often detected once well established and after it has spread beyond the bowel (Stage IIA-C and Stage IIIA-C). A diagnosis at such advanced stages is associated with poor treatment response and survival. However, studies have identified two sub-groups of post-treatment CRC patients--those with good outcome (reactive disease) and those with poor outcome (non-reactive disease). We aim to review the state-of-the-art for CRC with respect to the expression of cancer-testis antigens (CTAs) and their identification, evaluation and correlation with disease progression, treatment response and survival. We will also discuss the relationship between CTA expression and regulatory T-cell (Treg) activity to tumorigenesis and tumor immune evasion in CRC and how this could account for the clinical presentation of CRC. Understanding the molecular basis of reactive CRC may help us identify more potent novel immunotherapeutic targets to aid the effective treatment of this disease. In this review, based on our presentation at the 2012 International Society for the Cell and Gene Therapy of Cancer annual meeting, we will summarize some of the most current advances in CTA and CRC research and their influence on the development of novel immunotherapeutic approaches for this common and at times difficult to treat disease.


Atrial natriuretic peptide and renal cGMP in rats with experimental heart failure.
Rats with chronic aortocaval (AV) fistula, an experimental model of congestive heart failure, display high plasma levels of atrial natriuretic factor (ANF) and a blunted natriuretic response to ANF infusion. We previously reported that rats with AV fistula either develop progressive sodium retention (urinary sodium excretion, UNaV less than 100 microeq/24 h) or compensate (UNaV greater than 1,200 microeq/24 h). To gain further insight into the mechanism of renal hyporesponsiveness to ANF, we evaluated the effect of ANF on renal guanosine 3',5'-cyclic monophosphate (cGMP) production in sham-operated control rats and in the two groups of rats with AV fistula. Infusion of synthetic ANF-(99-126) (at either 10 or 50 micrograms.kg-1.h-1) resulted in a reduced fractional sodium excretion (P less than 0.05) in both compensated rats (0.7 +/- 0.2 and 7.9 +/- 1.6%) and sodium-retaining rats (0.3 +/- 0.1 and 0.5 +/- 0.1%) compared with controls (8.5 +/- 1.2 and 13.7 +/- 2.3% for low and high doses, respectively). Similarly, urinary cGMP excretion corrected by glomerular filtration rate (UcGMPV/GFR) during low-dose ANF infusion was significantly reduced (P less than 0.05) in both groups with AV fistula (compensated: 39 +/- 10 pmol/ml; sodium-retaining: 55 +/- 13 pmol/ml) compared with controls (115 +/- 16 pmol/ml). During high-dose ANF infusion, compensated rats, but not sodium-retaining rats, displayed a significant increase in UcGMPV/GFR. The differences in UcGMPV/GFR are probably not due to variations in urine flow because furosemide infusion to a separate group of rats with AV fistula increased urine flow approximately eightfold but did not increase UcGMPV/GFR.(ABSTRACT TRUNCATED AT 250 WORDS)


On the Multilevel Nature of Meta-Analysis: A Tutorial, Comparison of Software Programs, and Discussion of Analytic Choices.
The term "multilevel meta-analysis" is encountered not only in applied research studies, but in multilevel resources comparing traditional meta-analysis to multilevel meta-analysis. In this tutorial, we argue that the term "multilevel meta-analysis" is redundant since all meta-analysis can be formulated as a special kind of multilevel model. To clarify the multilevel nature of meta-analysis the four standard meta-analytic models are presented using multilevel equations and fit to an example data set using four software programs: two specific to meta-analysis (metafor in R and SPSS macros) and two specific to multilevel modeling (PROC MIXED in SAS and HLM). The same parameter estimates are obtained across programs underscoring that all meta-analyses are multilevel in nature. Despite the equivalent results, not all software programs are alike and differences are noted in the output provided and estimators available. This tutorial also recasts distinctions made in the literature between traditional and multilevel meta-analysis as differences between meta-analytic choices, not between meta-analytic models, and provides guidance to inform choices in estimators, significance tests, moderator analyses, and modeling sequence. The extent to which the software programs allow flexibility with respect to these decisions is noted, with metafor emerging as the most favorable program reviewed.


