Towards more efficient glutathione peroxidase mimics: substrate recognition and catalytic group assembly.
Glutathione peroxidase (GPX) is a well-known selenoenzyme that functions as an antioxidant and catalyzes the reduction of harmful peroxide by glutathione and protects cells against oxidative damage. Because many diseases are related to oxidative stress, GPX is an ancient foe of many diseases. Antioxidants are very useful for biological bodies, and considerable effort has been spent to find compounds that could imitate the properties of GPX. This paper reviews GPX mimics developed so far and describes a new, more effective strategy for fabricating them. Although many GPX mimics have been made, they possess serious disadvantages: low activity, low solubility in water, and, in some cases, toxicity. In order to overcome these drawbacks, we have proposed a new strategy of imitating GPX. First, a receptor with a substrate binding site is generated. Next, a catalytic group is incorporated into the receptor near the substrate binding site, allowing the catalytic group access to the functional group of the substrate. Finally, a highly efficient enzyme mimic is obtained. Using this strategy, we successfully fabricated GPX mimics that use antibodies, cyclodextrins, some enzymes and proteins as receptors and chemical modification to incorporate the catalytic group, selenocysteine (Sec). The general principle of combining a functional group involved in catalysis with a specific binding site for the substrate is an approach that could be applied to the generation of other efficient semisynthetic biocatalysts. We describe the antioxidant activities of these GPX mimics and the reasons of their being promising candidates for medicinal applications.


Proteomic and pathway analyses reveal a network of inflammatory genes associated with differences in skin tumor promotion susceptibility in DBA/2 and C57BL/6 mice.
Genetic susceptibility to two-stage skin carcinogenesis is known to vary significantly among different stocks and strains of mice. In an effort to identify specific protein changes or altered signaling pathways associated with skin tumor promotion susceptibility, a proteomic approach was used to examine and identify proteins that were differentially expressed in epidermis between promotion-sensitive DBA/2 and promotion-resistant C57BL/6 mice following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). We identified 19 differentially expressed proteins of which 5 were the calcium-binding proteins annexin A1, parvalbumin α, S100A8, S100A9, and S100A11. Further analyses revealed that S100A8 and S100A9 protein levels were also similarly differentially upregulated in epidermis of DBA/2 versus C57BL/6 mice following topical treatment with two other skin tumor promoters, okadaic acid and chrysarobin. Pathway analysis of all 19 identified proteins from the present study suggested that these proteins were components of several networks that included inflammation-associated proteins known to be involved in skin tumor promotion (e.g. TNF-α, NFκB). Follow-up studies revealed that Tnf, Nfkb1, Il22, Il1b, Cxcl1, Cxcl2 and Cxcl5 mRNAs were highly expressed in epidermis of DBA/2 compared with C57BL/6 mice at 24h following treatment with TPA. Furthermore, NFκB (p65) was also highly activated at the same time point (as measured by phosphorylation at ser276) in epidermis of DBA/2 mice compared with C57BL/6 mice. Taken together, the present data suggest that differential expression of genes involved in inflammatory pathways in epidermis may play a key role in genetic differences in susceptibility to skin tumor promotion in DBA/2 and C57BL/6 mice.


Selenols: a new class of carbonic anhydrase inhibitors.
Stable aryl selenols were obtained through a convenient procedure. Selenols represent a new chemotype acting as carbonic anhydrase inhibitors (CAIs), inhibiting four human isoforms, CAs I, II, VII and the tumor-associated CA IX. X-ray crystallographic, physical and computational studies provided insights into the binding mode of this conceptually new class of CAIs.


Autologous breast reconstruction following mastectomy.
The options for breast reconstruction following mastectomy have greatly expanded. Current techniques include pedicle flaps and free tissue transfers. With the advent of perforator flaps, additional options have become available that have the advantage of reduced donor site morbidity. The purpose of this manuscript is to review the most common methods of breast reconstruction using autologous tissues.


Experimental lead paint poisoning in nonhuman primates. III. Pathologic findings.
Necropsies were performed on 25 rhesus monkeys, three cebus monkeys and three baboons which had been fed leaded paint or lead acetate at various doses up to 666 days. The 31 test primates and six controls ranged in age from five days to about eight years. In addition, the brains of 13 subadult squirrel monkeys fed lead oxide and two controls were studied grossly and microscopically. Lead content of liver, kidney and brain correlated with clinical outcome and typical histologic changes. Neuropathologic lesions, most severe in the young, occurred in 28 of 43 test primates despite a paucity of neurological signs. Brain lesions were similar to those occurring in human lead encephalopathy and included degenerative and proliferative changes of small vessels, ring hemorrhages, edema, perivascular hyalin droplets, rosette-like deposits of proteinaceous exudates, focal loss of myelin, astrogliosis and necrosis of hippocampal neurons.


The information-motivation-behavioral skills model explains physical activity levels for adults with type 2 diabetes across all weight classes.
Physical activity is an evidence-based, effective treatment for type 2 diabetes mellitus (T2D), yet insufficient numbers of adults achieve recommended daily levels, particularly amongst higher weight classes. This cross-sectional study assessed whether the Information-Motivation-Behavioural Skills (IMB) Model explained physical activity levels in adults with T2D across different body mass index (BMI) levels (N = 381). Measures included the American Adults Knowledge of Exercise Recommendations (AAKER), Behavioural Regulation in Exercise Questionnaire (BREQ-2), Barriers Specific Self-Efficacy Scale (BARSE) and the outcome measure, International Physical Activity Questionnaire (IPAQ-short form). Analyses included structural equation modelling (SEM) and ordinal logistic regression models. SEM demonstrated a good fit of the IMB Model to the data, accounting for 44% of variance in physical activity levels. Both motivation and self-efficacy had a direct effect, and motivation indirectly predicted physical activity through self-efficacy. Further analyses found the effect of the IMB predictors did not vary according to BMI status. This study supports the application of the IMB Model in explaining physical activity behavior in adults with T2D. In particular, the contribution of motivation and self-efficacy as substantive and modifiable predictors of physical activity will facilitate the development of targeted and evidence-based interventions for individuals of all BMI classes.


Spectrum of Dental Phenotypes in Nonsyndromic Orofacial Clefting.
Children with oral clefts show a wide range of dental anomalies, adding complexity to understanding the phenotypic spectrum of orofacial clefting. The evidence is mixed, however, on whether the prevalence of dental anomalies is elevated in unaffected relatives and is mostly based on small samples. In the largest international cohort to date of children with nonsyndromic clefts, their relatives, and controls, this study characterizes the spectrum of cleft-related dental anomalies and evaluates whether families with clefting have a significantly higher risk for such anomalies compared with the general population. A total of 3,811 individuals were included: 660 cases with clefts, 1,922 unaffected relatives, and 1,229 controls. Dental anomalies were identified from in-person dental exams or intraoral photographs, and case-control differences were tested using χ(2) statistics. Cases had higher rates of dental anomalies in the maxillary arch than did controls for primary (21% vs. 4%, P = 3 × 10(-8)) and permanent dentitions (51% vs. 8%, P = 4 × 10(-62)) but not in the mandible. Dental anomalies were more prevalent in cleft lip with cleft palate than other cleft types. More anomalies were seen in the ipsilateral side of the cleft. Agenesis and tooth displacements were the most common dental anomalies found in case probands for primary and permanent dentitions. Compared with controls, unaffected siblings (10% vs. 2%, P = 0.003) and parents (13% vs. 7%, P = 0.001) showed a trend for increased anomalies of the maxillary permanent dentition. Yet, these differences were nonsignificant after multiple-testing correction, suggesting genetic heterogeneity in some families carrying susceptibility to both overt clefts and dental anomalies. Collectively, the findings suggest that most affected families do not have higher genetic risk for dental anomalies than the general population and that the higher prevalence of anomalies in cases is primarily a physical consequence of the cleft and surgical interventions.


Disseminated tumor cells in lymph nodes as a determinant for survival in surgically resected non-small-cell lung cancer.
In recent years, the detection of even a few tumor cells in lymph nodes of patients with surgically resected non-small-cell lung cancer (NSCLC) became possible with immunohistochemical staining procedures. Tumor cells in lymph nodes have been shown to be associated with an increased rate of early recurrence. However, the prognostic significance of this minimal tumor cell spread for overall survival remains unclear. We used the epithelium-specific monoclonal antibody Ber-EP4, which recognizes the 17-1A antigen (also called EGP40 or Ep-CAM), to discover small tumor cell deposits (< or = three cells) in 565 regional lymph nodes judged as tumor-free by conventional histopathology in patients with NSCLC staged as pT1-4, pN0-2, M0, R0. In a prospective analysis, we studied the influence of the detected tumor cells on the cancer recurrence rate and survival of 117 patients. Ber-EP4-positive cells were found in 27 of 125 patients (21.6%). After an observation period of 64 months, patients with disseminated tumor cells had reduced disease-free survival (P < .0001) and overall survival (P = .0001) rates in univariate analyses (logrank test). Multivariate analysis (Cox model) showed a 2.7 times increased risk for tumor relapse and a 2.5 times increased risk for shorter survival in patients with disseminated tumor cells compared with patients without such cells. Patients without any evidence of histopathologic and immunohistochemical lymph node involvement had an overall survival rate of 78%. The immunohistochemical detection of disseminated tumor cells in lymph nodes of patients with completely resected NSCLC is an independent prognostic factor for overall survival.


