Optimal activity of [18F]FDG for Hodgkin lymphoma imaging performed on PET/CT camera with BGO crystals.
We aimed to find the minimum feasible activity of fluorodeoxyglucose ([18F]FDG) in positron emission tomography/computed tomography (PET/CT) of Hodgkin lymphoma patients performed on a camera with bismuth germanate (BGO) crystals. Ninety-one [18F]FDG PET/CT scans (each in seven Bayesian Penalized Likelihood [BPL] reconstructions with varying acquisition time per bed position - 2 min, 1.5 min, 1 min, 50 s, 40 s, 30 s, and 20 s) were independently assessed by three physicians to evaluate image quality. Mean administered activity was 3.0 ± 0.1 MBq/kg and mean uptake time was 54.0 ± 8.7 min. The series quality was subjectively marked on a 1-10 scale and then ranked 1-7 based on the mean mark. Interobserver rank correlation and intraclass correlation within each series for the three observers were calculated. Phantom studies were also performed to determine if reduced acquisition time can be directly translated into a reduced activity. Time series were marked and ranked unanimously - the longer the time of acquisition the higher the mark and rank. The interobserver agreement in the ranking was excellent (100%) with a kappa coefficient of 1.00 (95% CI [0.83-1.0]). The general intraclass correlation coefficient (agreement between the marks observers gave each time series) was very high (0.945, 95% CI [0.936-0.952]) and was higher the shorter the time per bed. According to all three observers only the series with 2 min and 1.5 min acquisition time were appropriate for assessment (mean mark ≥ 7). In phantom studies there was a linear correlation between time per bed, administered activity, and number of total prompts detected by a scanner. Hence, a reduction of acquisition time of 25% (from 2 min to 1.5 min) could be directly translated into a 25% activity reduction (from 3.0 to 2.25 MBq/kg). In patients with HL, [18F]FDG activity can be reduced by up to 25% when using a BGO crystal camera, without substantial impact on image quality.


Intervention for Children with Obesity and Overweight and Motor Delays from Low-Income Families: Fostering Engagement, Motor Development, Self-Perceptions, and Playtime.
Obesity is increasing globally, affecting children's health and development. This study examines the influence of a motor skill intervention on the daily routine, self-perceptions, body mass index, motor development, and engagement in physical education lessons of children with obesity and overweight with motor delays. Children were randomly assigned to intervention and control groups. The daily routine at home, self-perceptions, motor development, BMI, and engagement were assessed. Significant group by time interactions were found for play (p < 0.0001) and television (p < 0.0001) time, perceived social (p = 0.003) and motor (p < 0.0001) competence, global self-worth (p < 0.0001), BMI (p = 0.001), motor development (p < 0.0001), and engagement (p = 0.029). From pre-to-post intervention, children with obesity and overweight in the intervention group increased (1) playtime at home; (2) self-perceptions of social and motor competence and global worth; (4) engagement in the lessons, and improved scores, in motor skills; and (6) reduced BMI and screen time. The intervention promoted the health and improved the self-concept of children with obesity/ overweight.


Staff management and capacity building under conditions of insecurity: lessons from developing mental health service and research programs in post-conflict Timor-Leste.
The task of staff capacity building is particularly important, albeit challenging, in low and middle income countries emerging from prolonged periods of persecution and conflict. Mental health professionals engaged in development and research projects are acutely aware of the impact of past and current conditions including trauma exposure, insecurity, and poverty on the capacity of local workers to acquire and apply skills. In this article we reflect on these challenges by drawing on our experience spanning 10 years of mental health work and capacity building in Timor-Leste. It is important to be proactive in identifying the needs and career objectives of workers early in any development initiative so that an effective program of capacity building can be initiated. Careful consideration needs to be given to ensure a compassionate and considered response to the psychosocial needs of staff, one that takes into account the impact of past trauma, ongoing insecurity and socioeconomic conditions on the capacity of workers to function effectively.