Novel genetic variants in miR-191 gene and familial ovarian cancer.
Half of the familial aggregation of ovarian cancer can't be explained by any known risk genes, suggesting the existence of other genetic risk factors. Some of these unknown factors may not be traditional protein encoding genes. MicroRNA (miRNA) plays a critical role in tumorigenesis, but it is still unknown if variants in miRNA genes lead to predisposition to cancer. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis in familial ovarian cancer, we screened for genetic variants in thirty selected miRNA genes, which are predicted to regulate key ovarian cancer genes and are reported to be misexpressed in ovarian tumor tissues, in eighty-three patients with familial ovarian cancer. All of the patients are non-carriers of any known BRCA1/2 or mismatch repair (MMR) gene mutations. Seven novel genetic variants were observed in four primary or precursor miRNA genes. Among them, three rare variants were found in the precursor or primary precursor of the miR-191 gene. In functional assays, the one variant located in the precursor of miR-191 resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-191. In further analysis, we found that this particular variant exists in five family members who had ovarian cancer. Our findings suggest that there are novel genetic variants in miRNA genes, and those certain genetic variants in miRNA genes can affect the expression of mature miRNAs and, consequently, might alter the regulation of TSGs or oncogenes. Additionally, the variant might be potentially associated with the development of familial ovarian cancer.


Coagulation factor XIIIa substrates in human plasma: identification and incorporation into the clot.
Coagulation factor XIII (FXIII) is a transglutaminase with a well defined role in the final stages of blood coagulation. Active FXIII (FXIIIa) catalyzes the formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific Gln and Lys residues. The primary physiological outcome of this catalytic activity is stabilization of the fibrin clot during coagulation. The stabilization is achieved through the introduction of cross-links between fibrin monomers and through cross-linking of proteins with anti-fibrinolytic activity to fibrin. FXIIIa additionally cross-links several proteins with other functionalities to the clot. Cross-linking of proteins to the clot is generally believed to modify clot characteristics such as proteolytic susceptibility and hereby affect the outcome of tissue damage. In the present study, we use a proteomic approach in combination with transglutaminase-specific labeling to identify FXIIIa plasma protein substrates and their reactive residues. The results revealed a total of 147 FXIIIa substrates, of which 132 have not previously been described. We confirm that 48 of the FXIIIa substrates were indeed incorporated into the insoluble fibrin clot during the coagulation of plasma. The identified substrates are involved in, among other activities, complement activation, coagulation, inflammatory and immune responses, and extracellular matrix organization.


A Swiss cheese error detection method for real-time EPID-based quality assurance and error prevention.
To develop a robust and efficient process that detects relevant dose errors (dose errors of ≥5%) in external beam radiation therapy and directly indicates the origin of the error. The process is illustrated in the context of electronic portal imaging device (EPID)-based angle-resolved volumetric-modulated arc therapy (VMAT) quality assurance (QA), particularly as would be implemented in a real-time monitoring program. A Swiss cheese error detection (SCED) method was created as a paradigm for a cine EPID-based during-treatment QA. For VMAT, the method compares a treatment plan-based reference set of EPID images with images acquired over each 2° gantry angle interval. The process utilizes a sequence of independent consecutively executed error detection tests: an aperture check that verifies in-field radiation delivery and ensures no out-of-field radiation; output normalization checks at two different stages; global image alignment check to examine if rotation, scaling, and translation are within tolerances; pixel intensity check containing the standard gamma evaluation (3%, 3 mm) and pixel intensity deviation checks including and excluding high dose gradient regions. Tolerances for each check were determined. To test the SCED method, 12 different types of errors were selected to modify the original plan. A series of angle-resolved predicted EPID images were artificially generated for each test case, resulting in a sequence of precalculated frames for each modified treatment plan. The SCED method was applied multiple times for each test case to assess the ability to detect introduced plan variations. To compare the performance of the SCED process with that of a standard gamma analysis, both error detection methods were applied to the generated test cases with realistic noise variations. Averaged over ten test runs, 95.1% of all plan variations that resulted in relevant patient dose errors were detected within 2° and 100% within 14° (<4% of patient dose delivery). Including cases that led to slightly modified but clinically equivalent plans, 89.1% were detected by the SCED method within 2°. Based on the type of check that detected the error, determination of error sources was achieved. With noise ranging from no random noise to four times the established noise value, the averaged relevant dose error detection rate of the SCED method was between 94.0% and 95.8% and that of gamma between 82.8% and 89.8%. An EPID-frame-based error detection process for VMAT deliveries was successfully designed and tested via simulations. The SCED method was inspected for robustness with realistic noise variations, demonstrating that it has the potential to detect a large majority of relevant dose errors. Compared to a typical (3%, 3 mm) gamma analysis, the SCED method produced a higher detection rate for all introduced dose errors, identified errors in an earlier stage, displayed a higher robustness to noise variations, and indicated the error source.