Blood cell adhesion to arterial filters analysis by scanning electron microscopy and real-time PCR assay: observational clinical study in cardiac surgery patients.
Arterial filter is the part of the cardiopulmonary bypass circuit where blood cells are exposed to high mechanical stress and where cellular aggregates may fasten in large quantities. The aim of this study was to analyse blood cell adhesiveness in the arterial filter through scanning electron microscopy and real-time PCR assay. Prospective, clinical and observational study performed on 28 patients undergoing cardiac surgery with cardiopulmonary bypass. Arterial filters were analysed by scanning electron microscopy. Real-time PCR assay was performed in extracted material from the arterial filters for analysis of platelet GPIb and CD45 leucocyte gene expression. Blood coagulation was analysed during cardiopulmonary bypass. Patients were followed until hospital discharge or 28 days after surgery. All studied arterial filters used in the subject patients showed a degree of adhesion from blood elements at scanning electron microscopy. All studied filters were positive for platelets GPIb gene expression and 15% had CD45 leucocyte gene expression. The GPIb platelet gene expression in blood lowered at the end of cardiopulmonary bypass (p = 0.019). There was negative correlation between blood GPIb platelet gene expression and Clot SR (HEPSCREEN2 ReoRox®) (rho = 0.635; p = 0.027). The filter fields count was correlated to the D-dimer dosage (rho = 0.828; p < 0.001). There was adhesion of blood elements, especially nucleated platelets, on all arterial filters studied. Although the arterial filter worked as a safety device, that possibly prevented arterial embolisation, it may also have caused greater hyperfibrinolysis during cardiopulmonary bypass.


Learning from errors in radiology: a comprehensive review.
An important goal of error analysis is to create processes aimed at reducing or preventing the occurrence of errors and minimizing the degree of harm. The discovery of any errors presents an opportunity to study the types that occur and to examine their sources and develop measures to prevent them from recurring. The development of an effective system for detecting and appropriately managing errors is essential to substantially attenuate their consequences. At this stage, the error analysis process identifies contributing factors to enable the implementation of concrete steps to prevent such errors from occurring in the future. Active and comprehensive management of errors and adverse events requires ongoing surveillance processes. Educational programs, morbidity and mortality meetings, and a comprehensive and respected root cause analysis process are also essential components of this comprehensive approach. To reduce the incidence of errors, health care providers must identify their causes, devise solutions, and measure the success of improvement efforts. Moreover, accurate measurements of the incidence of error, based on clear and consistent definitions, are essential prerequisites for effective action.


Block in the expression of differentiation markers of rat thyroid epithelial cells by transformation with Kirsten murine sarcoma virus.
Well-differentiated epithelial cells, derived from primary cultures of normal rat thyroid glands (T-79 cells), as well as a cloned cell line also derived from normal rat thyroid glands (FRT-L cells) were infected with Kirsten murine sarcoma virus carrying outer coat of the helper Kirsten murine leukemia virus. Infected T-79 and FRT-L cells changed morphologically and began to proliferate rapidly, suggesting malignant transformation by the virus. Both cell lines can support the replication of both transformation-competent and transformation-incompetent viruses such as murine or rat leukemia viruses. Infected T-79 and FRT-L cells had a high colony-forming efficiency (68 and 64%, respectively) when grown in agar and formed tumors when transplanted s.c. into syngeneic rats. These tumors morphologically resemble undifferentiated adenocarcinomas, thus showing that Kirsten sarcoma virus carrying the outer coat of the helper Kirsten murine leukemia virus is able to transform differentiated epithelial cells. Transformed T-79 and FRT-L cells, in contrast to uninfected cells, neither secrete thyroglobulin concentrate iodide, two biochemical markers of differentiated thyroid function. Thus, expression of the differentiated phenotype is blocked as a consequence of cell transformation. The system described may be useful in studying epithelial cell carcinogenesis in terms of regulated expression of differentiated functions.


Evaluating the impact of the live healthy, work healthy program on organizational outcomes: A randomized field experiment.
The prevalence of chronic health conditions is increasing, with over half the current workforce attempting to manage one or more chronic conditions. The Live Healthy, Work Healthy (LHWH) program is a version of the Chronic Disease Self-Management Program translated to the workplace, with the goal of improving and sustaining the health, well-being, and productivity of employees living with chronic health conditions. Using organizational support theory as a theoretical framework and a clustered randomized controlled trial design, this article demonstrates how the LHWH program positively impacts work-related quality of life, orientations toward the organization, and organizational cognitions and behaviors. Participants in the program experienced increases in perceived organizational support (POS), with a large intervention effect. Direct intervention effects were also found for burnout, work engagement, work ability, affective organizational commitment, and organizational citizenship behaviors. Within-person changes in POS during the intervention was a key mechanism through which participants of the program experienced changes in organizationally relevant outcomes. Finally, offering the program on work time strengthened these effects indirectly through greater changes in POS during the intervention period. This article provides evidence to researchers and organizational decision-makers that offering the LHWH program not only improves the health and well-being of employees but also improves important organizational outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation. We recently identified the gene causing FMF, designated MEFV, and found it to be expressed in mature neutrophils, suggesting that it functions as an inflammatory regulator. To facilitate our understanding of the normal function of MEFV, we extended our previous studies. MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization. CD34 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment. The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation. MEFV was also expressed in the monocytic cell lines U937 and THP-1. Among peripheral blood leukocytes, MEFV expression was detected in neutrophils, eosinophils, and to varying degrees, monocytes. Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements. In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN) gamma, tumor necrosis factor, and lipopolysaccharide induced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta inhibited such expression. Induction by IFN-gamma occurred rapidly and was resistant to cycloheximide. IFN-alpha also induced MEFV expression. In granulocytes, MEFV was up-regulated by IFN-gamma and the combination of IFN-alpha and colchicine. These results refine understanding of MEFV by placing the gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an IFN-gamma immediate early gene.


Physiological and anthropometric determinants of rhythmic gymnastics performance.
To identify the physiological and anthropometric predictors of rhythmic gymnastics performance, which was defined from the total ranking score of each athlete in a national competition. Thirty-four rhythmic gymnasts were divided into 2 groups, elite (n = 15) and nonelite (n = 19), and they underwent a battery of anthropometric, physical fitness, and physiological measurements. The principal-components analysis extracted 6 components: anthropometric, flexibility, explosive strength, aerobic capacity, body dimensions, and anaerobic metabolism. These were used in a simultaneous multiple-regression procedure to determine which best explain the variance in rhythmic gymnastics performance. Based on the principal-component analysis, the anthropometric component explained 45% of the total variance, flexibility 12.1%, explosive strength 9.2%, aerobic capacity 7.4%, body dimensions 6.8%, and anaerobic metabolism 4.6%. Components of anthropometric (r = .50) and aerobic capacity (r = .49) were significantly correlated with performance (P < .01). When the multiple-regression model-y = 10.708 + (0.0005121 x VO2max) + (0.157 x arm span) + (0.814 x midthigh circumference) - (0.293 x body mass)-was applied to elite gymnasts, 92.5% of the variation was explained by VO2max (58.9%), arm span (12%), midthigh circumference (13.1%), and body mass (8.5%). Selected anthropometric characteristics, aerobic power, flexibility, and explosive strength are important determinants of successful performance. These findings might have practical implications for both training and talent identification in rhythmic gymnastics.


Occurrence of Leaf Spot Disease Caused by Alternaria crassa (Sacc.) Rands on Jimson Weed and Potential Additional Host Plants in Algeria.
A leaf spot pathogen Alternaria sp. was recovered from jimson weed, tomato, parsley, and coriander collected during surveys of blight diseases on Solanaceae and Apiaceae in Algeria. This species produced large conidial body generating long apical beaks that tapered gradually from a wide base to a narrow tip and short conidiophores originating directly from the agar surface. This species exhibited morphological traits similar to that reported for Alternaria crassa. The identification of seven strains from different hosts was confirmed by sequence analyses at the glyceraldehyde-3-phosphate dehydrogenase, RNA polymerase second largest subunit, and translation elongation factor 1-alpha loci. Further the pathogen was evaluated on jimson weed, coriander, parsley, and tomato plants, and this fungus was able to cause necrotic lesions on all inoculated plants. A. crassa is reported for the first time as a new species of the Algerian mycoflora and as a new potential pathogen for cultivated hosts.


[Cardiac and vascular morphology in patients with "white-coat hypertension": echocardiographic and ultrasonographic study].
The introduction of ambulatory blood pressure (ABPM) in the clinical practice has defined a new subgroup of hypertensive patients (pts) called "white coat" hypertensive pts. It has been reported that white coat hypertensive pts have less cardiac involvement than established hypertensive pts. This study was designed to examine the extent of cardiac and vascular involvement in pts with white coat hypertension and established hypertension. Fifty-four previously never treated pts with mild or moderate hypertension underwent a 24h ABPM and an echocardiographic and vascular ultrasonographic study in order to assess left ventricular anatomical parameters and the intima-media thickness of common carotid arteries. Left ventricular dimensions and mass were obtained according to Penn convention. The intima-media thickness of the far wall of both common carotid arteries was measured at 5, 10 and 20 mm caudally to the flow-divider; the average values were considered. Twenty-eight pts (age 43 +/- 8 years) had an average daytime ABPM below 140/90 mm Hg ("white coat") and 26 pts (age 46 +/- 10) had a consistently elevated diastolic blood pressure. Both groups had similar office blood pressure (152 +/- 9/101 +/- 7 vs 155 +/- 10/103 +/- 6 mm Hg) body surface mass (1.79 +/- 0.23 vs 1.86 +/- 0.21 mq), sex (18M/20F vs 18M/8F), duration of hypertension, glycolipidic parameters and smoking habit. The daytime ABPM was (by definition) significantly higher in established hypertensive pts than in white coat hypertensive pts (145 +/- 11/97 +/- 4 vs 129 +/- 7/83 +/- 5 mm Hg, p < 0.001). Left ventricular mass index and intima-media thickness resulted significantly greater in established (119 +/- 1.7 g/m2; 0.70 +/- 0.11 mm) than in white coat hypertensive pts (99 +/- 16 g/m2; 0.60 +/- 0.1 mm, p < 0.002). The prevalence of left ventricular hypertrophy and cardiac remodeling was more frequent in established hypertensive pts (53%) compared to white coat hypertensive pts (7.7%). The results of our study confirm that structural changes of left ventricle in white coat hypertensive pts are more limited than in established hypertensive pts and for the first time show that in white coat hypertensive pts the involvement of the conductance vessels is significantly lower than in established hypertensive pts.