Characterization and Topical Study of Aloe Vera Hydrogel on Wound-Healing Process.
Wound healing is fundamental to restore the tissue integrity. A topical study of the influence of Aloe vera hydrogel, formulated with 1,2-propanediol (propanediol) and triethanolamine (TEA), on the skin wound-healing process was investigated in female Wistar rats. FTIR spectroscopy confirms the presence of carboxylic acid and methyl ester carboxylate groups related with important compounds that confer the hydrogel a good interaction with proteins and growth factors. SEM images show a microstructure and micro-roughness that promote a good adhesion to the wound. Therefore, the swelling kinetics and the contact angle response contribute to the understanding of the in vivo results of the animal test. The results indicated that the Aloe vera hydrogel, prepared with propanediol and TEA, together with its superficial characteristics, improve its rapid penetration without drying out the treated tissue. This produced a positive influence on inflammation, angiogenesis, and wound contraction, reducing 29% the total healing time, reaching the total closure of the wound in 15 days.


The effect of variability in the fertility schedule on numbers of kin.
"The kinship formulas developed by Goodman, Keyfitz, and Pullum (1974) are extended to encompass populations in which fertility varies among women. An expression is derived to determine the amount by which the number of sisters in a heterogeneous population exceeds that in a population with homogeneous fertility. This expression, which is a function of the variance in the gross reproduction rate of the population, can readily be applied to numbers of other kin, such as aunts and cousins. Several trial calculations indicate that calculations of average numbers of sisters based on an assumption of uniform fertility could result in a underestimate of about 13 percent." (SUMMARY IN FRE)


Mesenteric volvulus in children: two autopsy cases and review of the literature.
Small bowel mesenteric volvulus when compared with mesocolonic volvulus, have not high incidence. Two autopsy cases of small bowel mesenteric volvulus in infants, highlighting the importance of a suspicion in early recognition of this rare but potentially fatal intra-abdominal emergency are reported. We also review the literature on possible aetiologies and mechanism of small bowel mesenteric volvulus, as well as its management.


Pitavastatin suppressed liver cancer cells in vitro and in vivo.
Pitavastatin classically functions as a blood cholesterol-lowering drug. Previously, it was discovered with antiglioma stem cell properties through drug screening. However, whether it can be used for liver cancer cell therapy has never been reported. In this study, the cell viability and colony formation assay were utilized to analyze the cytotoxicity of pitavastatin on liver cancer cells. The cell cycle alteration was checked after pitavastatin treatment. Apoptosis-related protein expression and the effect of caspase inhibitor were also checked. The in vivo inhibitory effect of pitavastatin on the growth of liver tumor was also tested. It was found that pitavastatin inhibited growth and colony formation of liver cancer Huh-7 cells and SMMC7721 cells. It induced arrest of liver cancer cells at the G1 phase. Increased proportion of sub-G1 cells was observed after pitavastatin treatment. Pitavastatin promoted caspase-9 cleavage and caspase-3 cleavage in liver cancer cells. Caspase inhibitor Z-VAD-FMK reversed the cleavage of cytotoxic effect of pitavastatin. Moreover, pitavastatin decreased the tumor growth and improved the survival of tumor-bearing mice. This study suggested the antiliver cancer effect of the old drug pitavastatin. It may be developed as a drug for liver cancer therapy.


Apolipoprotein E is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages.
Apolipoprotein E (ApoE) belongs to a class of cellular proteins involved in lipid metabolism. ApoE is a polymorphic protein produced primarily in macrophages and astrocytes. Different isoforms of ApoE have been associated with susceptibility to various diseases including Alzheimer's and cardiovascular diseases. ApoE expression has also been found to affect susceptibility to several viral diseases, including Hepatitis C and E, but its effect on the life cycle of HIV-1 remains obscure. In this study, we initially found that HIV-1 infection selectively up-regulated ApoE in human monocyte-derived macrophages (MDMs). Interestingly, ApoE knockdown in MDMs enhanced the production and infectivity of HIV-1, and was associated with increased localization of viral envelope (Env) proteins to the cell surface. Consistent with this, ApoE over-expression in 293T cells suppressed Env expression and viral infectivity, which was also observed with HIV-2 Env, but not with VSV-G Env. Mechanistic studies revealed that the C-terminal region of ApoE was required for its inhibitory effect on HIV-1 Env expression. Moreover, we found that ApoE and Env co-localized in the cells, and ApoE associated with gp160, the precursor form of Env, and that the suppression of Env expression by ApoE was cancelled by the treatment with lysosomal inhibitors. Overall, our study revealed that ApoE is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages that exerts its anti-HIV-1 activity through association with gp160 Env via the C-terminal region, which results in subsequent degradation of gp160 Env in the lysosomes.