Worth living or worth dying? The views of the general public about allowing disabled children to die.
Decisions about withdrawal of life support for infants have given rise to legal battles between physicians and parents creating intense media attention. It is unclear how we should evaluate when life is no longer worth living for an infant. Public attitudes towards treatment withdrawal and the role of parents in situations of disagreement have not previously been assessed. An online survey was conducted with a sample of the UK public to assess public views about the benefit of life in hypothetical cases similar to real cases heard by the UK courts (eg, Charlie Gard, Alfie Evans). We then evaluated these public views in comparison with existing ethical frameworks for decision-making. One hundred and thirty participants completed the survey. The majority (94%) agreed that an infant's life may have no benefit when well-being falls below a critical level. Decisions to withdraw treatment were positively associated with the importance of use of medical resources, the infant's ability to have emotional relationships, and mental abilities. Up to 50% of participants in each case believed it was permissible to either continue or withdraw treatment. Despite the controversy, our findings indicate that in the most severe cases, most people agree that life is not worth living for a profoundly disabled infant. Our survey found wide acceptance of at least the permissibility of withdrawal of treatment across a range of cases, though also a reluctance to overrule parents' decisions. These findings may be useful when constructing guidelines for clinical practice.


Telford H. Work--a tribute.
The major contributions of Telford H. Work to the field of arbovirology and epidemiology of arthropod-transmitted diseases are detailed. The human aspects of his life are mentioned in this memorial address.


Nonlinear relationship between emotional valence and brain activity: evidence of separate negative and positive valence dimensions.
Emotion plays a significant role in goal-directed behavior, yet its neural basis is yet poorly understood. In several psychological models the cardinal dimensions that characterize the emotion space are considered to be valence and arousal. Here 3T functional magnetic resonance imaging (fMRI) was used to reveal brain areas that show valence- and arousal-dependent blood oxygen level dependent (BOLD) signal responses. Seventeen healthy adults viewed pictures from the International Affective Picture System (IAPS) for brief 100 ms periods in a block design paradigm. In many brain regions BOLD signals correlated significantly positively with valence ratings of unpleasant pictures. Interestingly, partly in the same regions but also in several other regions BOLD signals correlated negatively with valence ratings of pleasant pictures. Therefore, there were several areas where the correlation across all pictures was of inverted U-shape. Such correlations were found bilaterally in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC) extending to anterior cingulate cortex (ACC), and insula. Self-rated arousal of those pictures which were evaluated to be unpleasant correlated with BOLD signal in the ACC, whereas for pleasant pictures arousal correlated positively with the BOLD signal strength in the right substantia innominata. We interpret our results to suggest a major division of brain mechanisms underlying affective behavior to those evaluating stimuli to be pleasant or unpleasant. This is consistent with the basic division of behavior to approach and withdrawal, where differentiation of hostile and hospitable stimuli is crucial.


Poly[bis[μ₂-3-(pyridin-4-yl)benzoato-κ³N:O,O']lead(II)].
In the title compound, [Pb(C₁₂H₈NO₂)₂]n, the Pb atom sits on a crystallographic C₂ axis and is six-coordinate, ligated by two chelating carboxylate groups from two 3-(pyridin-4-yl)benzoate (L) ligands and by two N atoms from another two ligands. Each ligand bridges two PbII centres, extending the structure into a corrugated two-dimensional (4,4) net. The ligand L is conformationally chiral, with a torsion angle of 27.9 (12)° between the planes of its two rings. The torsion angle has the same sense throughout the structure, so that the extended two-dimensional polymer is homochiral. Investigation of the thermal stability shows that the network is stable up to 613 K. In the absence of any stereoselective factor in the preparation of the compound, the enantiomeric purity of the crystal studied, based only on the torsional conformation of the ligand, implies that the bulk sample is a racemic conglomerate.