Stereochemistry of polymerization by DNA-dependent RNA-polymerase from Escherichia coli: an investigation with a diastereomeric ATP-analogue.
The phosphodiester bond formation by DNA-dependent RNA-polymerase (RNA nucleotidyltransferase, nucleosidetriphosphate:RNA nucleotidyltransferase, EC 220.127.116.11) can in principle result in retention, inversion, or racemization of configuration at the alpha-phosphorus of the nucleoside 5'-triphosphate being polymerized. As a first step in elucidating the stereochemistry of this reaction, one diastereomer (A) of adenosine 5'-O-(1-thiotriphosphate) (ATPalphaS) was polymerized with UTP in the presence of poly(dA-dT)-poly(dA-dT). The resulting polymer was enzymatically cleaved to uridine 2',3'-cyclic phosphorothioate which was determined to be the endo-isomer by comparison with an authentic sample. This shows that no reacemization had occurred and that isomer A of ATPalphaS gives a phosphorothioate diester bond with the R-configuration. Whether this represents inversion of retention of configuration awaits elucidation of the absolute configuration of isomer A for ATPalphaS.


A transient inhibition and permanent lack of catechol-O-methyltransferase have minor effects on feeding pattern of female rodents.
Abnormal feeding behaviours have long been linked to disruptions in brain dopaminergic activity. Dopamine is metabolized, amongst others, by catechol-O-methyltransferase (COMT). Normally, COMT only plays a subordinate role in dopamine metabolism. However, changes in COMT activity, especially in the prefrontal cortex, become more important during events that evoke dopamine release. The current study investigated the effect of acute COMT inhibition on feeding in Wistar rats and C57BL/6 mice using a selective, brain penetrating COMT inhibitor (OR-1139). Furthermore, the effect of a long-term lack of COMT on feeding behaviour was studied in COMT-deficient (COMT -/-) mice. Apart from following the gross feeding behaviour of fasted rats and mice, the first 4 hr of re-feeding were recorded with a video camera to allow a more detailed analysis of feeding microstructure. In the acute study, rats and mice received a single injection of OR-1139 (3, 10 or 30 mg/kg), just before the experiment. We found that rats and mice receiving OR-1139 had fewer very short meals but more long meals than the controls. Treated mice even ate more frequently than the controls, but other feeding parameters remained unchanged. Conversely, COMT -/- mice displayed an increased latency to initiate the first meal and spent less total time eating than wild-type mice. In conclusion, although decreased/lack of COMT activity did not robustly alter feeding behaviour of female rodents, we observed some alterations in the microstructure of feeding. However, these minor changes were highly dependent on the extent and fashion in which COMT was manipulated.


Spatial aspects of interspecific competition.
Using several variants of a stochastic spatial model introduced by Silvertown et al., we investigate the effect of spatial distribution of individuals on the outcome of competition. First, we prove rigorously that if one species has a competitive advantage over each of the others, then eventually it takes over all the sites in the system. Second, we examine tradeoffs between competition and dispersal distance in a two-species system. Third, we consider a cyclic competitive relationship between three types. In this case, a nonspatial treatment leads to densities that follow neutrally stable cycles or even unstable spiral solutions, while a spatial model yields a stationary distribution with an interesting spatial structure.


Exercise-induced variations in muscle tissue oxygen pressure in claudicants: effects of buflomedil.
The amount of oxygen actually supplied to the ischemic muscle tissue of patients with intermittent claudication was quantified before and after a standardized pedal ergometric test. Muscle tissue pO2 was measured with micro-platin needle electrodes directly in the lower limb muscles at rest and 3, 10, 20 and 60 min after a 4-min work load. Time-dependent variations in the behavior of pO2 values as well as changes in the shapes of pooled pO2 histograms make it possible to monitor the effect of therapeutic measures. In claudicants (stage IIb) with ascertained occlusions or stenosis of the femoral artery or the pelvis region, it was demonstrated that the delayed increase in tissue pO2 after exercise could be improved by the infusion of 400 mg buflomedil. Comparison between the time-related pooled histograms confirmed improvement of oxygen supply under the influence of this drug.


Clonogenic potential and phenotypic analysis of CD34+ cells mobilized by different chemotherapy regimens.
Since limited data concerning quantitative and qualitative differences of CD34+ cells collected after different mobilization schedules are available, we investigated phenotype, proliferative capacity and primitive progenitor cell content of CD34+ cells mobilized with four different regimens. The number, phenotype, and progenitor cell content of CD34+ cells were investigated in 46 patients mobilized with cyclophosphamide (CY) 7 g/m(2) plus granulocyte colony-stimulating factor (G-CSF, 5 microg/kg) (CY7+G-CSF) (n=16), CY 4 g/m(2) plus G-CSF (CY4+G-CSF) (n=8), IVE [ifosphamide (2.5 g/m(2) for 3 d), etoposide (150 mg/m(2) for 3 d), epirubicin (100 mg/m(2) on day 1)] plus G-CSF (IVE+G-CSF) (n=9), or G-CSF (10 microg/kg) alone (n=13). The number of CD34+ cells collected per liter of processed blood was significantly higher in the CY7+G-CSF group than in the CY4+G-CSF and G-CSF groups (p </= .005), but not the IVE+G-CSF group. As compared to patients in the CY4+G-CSF group, those mobilized with CY7+G-CSF and IVE+G-CSF produced significantly lower percentages of CD34+ cells lacking CD38, CD33, CD45RA, and HLA-DR (p </= .016, at least). In addition, CY4+G-CSF mobilized CD34+ cells had a significantly higher plating efficiency than the cells mobilized in other ways (p </= r .036). In the G-CSF group, colony-forming cells and long-term culture-initiating cells were significantly lower than in the CY groups (p </= .0014 and </= 013, respectively). Our data demonstrate that: (i) different mobilization regimens allow the collection of CD34+ cells with distinct phenotypic and proliferative features; (ii) evaluation of the absolute number of CD34+ cells by itself is not a reliable indicator of the clonogenic content of blood mobilized with different chemotherapy regimens; (iii) because of the substantial impact that chemotherapy regimens have on the quantity and quality of collected CD34+ cells, anticancer effects and optimal blood progenitor cell yields should be evaluated for each chemotherapy schedule.


A Novel Voltage Controlled Decoupling Method for Transmit Coils in MRI.
Array coils are ubiquitous in MRI and are becoming more widely used in MR spectroscopy. Conventional PIN diode decoupling circuits require significant currents to forward bias the diodes. The approach proposed here does not require significant current and thus reduces concerns for contaminating the B0 homogeneity with the detune current. Additionally, the proposed approach will facilitate the construction of array coils for MRI due to its simplicity.Clinical Relevance- Decoupling is critical for constructing RF coil arrays and enables rapid MR imaging.


Feeding mechanisms of adult Lepidoptera: structure, function, and evolution of the mouthparts.
The form and function of the mouthparts in adult Lepidoptera and their feeding behavior are reviewed from evolutionary and ecological points of view. The formation of the suctorial proboscis encompasses a fluid-tight food tube, special linking structures, modified sensory equipment, and novel intrinsic musculature. The evolution of these functionally important traits can be reconstructed within the Lepidoptera. The proboscis movements are explained by a hydraulic mechanism for uncoiling, whereas recoiling is governed by the intrinsic proboscis musculature and the cuticular elasticity. Fluid uptake is accomplished by the action of the cranial sucking pump, which enables uptake of a wide range of fluid quantities from different food sources. Nectar-feeding species exhibit stereotypical proboscis movements during flower handling. Behavioral modifications and derived proboscis morphology are often associated with specialized feeding preferences or an obligatory switch to alternative food sources.


An evaluation of the process of informed consent: views from research participants and staff.
The process of informed consent for enrolment to a clinical research study can be complex for both participants and research staff. Challenges include respecting the potential participant's autonomy and information needs while simultaneously providing adequate information to enable an informed decision. Qualitative research with small sample sizes has added to our understanding of these challenges. However, there is value in garnering the perspectives of research participants and staff across larger samples to explore the impact of contextual factors (time spent, the timing of the discussion and the setting), on the informed consent process. Research staff and research participants from Ireland and the UK were invited to complete an anonymous survey by post or online (research participants) and online (research staff). The surveys aimed to quantify the perceptions of research participants and staff regarding some contextual factors about the process of informed consent. The survey, which contained 14 and 16 multiple choice questions for research participants and staff respectively, was analysed using descriptive statistics. Both surveys included one optional, open-ended question, which were analysed thematically. Research participants (169) and research staff (115) completed the survey. Research participants were predominantly positive about the informed consent process but highlighted the importance of having sufficient time and the value of providing follow-up once the study concludes, e.g. providing results to participants. Most staff (74.4%) staff reported that they felt very confident or confident facilitating informed consent discussions, but 63% felt information leaflets were too long and/or complicated, 56% were concerned about whether participants had understood complex information and 40% felt that time constraints were a barrier. A dominant theme from the open-ended responses to the staff survey was the importance of adequate time and resources. Research participants in this study were overwhelmingly positive about their experience of the informed consent process. However, research staff expressed concern about how much participants have understood and studies of patient comprehension of research study information would seem to confirm these fears. This study highlights the importance of allocating adequate time to informed consent discussions, and research staff could consider using Teach Back techniques. Not applicable.