Microbial reduction of amended sulfate in anaerobic mature fine tailings from oil sand.
Bitumen extraction from oil sands has resulted in large tailings ponds, containing suspended material that requires over one hundred years to densify. The mature fine tailings (MFT) have become anaerobic and bubbles of gas are observed on the pond surface. Gypsum has been proposed as an additive to increase the rate of MFT consolidation. In a laboratory study, MFT was amended with sulfate and monitored. Pore water sulfate concentrations declined and bicarbonate concentration increased. Nitrate was depleted within 36 d and the levels of soluble iron remained below 0.8 mg L(-1). Thiosulfate and sulfide were detected only near the end of the experiment. Acid volatile sulfides (AVS) increased until day 39, and then reached a plateau. Methane was not detected throughout the incubation in samples amended with sulfate. The increase in AVS supports sulfide incorporation into the solid phase, however, the plateau after 39 d suggests a secondary fate of reduced sulfide.


Nonsurgical treatment of osteoarticular tuberculosis. A retrospective study in 143 adults.
Data are sparse on nonsurgical treatments currently used for osteoarticular tuberculosis in industrialized countries. We conducted a multicenter retrospective study in the Paris urban area, France, in 206 cases of osteoarticular tuberculosis documented by examination of a local specimen. This article reports our findings in the 143 patients who were followed up at least until treatment completion. Mean follow-up after treatment completion was 16 months. Seventy-five (52%) patients had spondylitis and 68 (48%) did not. The number of antituberculous agents used during the initial treatment phase was four in 65% of cases and three in 35%. In the spondylitis subgroup, mean (+/- SD) antibiotic therapy duration was 14.7 +/- 3.4 months, and 25% of patients required surgery; 3% of patients died, 1% suffered a relapse, and 96% achieved a full recovery with no relapse. In the nonspondylitis subgroup, mean antibiotic therapy duration was 13 +/- 3 months and 29% of patients required surgery. The only HIV-positive patient had osteitis of the calcaneus with a relapse that led to discovery of secondary rifampin resistance. Based on our findings and on data from the literature, we believe that 12 months is a reasonable duration for antituberculous therapy in osteoarticular tuberculosis, including tuberculous spondylitis.


Risk factors and frequency of acute and permanent femoral arterial occlusion in neonates with CHD who undergo ultrasound-guided femoral arterial access.
We investigated frequency and risk factors of acute loss of the arterial pulse and permanent femoral arterial occlusion in neonates with CHD who underwent ultrasound-guided femoral arterial access. We divided the patients into groups according to the presence of acute loss of the arterial pulse and permanent femoral arterial occlusion. We obtained data related to patient characteristics and access variables of ultrasound-guided femoral arterial access from our database of cardiac catheterisation between August, 2017 and May, 2021. We used an echocardiography-S6, 12-MHz linear probe, 21-gauge needle, 0.018"guidewire, and a 4F sheath for arterial access. Ultrasound-guided femoral arterial access was obtained in 323 (98.8%) of the 327 neonates. We identified acute loss of the arterial pulse in 130 (40.2%) patients and permanent femoral arterial occlusion in 19 (5.9%) patients. Median weight was 3.05 (Interquartile range (IQR): 2.80-3.40) kg, first attempt success rate was 88.2%, and median access time was 46 sec (IQR: 23-94). Logistic regression analysis identified coarctation of the aorta (odds ratio: 2.46; 95% CI: 1.30-4.66; p = 0.006) as independent risk factor for acute loss of the arterial pulse, but did not identify any independent risk factors for permanent femoral arterial occlusion. This study showed coarctation of the aorta as an independent risk factor for acute loss of the arterial pulse, but did not identify any independent factors for permanent femoral arterial occlusion in neonates with CHD. Although most cases of acute loss of the arterial pulse resolve in the early period, the frequency of permanent femoral arterial occlusion remains high despite effective treatment.


Amiodarone-induced pulmonary toxicity in an adolescent.
We report amiodarone-induced pulmonary toxicity in an 18-year-old boy who had undergone corrective surgery for tetralogy of Fallot 4 years earlier, and was treated with amiodarone because of recurrent malignant postoperative ventricular tachyarrhythmias. Toxicity was recognized on the basis of clinical features, chest X-ray, high-resolution contrast enhanced computerized tomography, and resolution of the findings subsequent to withdrawal of amiodarone and treatment with steroids. Pulmonary toxicity due to amiodarone, as far as we know, has not been reported in children and young adults, and its occurence even in young adults requires wider appreciation.