Effect of Clinically Meaningful Antibiotic Concentrations on Recovery of Escherichia coli and Klebsiella pneumoniae Isolates from Anaerobic Blood Culture Bottles with and without Antibiotic Binding Resins.
Blood cultures are routinely collected in pairs of aerobic and anaerobic bottles. Artificial sterilization of Gram-negative bacteria in aerobic bottles containing clinically meaningful antibiotic concentrations has previously been observed. This study assessed recovery from anaerobic bottles with and without antibiotic binding resins. We studied the recovery of Escherichia coli and Klebsiella pneumoniae when exposed to meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam in resin-containing BacT/Alert FN Plus and BD Bactec Plus anaerobic/F bottles as well as resin-free BacT/Alert SN and BD Bactec standard anaerobic bottles. Bottles were inoculated with bacteria and whole blood containing peak, midpoint, or trough concentrations and incubated for up to 120 hours in their respective detection systems. In E. coli resin-containing bottles, recovery was observed in 10/24 (42%), 17/24 (71%), and 18/24 (75%) (P = 0.034) of those exposed to peak, midpoint, and trough concentrations, respectively. In K. pneumoniae resin-containing bottles, recovery was observed in 8/16 (50%), 10/16 (63%), and 10/16 (63%) (P = 0.710), respectively. No growth was detected in bottles containing cefepime regardless of concentration, while recovery was observed in the presence of all concentrations of cefazolin and piperacillin-tazobactam. Recovery in bottles with meropenem and imipenem was more frequently observed in BacT/Alert FN Plus bottles compared with Bactec Plus bottles. Resin-free bottles demonstrated significantly lower recovery than bottles containing binding resin. Clinical concentrations of certain antibiotics can adversely affect detection of E. coli and K. pneumoniae in anaerobic blood culture bottles. Obtaining blood cultures immediately before a dose and utilizing resin-containing anaerobic bottles will maximize the likelihood of recovery.


Distinguishing iron-reducing from sulfate-reducing conditions.
Ground water systems dominated by iron- or sulfate-reducing conditions may be distinguished by observing concentrations of dissolved iron (Fe(2+)) and sulfide (sum of H(2)S, HS(-), and S(=) species and denoted here as "H(2)S"). This approach is based on the observation that concentrations of Fe(2+) and H(2)S in ground water systems tend to be inversely related according to a hyperbolic function. That is, when Fe(2+) concentrations are high, H(2)S concentrations tend to be low and vice versa. This relation partly reflects the rapid reaction kinetics of Fe(2+) with H(2)S to produce relatively insoluble ferrous sulfides (FeS). This relation also reflects competition for organic substrates between the iron- and the sulfate-reducing microorganisms that catalyze the production of Fe(2+) and H(2)S. These solubility and microbial constraints operate in tandem, resulting in the observed hyperbolic relation between Fe(2+) and H(2)S concentrations. Concentrations of redox indicators, including dissolved hydrogen (H(2)) measured in a shallow aquifer in Hanahan, South Carolina, suggest that if the Fe(2+)/H(2)S mass ratio (units of mg/L) exceeded 10, the screened interval being tapped was consistently iron reducing (H(2) approximately 0.2 to 0.8 nM). Conversely, if the Fe(2+)/H(2)S ratio was less than 0.30, consistent sulfate-reducing (H(2) approximately 1 to 5 nM) conditions were observed over time. Concomitantly high Fe(2+) and H(2)S concentrations were associated with H(2) concentrations that varied between 0.2 and 5.0 nM over time, suggesting mixing of water from adjacent iron- and sulfate-reducing zones or concomitant iron and sulfate reduction under nonelectron donor-limited conditions. These observations suggest that Fe(2+)/H(2)S mass ratios may provide useful information concerning the occurrence and distribution of iron and sulfate reduction in ground water systems.


Molecular characterization of a meiotic recombinational hotspot enhancing homologous equal crossing-over.
We have cloned and sequenced a meiotic recombinational hotspot between the A beta 3 and A beta 2 genes in the major histocompatibility complex (MHC) of the mouse. This recombinational hotspot in the Mus musculus castaneus cas3 haplotype was previously localized to a region of 9.5 kb of DNA in which five independent crossing-over events occurred at the unusually high frequency of 0.6%. Aside from cas3, the hotspot appears to be absent in many other MHC haplotypes. We have now confined the five recombinational breakpoints to a stretch of 3.5 kb of DNA. From the nucleotide sequence around the recombinational breakpoints, determined in the parental cas3 and b haplotypes as well as for two recombinant haplotypes, we show that the two recombinant haplotypes were generated by homologous equal crossing-over and place the breakpoints within two non-overlapping stretches of 10 and 36 bp, respectively. Comparison of the DNA sequences of the hotspot-positive cas3 and the hotspot-negative b haplotypes reveals a number of differences, in particular, a CAGA-repeat sequence which is present in CAS3 in six, but only four copies in C57BL/6 DNA. This repeat sequence is reminiscent of one in a previously characterized hotspot in the E beta gene.