A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease.
The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ~150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ~110, ~160, ~210, and ~310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted "U-shaped" relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model.


Attachment studies with borderline patients: a review.
Clinical theorists have suggested that disturbed attachments are central to borderline personality disorder (BPD) psychopathology. This article reviews 13 empirical studies that examine the types of attachment found in individuals with this disorder or with dimensional characteristics of BPD. Comparison among the 13 studies is handicapped by the variety of measures and attachment types that these studies have employed. Nevertheless, every study concludes that there is a strong association between BPD and insecure attachment. The types of attachment found to be most characteristic of BPD subjects are unresolved, preoccupied, and fearful. In each of these attachment types, individuals demonstrate a longing for intimacy and--at the same time--concern about dependency and rejection. The high prevalence and severity of insecure attachments found in these adult samples support the central role of disturbed interpersonal relationships in clinical theories of BPD. This review concludes that these types of insecure attachment may represent phenotypic markers of vulnerability to BPD, suggesting several directions for future research.


Longest Survival of Expectantly Managed Twin Gestation Complicated by Previable Preterm Premature Rupture of Membranes at 13 Weeks' Gestation.
Previable preterm premature rupture of membranes (PV-PPROM) is defined as rupture of membranes prior to 24 weeks and is a rare phenomenon with an estimated prevalence of 0.5% of all pregnancies. Given that this phenomenon is even more rare in patients with dichorionic diamniotic (DCDA) twin pregnancies, there is no clear consensus in the literature on outcomes and management of DCDA PV-PPROM due to the scarcity of reports. We report a case of a rare successful prolongation of first trimester DCDA PV-PPROM pregnancy with rupture of the amniotic sac of one twin with survival of both twins without major complications. A 20-year-old female gravida 1 para 0 at about 13 weeks and three days presented with vaginal watery discharge mixed with vaginal bleeding. Abdominal ultrasound revealed a live twin dichorionic diamniotic (DCDA) spontaneous intrauterine gestation and a significantly low amniotic fluid volume involving fetus A. At 23 weeks gestational age, she experienced increased leaking of clear fluid, and she was admitted to the hospital for continuous monitoring with daily non-stress tests (NST), and ultrasounds every four weeks, and received antibiotics, betamethasone, and magnesium. Preterm labor occurred at 30w1d, and a primary low transverse cesarean section was performed on the 114th day after PPROM. Though, twin A required prolonged hospitalization both twins recovered and progressed well without complications. To the best of our knowledge, this is the longest case of successful expectant management of both twins with PV-PPROM yet reported.


Guanidinoacetate methyltransferase (GAMT) deficiency: a rare but treatable epilepsy.
Epilepsy commonly presents in childhood as part of a syndrome, and some such children may reach adult services without an underlying syndromic diagnosis. For adult neurologists taking over their care, it is often unclear how hard to search for an underlying diagnosis. The diagnostic yield may be small and such a diagnosis may not change management. Young adults with learning difficulties are also challenging to investigate, as they may not tolerate standard epilepsy tests.We present such a case in which simple tests identified a unifying diagnosis. With the new diagnosis came a new treatment that had a significant impact on seizures and quality of life.


Proteome Analysis of Human Neutrophil Granulocytes From Patients With Monogenic Disease Using Data-independent Acquisition.
Neutrophil granulocytes are critical mediators of innate immunity and tissue regeneration. Rare diseases of neutrophil granulocytes may affect their differentiation and/or functions. However, there are very few validated diagnostic tests assessing the functions of neutrophil granulocytes in these diseases. Here, we set out to probe omics analysis as a novel diagnostic platform for patients with defective differentiation and function of neutrophil granulocytes. We analyzed highly purified neutrophil granulocytes from 68 healthy individuals and 16 patients with rare monogenic diseases. Cells were isolated from fresh venous blood (purity >99%) and used to create a spectral library covering almost 8000 proteins using strong cation exchange fractionation. Patient neutrophil samples were then analyzed by data-independent acquisition proteomics, quantifying 4154 proteins in each sample. Neutrophils with mutations in the neutrophil elastase gene ELANE showed large proteome changes that suggest these mutations may affect maturation of neutrophil granulocytes and initiate misfolded protein response and cellular stress mechanisms. In contrast, only few proteins changed in patients with leukocyte adhesion deficiency (LAD) and chronic granulomatous disease (CGD). Strikingly, neutrophil transcriptome analysis showed no correlation with its proteome. In case of two patients with undetermined genetic causes, proteome analysis guided the targeted genetic diagnostics and uncovered the underlying genomic mutations. Data-independent acquisition proteomics may help to define novel pathomechanisms in neutrophil diseases and provide a clinically useful diagnostic dimension.


Acquired immunodeficiency syndrome: manifestations in the oral cavity.
Human immunodeficiency virus (HIV) infection is a pandemic disease characterised by impairment of the immune system; the main parameter is a progressive decline in the number of CD4 lymphocytes. This circumstance paves the way for opportunistic infections and the development of neoplastic processes that can lead the patient to a state known as acquired immunodeficiency syndrome (AIDS) and ultimately, results in death. The incorporation of treatment based on a cocktail of different active drugs (highly active antiretroviral therapy) has made it possible to drastically change the panorama of the disease in developed nations; improving quality of life for the patient and delaying the progression of the disease. The oral manifestations of HIV infection have been and continue to be an important component of the disease from the very first descriptions and are indicative of progression. At some point in the course of the disease, nine out of every ten patients will present oral manifestations and, on occasion, these symptoms will be the first sign of the syndrome. It is essential that oral healthcare professionals recognize the hallmarks of the illness. In developed countries, the emergence of new therapies has made it possible to significantly reduce immune deficiency-related oral manifestations, both in terms of frequency, as well as severity. This review analyses the most important oral lesions associated with HIV infection and the current state of affairs in this regard.


Characterization of the mechanical nonlinear behavior of piezoelectric ceramics.
A characterization of the nonlinear behavior with high signal excitation in piezoceramic resonators was carried out. The behavior of power devices working at resonance, in which high strains are involved, is explained. A theoretical model previously described is used to explain the motional impedance variation proportional to the square of the motional current. This impedance increase DeltaZ is independent of the frequency and explains: the nonlinear elasticity that produces the A-F effect, the nonlinear mechanical losses that increase greatly close to the resonance, and the hysteresis phenomenon produced with frequency sweeps. Different methods for measuring the mechanical nonlinear coefficients of piezoceramics with high signal excitation are presented. An experimental method is proposed to measure the mechanical loss tangent and the compliance variations as a function of the mean square strain in the piezoceramic. This consists in measuring the maximum admittance and the series resonance frequency for downward frequencies. At this jumping point, the phase angle remains zero whatever the amplitude of the excitation. Two main coefficients characterizing the material mechanical nonlinearity are deduced. Experimental measurements were carried out to compare the nonlinearity of different ceramic materials in longitudinal and transverse mode.


Occipitoatlantal dislocation.
Occipitoatlantal dislocation (OAD) can be devastating. This injury may be fatal in many cases, but more survivors are reported because of improvements in diagnosis and treatment. This article describes the diagnosis and treatment of OAD. To diagnose and treat OAD appropriately, neurosurgeons must have a detailed understanding of the anatomy of the craniocervical junction. Various radiographic criteria are used to establish the diagnosis of OAD. A destabilizing injury such as OAD requires surgical fixation. Many surgical techniques are available for fixation of the craniocervical junction. Future studies will continue to refine the diagnostic criteria for OAD and to develop improved methods for craniocervical stabilization.


Exploring benzylic gem-C(sp3)-boron-silicon and boron-tin centers as a synthetic platform.
A stepwise build-up of multi-substituted Csp3 carbon centers is an attractive, conceptually simple, but often synthetically challenging type of disconnection. To this end, this report describes how gem-α,α-dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an excellent stepping stone towards diverse substitution patterns. These gem-dimetalloids were readily accessed, either by known carbenoid insertion into C-B bonds or by the newly developed scalable deprotonation/metallation approach. Highly chemoselective transformations of either the C-Si (or C-Sn) or the C-B bonds in the newly formed gem-Csp3 centers have been achieved through a set of approaches, with a particular focus on exploiting the synthetically versatile polarity reversal in organometalloids by λ3-aryliodanes. Of particular note is the metal-free arylation of the C-Si (or C-Sn) bonds in such gem-dimetalloids via the iodane-guided C-H coupling approach. DFT calculations show that this transfer of the (α-Bpin)benzyl group proceeds via unusual [5,5]-sigmatropic rearrangement and is driven by the high-energy iodine(iii) center. As a complementary tool, the gem-dimetalloid C-B bond is shown to undergo a potent and chemoselective Suzuki-Miyaura arylation with diverse Ar-Cl, thanks to the development of the reactive gem-α,α-silyl/BF3K building blocks.