Recombinant adeno-associated virus-mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis type VII mouse.
The central nervous system (CNS) is a predominant site of involvement in several lysosomal storage diseases (LSDs); and for many patients, these diseases are diagnosed only after the onset of symptoms related to the progressive accumulation of macromolecules within lysosomes. The mucopolysaccharidosis type VII (MPS VII) mice are deficient for the lysosomal enzyme beta-glucuronidase and, by early adulthood, develop a significant degree of glycosaminoglycan storage within neuronal, glial, and leptomeningeal cells. Using this animal model, we investigated whether gene transfer mediated by a recombinant adeno-associated virus (rAAV) vector is capable of reversing the progression of storage lesions within the CNS. Adult MPS VII mice received intracerebral injections of 4 X 10(7) infectious units of a rAAV vector carrying the murine beta-glucuronidase (gus-s(a)) cDNA under the transcriptional direction of the cytomegalovirus immediate-early promoter and enhancer. By 1 month after vector administration, transgene-derived beta-glucuronidase was present surrounding the injection site. Enzyme levels were between 50 and 240% of that found in wild-type mice. This level of beta-glucuronidase activity was sufficient to reduce the degree of lysosomal storage. Moreover, the reduction in storage was maintained for at least 3 months post-rAAV administration. These data demonstrate that rAAV vectors can transduce the diseased CNS of MPS VII mice and mediate levels of transgene expression necessary for a therapeutic response. Thus, rAAV vectors are potential tools in the treatment of the mucopolysaccharidoses and other lysosomal storage diseases.


The Influence of Nesfatin-1 on Bone Metabolism Markers Concentration, Densitometric, Tomographic and Mechanical Parameters of Skeletal System of Rats in the Conditions of Established Osteopenia.
Our study aimed to evaluate the impact of nesfatin-1 administration on bone metabolism and properties in established osteopenia in ovariectomized female rats. In total, 21 female Wistar rats were assigned to two groups: sham-operated (SHAM, n = 7) and ovariectomized (OVA, n = 14). After 12 weeks of osteopenia induction in the OVA females, the animals were given i.p. physiological saline (OVA, n = 7) or 2 µg/kg body weight of nesfatin-1(NES, n = 7) for the next 8 weeks. The SHAM animals received physiological saline at the same time. Final body weight, total bone mineral density and content of the skeleton were estimated. Then, isolated femora and tibias were subjected to densitometric, tomographic, and mechanical tests. Bone metabolism markers, i.e., osteocalcin, bone specific alkaline phosphatase (bALP), and crosslinked N-terminal telopeptide of type I collagen (NTx) were determined in serum using an ELISA kit. Ovariectomy led to negative changes in bone metabolism associated with increased resorption, thus diminishing the densitometric, tomographic, and mechanical parameters. In turn, the administration of nesfatin-1 led to an increase in the value of the majority of the tested parameters of bones. The lowest bALP concentration and the highest NTx concentration were found in the OVA females. The bALP concentration was significantly higher after nesfatin-1 administration in comparison to the OVA rats. In conclusion, the results indicate that nesfatin-1 treatment limits bone loss, preserves bone architecture, and increases bone strength in condition of established osteopenia.