Multidisciplinary guidelines in Dutch mental health care: plans, bottlenecks and possible solutions.
This article describes the Dutch 'Multidisciplinary Guidelines in Mental Health Care' project and its first products (multidisciplinary guidelines on depressive and anxiety disorders). In the early 1990s, disciplines in Dutch mental health care formulated their first monodisciplinary guidelines, which disagreed on essential features. In 1998, the Dutch government invited representatives of the five core disciplines in mental health care (psychiatrists, general practitioners, psychotherapists (clinical), psychologists and psychiatric nurses) to start a joint project aimed at the development of new integrated multidisciplinary guidelines. The vision document, presented in 2000 by the five core disciplines, describes the directions for the development of new guidelines. The guidelines on depressive and anxiety disorders will appear in 2004. The first draft guidelines were presented in May 2003, in line with the vision document (2000). However, it is still not certain whether they will be authorised by all professional groups. Some disciplines do not recognise themselves in these guidelines. It is argued that these problems can be attributed at least in part to the evidence-based method that was used in drafting the guidelines. Interventions are compared on the basis of their 'level of evidence', the consequence of which is that cognitive behavioural therapy and drug treatment are almost always seen as the only appropriate interventions. Other interventions are excluded because of their lower level of evidence. The conclusion is that guidelines cannot be based on empirical evidence alone. It is argued that the collective sense of professions involved should also be integrated into the guideline, for example in relation to goal differentiation. It is finally argued that multidisciplinary guidelines must also offer a hierarchy between those goals, i.e. a vision of the appropriate type of care and the order in which the various care components should be administered.


Do different measures of early life socioeconomic circumstances predict adult mortality? Evidence from the British Whitehall II and French GAZEL studies.
Father's occupational position, education and height have all been used to examine the effects of adverse early life socioeconomic circumstances on health, but it remains unknown whether they predict mortality equally well. We used pooled data on 18,393 men and 7060 women from the Whitehall II and GAZEL cohorts to examine associations between early life socioeconomic circumstances and all-cause and cause-specific mortality. During the 20-y follow-up period, 1487 participants died. Education had a monotonic association with all mortality outcomes; the age, sex and cohort-adjusted HR for the lowest versus the highest educational group was 1.45 (95% CI 1.24 to 1.69) for all-cause mortality. There was evidence of a U-shaped association between height and all-cause, cancer and cardiovascular mortality robust to adjustment for the other indicators (HR 1.41, 95% CI 1.03 to 1.93 for those shorter than average and HR 1.36, 95% CI 0.98 to 1.88 for those taller than average for cardiovascular mortality). Greater all-cause and cancer mortality was observed in participants whose father's occupational position was manual rather than non-manual (HR 1.11, 95% CI 1.00 to 1.23 for all-cause mortality), but the risks were attenuated after adjusting for education and height. The association between early life socioeconomic circumstances and mortality depends on the socioeconomic indicator used and the cause of death examined. Height is not a straightforward measure of early life socioeconomic circumstances as taller people do not have a health advantage for all mortality outcomes.


Multiple pathways to identification: exploring the multidimensionality of academic identity formation in ethnic minority males.
Empirical trends denote the academic underachievement of ethnic minority males across various academic domains. Identity-based explanations for this persistent phenomenon describe ethnic minority males as disidentified with academics, alienated, and oppositional. The present work interrogates these theoretical explanations and empirically substantiates a multidimensional lens for discussing academic identity formation within 330 African American and Latino early-adolescent males. Both hierarchical and iterative person-centered methods were utilized and reveal 5 distinct profiles derived from 6 dimensions of academic identity. These profiles predict self-reported classroom grades, mastery orientation, and self-handicapping in meaningful and varied ways. The results demonstrate multiple pathways to motivation and achievement, challenging previous oversimplified stereotypes of marginalized males. This exploratory study triangulates unique interpersonal and intrapersonal attributes for promoting healthy identity development and academic achievement among ethnic minority adolescent males.