Heavy de novo methylation at symmetrical and non-symmetrical sites is a hallmark of RNA-directed DNA methylation.
Previous analysis of potato spindle tuber viroid (PSTVd) RNA-infected tobacco plants has suggested that an RNA-DNA interaction could trigger de novo methylation of PSTVd transgene sequences. Using the genomic sequencing technique, the methylation pattern associated with the RNA-directed DNA methylation process has been characterized. Three different PSTVd transgene constructs all showed a similar pattern of methylation. Most of the cytosines at symmetrical as well as non-symmetrical positions appeared to be methylated in both DNA strands of the viroid sequences. Heavy methylation was mostly restricted to the viroid cDNA sequences. Flanking DNA regions immediately adjacent to the viroid cDNA displayed a lower but significant level of cytosine methylation. The observation that the heavy methylation was essentially co-extensive with the length of the PSTVd cDNA sequences provided evidence that a direct RNA-DNA interaction can act as a strong and highly specific signal for de novo DNA methylation. These data also confirmed that de novo methylation was not limited to canonical CpG and CpNpG sites, but can also involve all the cytosine residues located in the genomic region where the RNA-DNA interaction takes place.


Role of gram-positive bacteria in chronic pelvic pain syndrome (CPPS).
Chronic pelvic pain syndrome (CPPS) is a complex disorder that affects a large proportion of all men. A limited understanding of its etiology and pathogenesis is reflected by the absence of effective therapies. Although CPPS is deemed clinically non-infectious with no well-defined etiological role for microbes, bacteria is readily isolated from both healthy and patient prostate secretion and urine samples. Our laboratory has previously demonstrated that a specific gram-negative bacterial isolate can induce CPPS-like symptoms in mice. Here we aimed to expand on these findings examining the role of gram-positive patient-derived bacteria in CPPS. A retrospective analysis of bacterial cultures from CPPS patients from a single center was performed. Gram-positive bacteria were isolated from the expressed prostatic secretion (EPS) of three CPPS-patients (pain inducers, PI) and one from a healthy volunteer (non-pain inducer, NPI). These bacteria were inoculated intra-urethrally in two mouse backgrounds and analyzed for their ability to induce tactile allodynia, voiding dysfunction, and colonize the murine prostate. Host immune responses to bacterial instillation were analyzed by flow cytometry. PI strains (Staphylococcus haemolyticus 2551, Enterococcus faecalis 427, and Staphylococcus epidermidis 7244) induced and maintained tactile allodynia responses (200% increase above baseline) for 28 days in NOD/ShiLtJ mice. Conversely the healthy subject derived strain (Staphylococcus epidermidis NPI) demonstrated no significant pelvic allodynia induction. Intra-urethral inoculation of the four bacterial strains into C57BL/6 mice did not induce significant increases in pain responses. Infected NOD/ShiLtJ displayed significant voiding dysfunction compared to their control counterparts. Colony counts of prostate tissues from both NOD/ShiLtJ and C57BL/6 mice at day 28 demonstrated that bacterial strains colonized equally well, including NPI. We also determined that mechanistically, the patient-isolates induced prostate inflammation specifically involving T-cells and monocytes. Gram-positive isolates from CPPS patients showed enhanced ability to induce tactile allodynia compared to a single taxonomically similar gram-positive strain isolated from a healthy control. Responses were shown to be dependent on host genetic background and not on colonization differences between strains.


Hyporeninemic hypoaldosteronism in a patient with cirrhosis and ascites.
A patient with cirrhosis and coexistent hyporeninemic hypoaldosteronism secondary to diabetic nephropathy rapidly formed ascites despite marked reductions in plasma aldosterone concentration and urinary aldosterone excretion. To my knowledge, this association has not been previously reported. This case supports the concept that hyperaldosteronism is not a necessary component of the salt retention of advanced liver disease. Furthermore, it suggests that certain renal disorders should be considered in cases of cirrhosis and ascites with decreased plasma renin activity.


Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction.
Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1-TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein-protein interactions, establish the structural requirements needed for efficient CD40-CD40L inhibition, and serve to guide the search for such immune therapeutics.


[Photoreceptor renewal and the pigment epithelium of the retina--congratulations to a pioneer in retinal research: Richard W. Young].
In 1999, a pioneer in retinal cell biology celebrates his seventieth birthday: Richard W. Young, Professor of Anatomy at the Dept. of Anatomy and Jules Stein Eye Institute, University of Southern California, Los Angeles, California, USA. Against the current dogma of visual cells as static structures he demonstrated that they undergo continual renewal of their light-sensitive outer segments. Entire membranes and/or single molecules are being replaced, and the tips of outer segments are shed (disk-shedding), and phagocytized and degrade by pigment epithelial (PE) cells. About 100 disks are made per rod within 24 hours, and about 30,000 disk membranes from overlying rods are degraded by one PE cell thus rendering the PE one of the most active phagocytic systems of the body. It is not surprising, therefore, that the age pigment lipofuscin accumulates within PE cells, which is mainly composed of undigestible outer segment material. It is generally concluded that lipofuscin can contribute to the pathogenesis of age related macular degeneration (AMD). Early on Young has postulated that light exposure may accelerate AMD and some forms of retinitis pigmentosa (RP). Today we know that indeed in several animal models of RP light exposure can significantly enhance the disease progression. With a similar insight and intuition he described apoptosis of the retina thus preceding the "apoptotic wave" in eye research. Apoptosis now is considered the final common death pathway of many retinal diseases including degenerations and dystrophies. With his work young has created may scientific children, who directly or indirectly were inspired by his pioneering work.


Test-retest reliability of the soleus H-reflex excitability measured during human walking.
The purpose of the study was to investigate with what accuracy the soleus H-reflex modulation and excitability could be measured during human walking on two occasions separated by days. The maximal M-wave (Mmax) was measured at rest in the standing position. During treadmill walking every stimulus elicited an M-wave of 25 ± 10% of Mmax in the soleus muscle and a supra-maximal stimulus elicited a maximal M-wave 60 ms after the first stimulus. Both Mmax during rest and during walking were later used for normalization. When normalized to resting Mmax, the peak reflex amplitude during walking was 5% lower on Day 2 than on Day 1 (p = .32). However, when the peak H-reflex was normalized to Mmax in every sweep, Day 2 showed a significant 15% lower amplitude (p = .037). The same pattern was found for the mean H-reflex. Spearman's Rho was .92 when normalized to resting Mmax but .88 when normalized to Mmax in every sweep. The Pearson product was used to identify one participant at a time on Day 1 among all seven participants on Day 2. For both normalization procedures 5 of 7 participants were identified by this test. Since 5 of 7 participants were recognized between days, it must be recommended to use 10-15 participants for training or intervention studies as far as the H-reflex pattern of modulation during movement is concerned.


Interpretation and applicability of empirical tissue enhancement metrics in dynamic contrast-enhanced MRI based on a multiple pathway model.
Computer simulations based on a physiologically realistic tracer kinetic model with multiple pathways was used to provide insights on the applicability and interpretation of tissue enhancement metrics such as the maximum slope, peak enhancement and area under curve, commonly used in dynamic contrast-enhanced (DCE) MRI. Results show that physiological conditions of the tissue that could affect the accuracy of the maximal slope method include a high blood flow, increased variability of flow within the vasculature or a low vascular volume. Interestingly, changes in permeability and interstitial volume might not affect the accuracy of the maximal slope method. Time-to-peak and peak value of the tissue enhancement curve are not strictly properties of the tissue alone, and they cannot be linearly related to intrinsic tissue parameters such as blood flow, blood volume, capillary permeability, interstitial volume and mean transit time. Similar to the normalized initial area under tissue concentration curve, an alternative estimate of the total tracer distribution volume can be simply given by the ratio of tracer concentration in the tissue and artery sampled at the final DCE scan.


[Value of determination of myoglobin concentration in blood in the diagnosis and prognosis of patients with acute myocardial infarction].
Seventy-seven patients with large-focal myocardial infarction (MI), admitted to the intensive-care ward within 5 hours after the attack, were studied. Their serum myoglobin (MG) levels and MB CPK activity were monitored through 3 or 4 days of the disease. All MI patients showed a considerable rise in their serum MG within the first hours of infarction. In addition to its high diagnostic value, the measurement of serum MG can be helpful in assessing the severity and prognosis of the disease. The obtained evidence of a high linear dependence between cumulative MB CPK activity and the area under the MG curve, as well as a high correlation coefficient between the areas under serum MG and MB CPK curves, point in favor of using MG levels as a measure of the extent of the necrotic focus.


KLF4 Inhibits the Differentiation of Goat Intramuscular Preadipocytes Through Targeting C/EBPβ Directly.
Intramuscular fat (IMF) deposition is a complicated process, and most of the underlying regulators of this biological process are unknown. Here, we cloned the intact CDS of KLF4 gene, investigated the role of KLF4 by gaining or losing function in vitro and further explored the pathways of KLF4 regulating differentiation of intramuscular preadipocytes in goat. Our results show that goat KLF4 gene consists of 1,536 bp encoding a protein of 486 amino acids. The expression of KLF4 is higher in the lung while lower in the heart and muscle in goat. Knockdown of KLF4 mediated by siRNA technique significantly promotes intramuscular preadipocyte lipid accumulation and upregulates mRNA expression of adipogenic related genes including C/EBPα, C/EBPβ, and PPARγ in vivo cultured cells. Consistently, overexpression of KLF4 inhibits intramuscular adipocyte lipid accumulation and significantly downregulation gene expression of C/EBPβ, PPARγ, aP2, and Pref-1. Further, we found that other members of KLFs were upregulated or downregulated after interference or overexpression of KLF4, including KLF2 and KLF5-7. We also found that C/EBPβ was a potential target of KLF4, because it had an opposite expression pattern with KLF4 during the differentiation of intramuscular preadipocytes and had putative binding sites of KLF4. The dual-luciferase reporter assay indicated that overexpression of KLF4 inhibited the transcriptional activity of C/EBPβ. These results demonstrate that KLF4 inhibits the differentiation of intramuscular preadipocytes in goat by targeting C/EBPβ.