Morphological Asymmetries Profile and the Difference between Low- and High-Performing Road Cyclists Using 3D Scanning.
The aims of this study are: (1) to identify morphological asymmetries in road cycling by using a novel 3D scanning method and electrical bioimpedance, (2) to investigate possible asymmetries in road cyclists of low (LPG) and high (HPG) performance group, (3) to compare the number of morphological asymmetries between HPG and LPG of cyclists, and (4) to explore correlations between asymmetry scores and competition performance. Body composition and 3D anthropometric measurements were conducted on 48 top-level male road cyclists (178.98 ± 5.39 cm; 68.37 ± 5.31 kg) divided into high (n = 22) and low (n = 26) performance groups. Competition performance (CP) is represented through racing points gathered at the end of the competition season. The latter was used to divide road cyclists into low- and high-performing groups. One-way ANOVA was used to determine differences between groups, while paired-samples T-test and Absolute Asymmetry index (AA) were calculated (p ≤ 0.05) for paired variables inside the groups, and the Spearman correlation coefficient was used to explore correlations between AA and CP. Results showed statistically significant differences between the left and right side of different body segments (16 paired variables) among low-performing road cyclists in five paired variables of the upper body: elbow girth (4.35, p = 0.000), forearm girth (6.31, p = 0.000), arm surface area (2.54, p = 0.018), and arm volume (2.71, p = 0.012); and six paired variables of the lower body: leg lean mass (5.85, p = 0.000), leg length (3.04, p = 0.005), knee girth (4.93, p = 0.000), calf girth (5.25, p = 0.000), leg surface area (4.03, p = 0.000), and leg volume (5.3, p = 0.000). Altogether, the high-performing group of road cyclists statistically differed only in 2 out of 16 paired variables of the upper body: elbow girth (4.93, p = 0.000) and in forearm girth (5.12, p = 0.000). Low- and high-performing groups were statistically significantly different in the asymmetry of leg lean mass F(1,46) = 6.25, p = 0.016 and asymmetry of the calf girth F(1,46) = 7.44, p = 0.009. AA of calf girth on the total sample (n = 48) showed a significant correlation with CP (r = -0.461; p = 0.001). In conclusion, the study's main finding was that high-performance road cyclists are more symmetrical than the low-performance group, for which it is significant to have a higher amount of morphological asymmetries.


[A Systematical Review of Researches on Oxygen Specificity in the Acupoint Area].
Oxygen, an important substance for metabolism, and its related nitric oxide (NO) and carbon dioxide (CO2) play a key role in regulating physiological activities. The study on the characteristics of oxygen in the acupoint region has been being conducted for nearly 30 years. In the present paper, the authors review recent development of researches on changes of partial oxygen pressure (PO2), NO, and CO2 levels in the acupoint regions. Some researches demonstrated that the PO2, CO2 and NO contents are relatively higher in some acupoints as Zusanli (ST 36), etc. in comparison with the neighbor tissues or non-acupoints under normal and pathological states in severe infection patients and rats. After acupuncture stimulation, CO2 and NO contents were increased, while PO2 content was increased or lowered in some acupoints not in non-acupoints. However, there were also some arguments about the conclusions of acupoint oxygen specificity. In order to verify the results of acupoint oxygen specificity researches, more attentions should be paid to the precise experimental design, repeatable experimental conditions, homogeneity of subjects, human body observation, Deqi effect of acupuncture needle manipulation, etc. in the future studies.


Diode laser ablation of a tracheal osteochondroma in a dog.
A mass almost completely obstructing the tracheal lumen was detected during endoscopic investigation of dyspnoea in a four-month-old golden retriever. Histopathology was consistent with osteochondroma. The lesion was ablated using endoscopic diode laser ablation.


Tetrodotoxin: sodium channel specific anti-arrhythmic activity.
Many Class I anti-arrhythmic drugs not only block the cardiac sodium channel but also block the calcium and/or potassium channels. The hypothesis tested in this study was that sodium channel blockade without blockade of calcium or potassium channels produced anti-arrhythmic activity in the treatment of malignant ventricular arrhythmias. The arrhythmia model consists of ventricular fibrillation induced by critically timed single extrastimuli at twice diastolic pacing threshold following 15 minutes of ischaemic injury in a rabbit heart perfused in vitro. Preparations were randomly assigned to either tetrodotoxin (a selective sodium channel blocking toxin) or vehicle. Ventricular fibrillation occurred in all vehicle treated preparations in response to single extrastimuli following ischaemic injury. Treatment with tetrodotoxin at concentrations of 0.1 to 1.0 micromolar protected some hearts from fibrillation, while at concentrations above 3 micromolar ventricular fibrillation was not inducible. Tetrodotoxin produced concentration dependent increases in ventricular effective refractory period and conduction time in the infarct zone which were associated with anti-arrhythmic activity. No concentration dependent change in action potential duration was seen with tetrodotoxin. Thus the electrophysiological and anti-arrhythmic activities of tetrodotoxin in this model demonstrate that the property of selective sodium channel blockade is sufficient to produce anti-arrhythmic activity.


Functionally impaired isoforms regulate TMPRSS6 proteolytic activity.
TMPRSS6 is a type II transmembrane serine protease involved in iron homeostasis expressed as 4 isoforms in humans. TMPRSS6 isoform 2 downregulates hepcidin production by cleaving hemojuvelin and other surface proteins of hepatocytes. The functions of catalytically impaired isoforms 3 and 4 are still unknown. Here we demonstrate that TMPRSS6 isoforms 3 and 4 reduce the proteolytic activity of isoform 2 and uncover the ability of isoforms to interact. Moreover, we identified 49 potential protein partners common to TMPRSS6 isoforms, including TfR1, known to be involved in iron regulation. By co-expressing TMPRSS6 and TfR1, we show that TfR1 is cleaved and shed from the cell surface. Further, we demonstrate that TMPRSS6 isoforms 3 and 4 behave as dominant negative.


Synthesis of Polystyrene-Coated Superparamagnetic and Ferromagnetic Cobalt Nanoparticles.
Polystyrene-coated cobalt nanoparticles (NPs) were synthesized through a dual-stage thermolysis of cobalt carbonyl (Co₂(CO)₈). The amine end-functionalized polystyrene surfactants with varying molecular weight were prepared via atom-transfer radical polymerization technique. By changing the concentration of these polymeric surfactants, Co NPs with different size, size distribution, and magnetic properties were obtained. Transmission electron microscopy characterization showed that the size of Co NPs stabilized with lower molecular weight polystyrene surfactants (Mn = 2300 g/mol) varied from 12⁻22 nm, while the size of Co NPs coated with polystyrene of middle (Mn = 4500 g/mol) and higher molecular weight (Mn = 10,500 g/mol) showed little change around 20 nm. Magnetic measurements revealed that the small cobalt particles were superparamagnetic, while larger particles were ferromagnetic and self-assembled into 1-D chain structures. Thermogravimetric analysis revealed that the grafting density of polystyrene with lower molecular weight is high. To the best of our knowledge, this is the first study to obtain both superparamagnetic and ferromagnetic Co NPs by changing the molecular weight and concentration of polystyrene through the dual-stage decomposition method.


Production of anti-P1A monoclonal antibodies.
Two peptides corresponding to the sequence of platelet glycoprotein IIIa between serine 27 and arginine 37 were synthesized and used to produce monoclonal antibodies. These two synthetic peptides were identical except for a single substitution at position 33, where a Pro/Leu polymorphism was shown to occur in human platelets and was predicted to be responsible for the P1A1-P1A2 alloantigen system (Newman et al., J. Clin Invest 1989:83:1778-81). Two monoclonal antibodies named 3C1 for the anti-"P1A1 peptide" and AD3 for the anti-"P1A2 peptide" were characterized. These monoclonal antibodies interacted with the two allelic forms of the reduced glycoprotein IIIa. They were used to type P1A1 and P1A2 homozygote as well as heterozygote platelets. Thus these two immunoprobes confirm that the Pro-Leu substitution is associated with the P1A1-P1A2 alloantigenic system. Although they interact only with reduced glycoprotein IIIa, these antibodies can be used to design simple tests for the typing of the P1A status of patients.


Altered emotional and BOLD responses to negative, positive and ambiguous performance feedback in OCD.
While abnormal processing of performance feedback has been associated with obsessive-compulsive disorder (OCD), neural responses to different kinds of feedback information, especially to ambiguous feedback are widely unknown. Using fMRI and a performance adaptive time-estimation task, we acquired blood oxygenation level-dependant responses and emotional ratings to positive, negative and ambiguous performance feedback in patients and healthy controls. Negative and ambiguous feedback led to increased levels of anxiety, guilt and shame in patients. Both negative and ambiguous feedback, as compared to positive feedback, induced increased activation of the insular cortex in patients. Furthermore, patients showed no differential activation to negative feedback in the putamen and to ambiguous feedback in the ventromedial prefrontal cortex (VMPFC). Finally, negative feedback induced increased activation in the midcingulate cortex in patients compared to controls. Findings indicate that both negative and ambiguous performance feedbacks are associated with abnormal negative emotions and altered brain activation, in particular increased insula activation, while activation in the putamen and VMPFC does not differentiate between feedback types in OCD patients. This suggests a parallel pattern of increased and decreased neural sensitivity to different kinds of feedback information and a general emotional hyperresponsivity to negative and ambiguous performance feedback in OCD.


Motor unit reorganization in progressive muscular dystrophies and congenital myopathies.
The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration.