Assessing the nutritional equivalency of DL-methionine and L-methionine in broiler chickens: a meta-analytical study.
The purpose of this study was to perform a meta-analysis comparing the biological efficiency of DL-methionine and L-methionine (DL-Met and L-Met) in broiler nutrition. This analysis was based on a dataset comprising experiment results published in peer-reviewed papers since 2007. All experiments investigated the response of broilers (aged 0-21 d) to different dietary concentrations of DL- and L-Met, achieved by supplementing crystalline Met. A graphical analysis was conducted on the database using ellipses coverage and nonparametric density techniques. Two methods of linear and nonlinear exponential meta-regression analysis were used to determine relative bioavailability based on average daily gain (ADG) and feed conversion ratio (FCR) responses to dietary Met sources. The analyses of ADG and FCR obtained from both linear and exponential models showed a relative difference between the tested methionine sources. The results showed that both ADG and FCR were improved in L-Met compared to DL-Met supplemented diets. Linear regression analysis revealed that DL-Met was 94.97% (for ADG) and 95.63% (for FCR) as efficacious as L-Met (P < 0.01). In contrast, the analysis of the fitted nonlinear exponential model showed that the biological efficiencies of DL-Met were 91.33% and 76.57% of the values for L-Met for ADG (P = 0.01) and FCR (P = 0.09), respectively. Based on the meta-analytical results, an equivalence of relative biological efficiency of DL-Met in comparison with L-Met for young broilers could not be confirmed.


Downregulation of hepatoma-derived growth factor contributes to retarded lung metastasis via inhibition of epithelial-mesenchymal transition by systemic POMC gene delivery in melanoma.
The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial-mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and α-smooth muscle actin (α-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma.


Characterisation of the biological effects of neurohypophysial peptides on seminiferous tubules.
Oxytocin (OT) is present in the mammalian testis and has been postulated to play a role in modulation of seminiferous tubule contractility. However, recent evidence suggests that the myoid cells responsible for such contractile activity do not express OT receptors. In this study computer-assisted analysis and time-lapse videomicrography were used to investigate the biological effects of neurohypophysial peptides and their analogues on seminiferous tubule contractility. Adult rat testes were placed in fresh oxygenated Dulbecco's modified Eagle's medium (DMEM) F12 medium, decapsulated and the tubules gently teased apart. A small section of tubule was placed in a microslide chamber and perifused with medium. Seminiferous tubules were treated with OT (2 nM), [Arg8]-vasopressin (AVP, 0.2 nM) or [Thr4,Gly7]-OT (TGOT, 2 nM, 8 nM and 0.2 microM). Specific antagonists were also given simultaneously with OT and AVP treatments. Data were analysed to give arbitrary units of contractility. Both OT and AVP increased tubule contractility, with AVP being at least 10 times more potent than OT. Treatment with the selective OT antagonist, desGly-NH2,d(CH2)5[d-Tyr2,Thr4]-ornithine vasotocin (OTA, 0.2 microM and 2 microM) significantly reduced OT-induced increases in seminiferous tubule contractility but had no effect on AVP-induced responses. In contrast, the AVP antagonist, Phaa-d-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (AVPA) was more potent at reducing AVP-induced increases than OT-induced responses. The selective non-peptide AVPA SR 49059 blocked the response to both peptides in a similar manner, whilst the non-peptide OTA L367,773 did not block OT-induced increases in seminiferous tubule contractility at doses that were slightly inhibitory to AVP-induced responses. The specific OT agonist TGOT did not induce a contractile response. The data in this study demonstrate that in the testis AVP acts via V1a receptors to stimulate contractile activity and suggest that OT may act via a receptor which differs from the classical V1a and uterine-type OT receptor. These findings support a role for OT in the regulation of seminiferous tubule contractility and raise the possibility that AVP may also be important in this process.


Comparative Evaluation of the Efficacy of Chlorhexidine, Fluoride and the Combined Use of Chlorhexidine and Fluoride Varnishes on Salivary Streptococcus mutans Count in Children with Mixed Dentition: An In Vivo Study.
To study the effect of combination of chlorhexidine and Fluoride on the growth and colonization of cariogenic bacteria (Streptococcus mutans) in children with mixed dentition. Sixty children of age 6-14 years with mixed dentition and S. mutans count > 1 × 105 CFU/mL of saliva were divided: group I-chlorhexidine varnish; group II-Fluoride varnish; group III-Combination of chlorhexidine and Fluoride varnish. chlorhexidine and Fluoride varnishes were applied to teeth once every week for four consecutive weeks in respective groups. Salivary S. mutans count was estimated and evaluated at baseline, 1, 3, and 6 months. No significant difference was seen in group I and II at the end of 1, 3, and 6 months (p > 0.001) but the reduction in S. mutans count was statistically more significant in group III after a period of 6 months (p < 0.001). Maximum reduction in count was noted in group III at all intervals of varnish application. The concomitant use of chlorhexidine and fluoride varnish would prove to be more effective than individual components over a longer period of time and especially in high caries risk children. More VP, Hugar SM, Sogi S, et al. Comparative Evaluation of the Efficacy of Chlorhexidine, Fluoride and the Combined Use of Chlorhexidine and Fluoride Varnishes on Salivary Streptococcus mutans Count in Children with Mixed Dentition: An In Vivo Study. Int J Clin Pediatr Dent 2022;15(3):267-272.


Choice of reference, influence of non-additivity, and present challenges in thermodynamic perturbation theory for mixtures.
This work revisits the fundamentals of thermodynamic perturbation theory for fluid mixtures. The choice of reference and governing assumptions can profoundly influence the accuracy of the perturbation theory. The statistical associating fluid theory for variable range interactions of the generic Mie form equation of state is used as a basis to evaluate three choices of hard-sphere reference fluids: single component, additive mixture, and non-additive mixture. Binary mixtures of Lennard-Jones fluids are investigated, where the ratios of σ (the distance where the potential is zero) and the ratios of ϵ (the well depth) are varied. By comparing with Monte Carlo simulations and results from the literature, we gauge the accuracy of different theories. A perturbation theory with a single-component reference gives inaccurate predictions when the σ-ratio differs significantly from unity but is otherwise applicable. Non-additivity becomes relevant in phase-equilibrium calculations for fluids with high ϵ-ratios or when the mixing rule of σ incorporates non-additivity through an adjustable parameter. This can be handled in three ways: by using a non-additive hard-sphere reference, by incorporating an extra term in the additive hard-sphere reference, or with a single-component reference when the σ-ratio is close to unity. For σ- and ϵ-ratios that differ significantly from unity, the perturbation theories overpredict the phase-equilibrium pressures regardless of reference. This is particularly pronounced in the vicinity of the critical region for mixtures with high ϵ-ratios. By comparing with Monte Carlo simulations where we compute the terms in the perturbation theory directly, we find that the shortcomings of the perturbation theory stem from an inaccurate representation of the second- and third-order perturbation terms, a2 and a3. As mixtures with molecules that differ significantly in size and depths of their interaction potentials are often encountered in industrial and natural applications, further development of the perturbation theory based on these results is an important future work.


Nursing attrition and the work environment in South African health facilities.
A number of media reports appeared on the shortages of professional health workers in the public health sector. Unsatisfactory working conditions in health facilities were mentioned as one of the key aspects responsible for the shortages. Literature indicates that stress caused by unsatisfactory work environments may play a major role in employees' decision to resign their jobs, in spite of enjoying the nature of their work. The aim of this article is to explore the current human resource situation in nursing i.e. to determine if a shortage of nursing skills exists, to establish the challenges that nurses have to face in performing their duties and to establish the potential effect of the work environment on attrition. Currently 155 484 nurses are practicing in South Africa at a rate of 343 nurses per 100 000 of the population, which compares favourably with the World Health Organisation minimum of 200:100 000. The lack of reliable data on the supply of and demand for nurses makes it difficult to determine whether real shortages exist. However the supply of nursing services is influenced by the uneven distribution of skills across regions and the outflow of professional skills. It seems that the existing situation will deteriorate because fewer people are interested in taking up or pursuing nursing as a career in South Africa. At the same time a need for more nurses was identified because of the growth in the population as well as a change in health care needs. Workplace conditions for health workers employed at hospitals and clinics in South Africa were explored as part of a recent national study on the impact of HIV/AIDS on the health sector. Health workers' opinions on aspects such as workload, staff morale and working hours were obtained during personal interviews, which were conducted at 222 health facilities. Nine hundred and twenty four professional nurses, enrolled nurses and nursing assistants, who were mostly employed in the public health sector, participated. A stressful work environment was identified in public hospitals and clinics. An increase in the number of patients visiting these facilities, accompanied by a lack of equipment, unsatisfactory work environment and a shortage of nurses were pointed out. Many patients cannot be accommodated elsewhere because of a lack of finance and alternative health care options. Nurses also indicated that they do not get much support from their employers. The effect of all these factors culminates in a stressed workforce who may be forced to consider alternative career options. This will be to the detriment of health care in the country.


Glucocorticoid receptor and protein/RNA synthesis-dependent mechanisms underlie the control of synaptic plasticity by stress.
Learning and memory are exquisitely sensitive to behavioral stress, but the underlying mechanisms are still poorly understood. Because activity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as the hippocampus we have examined the means by which stress affects synaptic plasticity in the CA1 region of the hippocampus of anesthetized rats. Inescapable behavioral stress (placement on an elevated platform for 30 min) switched the direction of plasticity, favoring low frequency stimulation-induced decreases in synaptic transmission (long-term depression, LTD), and opposing the induction of long-term potentiation by high frequency stimulation. We have discovered that glucocorticoid receptor activation mediates these effects of stress on LTD and long-term potentiation in a protein synthesis-dependent manner because they were prevented by the glucocorticoid receptor antagonist RU 38486 and the protein synthesis inhibitor emetine. Consistent with this, the ability of exogenously applied corticosterone in non-stressed rats to mimic the effects of stress on synaptic plasticity was also blocked by these agents. The enablement of low frequency stimulation-induced LTD by both stress and exogenous corticosterone was also blocked by the transcription inhibitor actinomycin D. Thus, naturally occurring synaptic plasticity is liable to be reversed in stressful situations via glucocorticoid receptor activation and mechanisms dependent on the synthesis of new protein and RNA. This indicates that the modulation of hippocampus-mediated learning by acute inescapable stress requires glucocorticoid receptor-dependent initiation of transcription and translation.


[Spanish translation and validation of the nursing dental coping beliefs scale].
Caregivers of disable and dependent people, institutionalized elderly and hospitalized, must provided oral health care for the patients under their care, for that reason, it is necessary to have a valid instrument in Spanish to measure oral health beliefs among caregivers. The aim of the study was to translate to Spanish the Nursing Dental Coping Beliefs Scale (Nursing DCBS) and validate this questionnaire to be used on Hispanic caregivers. The nursing DCBS was translated to Spanish and revised for linguistic adaptation. A group of experts revised their content and face validity. A pilot study of the questionnaire in Spanish, was held in a group of 118 nurse assistant students from two professional institutes. The reliability of the instrument, was evaluated by its internal consistency with Cronbach's Alpha and the measurement stability, through intraclass correlation coefficient (ICC). The questionnaire was validated by its appearance and content. The internal consistency for the questionnaire through Cronbach's Alpha was 0.64 and the stability of the instrument 0.5 for ICC. The Spanish version of the nursing Dental Coping Beliefs Scale is a questionnaire that has an internal consistency to be used as an instrument to measure oral health beliefs among caregivers, however, future investigations must re-evaluate there psychometric characteristics, specially its stability as an instrument.


[Multifocal motor neuropathy: a retrospective study of the response to high-dose intravenous immunoglobulin (IVIg) and current perspectives for diagnosis and treatment].
Multifocal motor neuropathy (MMN) was first distinguished from other motor neuropathies in 1986. It is characterised by slowly progressive predominantly distal and asymmetric limb weakness and wasting that predominates in the arms, with muscle cramps and fasciculations, within an anatomical distribution of individual motor nerves. Sensory involvement is minimal or absent. The electrodiagnostic hallmark is focal motor conduction block (CB), persisting for years at atypical sites. The most typical laboratory finding is increased serum IgM autoantibody titers to the ganglioside GM1. High-dose intravenous immunoglobulin (IVIg) is currently the gold-standard treatment for MMN. To document short-term and long-term responses to IVIg, we conducted a retrospective study of 40 patients with MMN defined using ENMC Workshop criteria and treated with periodic IVIg infusions (Tégéline) between 1995 and 2003. For the short-term analysis we compared the 22 patients who had never previously received IVIg with the 18 IVIg-experienced patients. For the long-term evaluation (> 6 months), the patients were classified into four groups according to their dependence on periodic IVIg. The MRC score improved significantly in 14 (70% ; 95% CI 0.46 to 0.88) of the 20 assessable treatment-naive patients (data were missing for two patients). This rate was significantly higher than at six months in a historical group of placebo-treated patients (20%; p < 0.0001). No criteria predictive of the response were identified. At the end of follow-up (mean 2.2 +/- 2.0 years) only 8 patients (22%) in the cohort remained in remission after a good initial response to IVIg, while 25 patients (68%) were dependent on periodic IVIg infusions. This study confirms the good short-term response of MMN to IVIg but indicates that the longer-term results are variable. New therapeutic strategies are required to increase the short-term and long-term efficacy of IVIg, and to reduce reliance on this treatment.


Macrophage heterogeneity and energy metabolism.
Macrophages are versatile and multifunctional cell types present in most vertebrate tissues. They are the first line of defense against pathogens through phagocytosis of microbial infections, particles and dead cells. Macrophages harbor additional functions besides immune protection by participating in essential homeostatic and tissue development functions. The immune response requires a concomitant and coordinated regulation of the energetic metabolism. In this review, we will discuss how macrophages influence metabolic tissues and in turn how metabolic pathways, particularly glucose and lipid metabolism, affect macrophage phenotypes.


Controlling the Hydration Structure with a Small Amount of Fluorine To Produce Blood Compatible Fluorinated Poly(2-methoxyethyl acrylate).
Poly(2-methoxyethyl acrylate) (PMEA) shows excellent blood compatibility because of the existence of intermediate water. Various modifications of PMEA by changing its main or side chain's chemical structure allowed tuning of the water content and the blood compatibility of numerous novel polymers. Here, we exploit a possibility of manipulating the surface hydration structure of PMEA by incorporation of small amounts of hydrophobic fluorine groups in MEA polymers using atom-transfer radical polymerization and the (macro) initiator concept. Two kinds of fluorinated MEA polymers with similar molecular weights and the same 5.5 mol % of fluorine content were synthesized using the bromoester of 2,2,3,3,4,4,5,5,6,6,7,7,8,8-pentadecafluoro-1-octanol (F15) and poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) as (macro) initiators, appearing liquid and solid at room temperature, respectively. The fibrinogen adsorption of the two varieties of fluorinated MEA polymers was different, which could not be explained only by the bulk hydration structure. Both polymers show a nanostructured morphology in the hydrated state with different sizes of the features. The measured elastic modulus of the domains appearing in atomic force microscopy and the intermediate water content shed light on the distinct mechanism of blood compatibility. Contact angle measurements reveal the surface hydration dynamics-while in the hydrated state, F15- b-PMEA reorients easily to the surface exposing its PMEA part to the water, the small solid PTFEMA block with high glass-transition temperature suppresses the movement of PTFEMA- b-PMEA and its reconstruction on the surface. These findings illustrate that in order to make a better blood compatible polymer, the chains containing sufficient intermediate water need to be mobile and efficiently oriented to the water surface.


Silver Nanoparticle Gradient Arrays: Fluorescence Enhancement of Organic Dyes.
Noble metal nanoparticles show pronounced extinction peaks in the visible wavelength range due to their localized surface plasmon resonances. The excitation of these resonances leads to strong confinement of electromagnetic energy at nanometer scales, which is critical for ultrasensitive, fluorescence-based detection of analytes. The strength and spatial distribution of this near-field zone depend on particle size, shape, and composition. To determine how these near-field effects depend on the particle size, we have prepared nanoparticle gradients on centimeter-scale substrates using a colloid-based approach. This plasmonic gradient is used to study the steady-state emission and fluorescence lifetime of a common organic dye that was embedded into the monolayer.


Extracts of Tsai Tai (Brassica chinensis): enhanced antioxidant activity and anti-aging effects both in vitro and in Caenorhabditis elegans.
Tsai Tai is one of the most widely consumed Brassica vegetables in Asian countries because of its good taste and its nutritional benefits. This study evaluated the antioxidant capacity and possible associated health benefits of 3 Tsai Tai (Brassica chinensis) varieties, namely, Hon Tsai Tai, Pak Choi and Choi Sum. The DPPH radical scavenging ability and reducing power assays were performed to evaluate the in vitro activities of the extracts. Caenorhabditis elegans was used as an in vivo model for evaluation of beneficial health effects, including antioxidant activity and delayed aging. In vitro, the Hon Tsai Tai extract exhibited higher antioxidant activities than Pak Choi and Choi Sum, and the total phenolic contents were significantly correlated with the DPPH and RP values. In vivo, the three assayed Tsai Tai extracts significantly increased resistance against paraquat-induced oxidative stress with an increase in survival rates from 15% to 28% compared with controls. However, only the extract from Hon Tsai Tai significantly prolonged the lifespan of Caenorhabditis elegans, with an 8% increase in the mean lifespan with respect to controls. Further evidence of antioxidant protection was obtained by assessing ROS production via the DCF assay. The analyses of intracellular SOD activity and MDA content confirmed the existence of an antioxidant protective effect. These results suggest that Tsai Tai might serve as a good source of natural antioxidants, and in particular, Hon Tsai Tai could be explored as a potential dietary supplement to retard aging.


Is it possible to resterilize disposable laparoscopy trocars in a hospital setting?
Nosocomial infections associated with interventional procedures have been attributed to improper decontamination of instruments. Disinfection of solid laparoscopic instruments, such as telescopes, by 2% glutaraldehyde and ethylene oxide was shown to be effective in preventing infection transmission. However, instrument design in more complex surgical instruments may hamper the quality of disinfection. The aim of this study is to investigate the safety of hospital disinfection of disposable laparoscopic instruments with a relatively more complex design. A total of 40 laparoscopic trocars were divided into two equal groups: group 1 was contaminated with bacteria and yeast, and group 2 was contaminated with the hepatitis B virus. Each group was then divided to two equal subgroups. After disinfecting subgroup A with 2% glutaraldehyde and B with ethylene oxide, samples were obtained for bacterial cultures and for virus detection using polymerase chain reaction (PCR). Bacterial and yeast cultures were positive in three instruments in group 1A and in two instruments in group 1B. Tests results for the hepatitis B virus were negative in group 2A, but positive in group 2B. Results of this study indicate that disinfection for multiple use of disposable laparoscopic instruments with a relatively complex structure is not effective and may result in nosocomial disease transmission by bacteria, fungi, and viruses.


Cervical artery dissection in young adults in the stroke in young Fabry patients (sifap1) study.
Patients with carotid artery dissection (CAD) have been reported to have different vascular risk factor profiles and clinical outcomes to those with vertebral artery dissection (VAD). However, there are limited data from recent, large international studies comparing risk factors and clinical features in patients with cervical artery dissection (CeAD) with other TIA or ischemic stroke (IS) patients of similar age and sex. We analysed demographic, clinical and risk factor profiles in TIA and IS patients ≤55 years of age with and without CeAD in the large European, multi-centre, Stroke In young FAbry Patients 1 (sifap1) study. Patients were further categorised according to age (younger: 18-44 years; middle-aged: 45-55 years), sex, and site of dissection. Data on the presence of dissection were available in 4,208 TIA and IS patients of whom 439 (10.4%) had CeAD: 196 (50.1%) had CAD, 195 (49.9%) had VAD, and 48 had multiple artery dissections or no information regarding the dissected artery. The prevalence of CAD was higher in women than in men (5.9 vs. 3.8%, p < 0.01), whereas the prevalence of VAD was similar in women and men (4.6 vs. 4.7%, n.s.). Patients with VAD were younger than patients with CAD (median = 41 years (IQR = 35-47 years) versus median = 45 years (IQR = 39-49 years); p < 0.01). At stroke onset, about twice as many patients with either CAD (54.0 vs. 23.1%, p < 0.001) or VAD (63.4 vs. 36.6%, p < 0.001) had headache than patients without CeAD and stroke in the anterior or posterior circulation, respectively. Compared to patients without CeAD, hypertension, concomitant cardiovascular diseases and a patent foramen ovale were significantly less prevalent in both CAD and VAD patients, whereas tobacco smoking, physical inactivity, obesity and a family history of cerebrovascular diseases were found less frequently in CAD patients, but not in VAD patients. A history of migraine was observed at a similar frequency in patients with CAD (31%), VAD (27.8%) and in those without CeAD (25.8%). We identified clinical features and risk factor profiles that are specific to young patients with CeAD, and to subgroups with either CAD or VAD compared to patients without CeAD. Therefore, our data support the concept that certain vascular risk factors differentially affect the risk of CAD and VAD.


Cancer rehabilitation in Denmark: the growth of a new narrative.
A fundamental assumption behind cancer rehabilitation in many Western societies is that cancer survivors can return to normal life by learning to deal with the consequences of their illness and their treatment. This assumption is supported by increasing political attention to cancer rehabilitation and a growth in residential cancer-rehabilitation initiatives in Denmark (Danish Cancer Society 1999; Government of Denmark 2003). On the basis of their ethnographic fieldwork in residential-cancer rehabilitation courses, the authors examine the new rehabilitation discourse. They argue that this discourse has challenged the dominant illness narrative, "sick-helped-cured," producing a new narrative, "sick-helped-as if cured," and that this new narrative is produced and reproduced through technologies of power and of the self.


Effects of DBS, premotor rTMS, and levodopa on motor function and silent period in advanced Parkinson's disease.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinson's disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor-evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity.


Transgenic mice for cre-inducible overexpression of the Cul4A gene.
The Cullin 4A(Cul4A) gene is important in cell survival, development, growth, and cell cycle control and is amplified in breast and hepatocellular cancers. Recently, we reported that Cul4A plays an oncogenic role in the pathogenesis of mesothelioma. An important strategy for studying Cul4A in different tissues is targeted overexpression of this gene in vivo. Studies of Cul4A in mice have been restricted to the loss-of-function studies using Cul4A knockout mice; gain-of-function studies of Cul4A using transgenic mice have not been reported. We, therefore, generated a gain-of-function transgenic mouse model that overexpresses Cul4A in a Cre-dependent manner. Before Cre recombination, these mice express LacZ during development in most adult tissues. After Cre-mediated excision of the LacZ reporter, the transfected Cul4A gene is expressed along with a C-terminal Myc-tag in different tissues. In this study, Cre-excision was induced in mouse lungs by inhalation of an adenovirus vector encoding Cre recombinase. This mouse model provides a valuable resource for investigating the significance of Cul4A overexpression in various tissues.


The expression of the homeobox gene Msx1 reveals two populations of dermal progenitor cells originating from the somites.
Experimental manipulation in birds has shown that trunk dermis has a double origin: dorsally, it derives from the somite dermomyotome, while ventrally, it is formed by the somatopleure. Taking advantage of an nlacZ reporter gene integrated into the mouse Msx1 locus (Msx1(nlacZ) allele), we detected segmental expression of the Msx1 gene in cells of the dorsal mesenchyme of the trunk between embryonic days 11 and 14. Replacing somites from a chick host embryo by murine Msx1(nlacZ )somites allowed us to demonstrate that these Msx1-(beta)-galactosidase positive cells are of somitic origin. We propose that these cells are dermal progenitor cells that migrate from the somites and subsequently contribute to the dorsalmost dermis. By analysing Msx1(nlacZ) expression in a Splotch mutant, we observed that migration of these cells does not depend on Pax3, in contrast to other migratory populations such as limb muscle progenitor cells and neural crest cells. Msx1 expression was never detected in cells overlying the dermomyotome, although these cells are also of somitic origin. Therefore, we propose that two somite-derived populations of dermis progenitor cells can be distinguished. Cells expressing the Msx1 gene would migrate from the somite and contribute to the dermis of the dorsalmost trunk region. A second population of cells would disaggregate from the somite and contribute to the dermis overlying the dermomyotome. This population never expresses Msx1. Msx1 expression was investigated in the context of the onset of dermis formation monitored by the Dermo1 gene expression. The gene is downregulated prior to the onset of dermis differentiation, suggesting a role for Msx1 in the control of this process.


High-performance image reconstruction in fluorescence tomography on desktop computers and graphics hardware.
Image reconstruction in fluorescence optical tomography is a three-dimensional nonlinear ill-posed problem governed by a system of partial differential equations. In this paper we demonstrate that a combination of state of the art numerical algorithms and a careful hardware optimized implementation allows to solve this large-scale inverse problem in a few seconds on standard desktop PCs with modern graphics hardware. In particular, we present methods to solve not only the forward but also the non-linear inverse problem by massively parallel programming on graphics processors. A comparison of optimized CPU and GPU implementations shows that the reconstruction can be accelerated by factors of about 15 through the use of the graphics hardware without compromising the accuracy in the reconstructed images.


[Some comments on the 2nd European drinking water guideline].
It took 18 years before issuing a revised version of the first EU Drinking Water Guideline. As is well known, it did not receive unanimous acclaim neither by the water supply nor by the public health authorities. The second guideline has now been released and can be welcomed as a quite logically constructed and consistent version in comparison to its predecessor. Borderline values are stated only for those microbiological and chemical ingredients of water that are relevant to health. These borderline values must be considered as minimum deadlines and may not be raised by a member country although their severity may be increased. Basing on recent toxicological findings some of the borderline values have been raised or lowered compared to the previous version. On the other hand, however, the aesthetic aspects of drinking water have been neglected. In this respect we may look forward with interest as to how German legislation will implement the new guideline. This will have to be done at the latest by 2000 A.D. end.


[Pulmonary hypertension related to pulmonary diseases or hypoxia and its treatment].
Pulmonary hypertension often complicates the course of patients with advanced lung disease, and it is associated with a worse prognosis. In the recent classification of pulmonary hypertensive disorders, pulmonary hypertension due to lung disease is considered as a separate category within a group of disorders that were previously referred to as "secondary". The incidence and clinical course of pulmonary hypertension associated with chronic obstructive pulmonary disease is best known among the pulmonary hypertension associated with lung diseases. The pathophysiology and treatment of pulmonary hypertension seen in the course of advanced lung diseases are generally distinct from those of pulmonary arterial hypertension. Chronic hypoxia is the major mechanism implicated for the development of pulmonary hypertension in patients with lung diseases. This article focuses on the recent advances in our knowledge about the pulmonary hypertension due to lung diseases or hypoxia.


Targeting Mcl-1 for the therapy of cancer.
Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers. Targeting Mcl-1 for extinction in these cancers, using genetic and pharmacological approaches, represents a potentially effectual means of developing new efficacious cancer therapeutics. Here we review the multiple strategies that have been employed in targeting this fundamental protein, as well as the significant potential these targeting agents provide in not only suppressing cancer growth, but also in reversing resistance to conventional cancer treatments. We discuss the potential issues that arise in targeting Mcl-1 and other Bcl-2 anti-apoptotic proteins, as well problems with acquired resistance. The application of combinatorial approaches that involve inhibiting Mcl-1 and manipulation of additional signaling pathways to enhance therapeutic outcomes is also highlighted. The ability to specifically inhibit key genetic/epigenetic elements and biochemical pathways that maintain the tumor state represent a viable approach for developing rationally based, effective cancer therapies.