Selected mutations in the myosin binding protein C gene in the Polish population of patients with hypertrophic cardiomyopathy.
Mutations in the gene of myosin binding protein C (MYBPC3) are currently considered the most frequent cause of hypertrophic cardiomyopathy (HCM). To assess the frequency of selected mutations in MYBPC3 in the Polish population of HCM patients. One hundred eighteen patients with HCM and 118 healthy, age and sex-matched controls were screened for the presence of 14 mutations of MYBPC3 using real time polymerase chain reaction. Five different mutations were found in six patients in the HCM group whereas no mutations were present in the control group. In three cases the mutations were missense (Arg502Gln, Cys566Arg, Asn755Lys) and in three cases terminal (Gln425ter, Gln1061ter in two unrelated probands). Mutations in MYBPC3 should be considered a frequent cause of HCM in Poland.


Enzalutamide and Apalutamide: In Vitro Chemical Reactivity Studies and Activity in a Mouse Drug Allergy Model.
Enzalutamide and apalutamide are two androgen receptor inhibitors approved for the treatment of castration-resistant prostate cancer (CRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC), respectively. Apalutamide is associated with an increased incidence of skin rash above the placebo groups in the SPARTAN trial in nmCRPC and in the TITAN trial in metastatic castration-sensitive prostate cancer patients. On the contrary, the rate of skin rash across all clinical trials (including PROSPER [nmCRPC]) for enzalutamide is similar to the placebo. We hypothesized that the apalutamide-associated increased skin rash in patients could be linked to a structural difference. The 2-cyanophenyl and dimethyl moieties in enzalutamide are substituted in apalutamide with 2-cyanopyridine and cyclobutyl, respectively. In our evaluations, the 2-cyanopyridine moiety of apalutamide was chemically reactive with the thiol nucleophile glutathione, resulting in rearranged thiazoline products. Radiolabeled apalutamide, but not radiolabeled enzalutamide, was shown to react with mouse and human plasma proteins. Thiol nucleophiles decreased the extent of covalent binding to the model protein bovine serum albumin, whereas amine and alcohol nucleophiles had no effect, suggesting reactivity with cysteine of proteins. Subcutaneous administration of apalutamide dose dependently increased lymphocyte cellularity in draining lymph nodes in a mouse drug allergy model (MDAM). Enzalutamide, and its known analogue RD162 in which the cyanophenyl was retained but the dimethyl was replaced by cyclobutyl, demonstrated substantially less covalent binding activity and negative results in the MDAM assay. Collectively, these data support the hypothesis that the 2-cyanopyridine moiety in apalutamide may react with cysteine in proteins forming haptens, which may trigger an immune response, as indicated by the activity of apalutamide in the MDAM assay, which in turn may be leading to increased potential for skin rash versus placebo in patients in the SPARTAN and TITAN clinical trials.


[Animal models of psychiatric disorder and their validity--from the perspective of behavioral pharmacology].
Animal models of psychiatric disorders are indispensable tools to gain insights into neural mechanisms underlying these disorders and to assess potential therapeutic actions of novel compounds in preclinical settings. However, it is difficult to establish appropriate animal models for these disorders because there is no proof on whether or not what occurs in the animal brain is comparable to what occurs in the human brain. The initial development of animal models of psychiatric disorders is often based on "face validity" as reflected in the similarity of behavioral signs and symptoms observed in humans and animal and subsequently based on "construct validity" as measured by strong correlation in behaviors and neural events between the animal model and patients of the disorder. The practical value of such animal models is reflected ultimately in their "predictive validity" in predicting the therapeutic efficacy of new treatments for psychiatric disorders. The present review will focus on animal models of schizophrenia and depression by the use of mainly environmental stress and pharmacological treatments, which are expected to induce signs and symptoms analogous to those of patients with such disorders.


Simultaneous detection of Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae by quantitative PCR from CSF samples with negative culture in Morocco.
Bacteriological cultures from cerebrospinal fluids (CSF) have less sensitivity and specificity compared to quantitative PCR (RT-PCR), and multiple facts still conduct to the increase of negative culture. The aims of this study are to determine the molecular epidemiology and the simultaneous detection of bacterial meningitis in Morocco by using RT-PCR and compared this molecular approach with culture method to improve the etiological diagnosis of meningitis. The CSFs were collected over one-year period in 2018 in different hospitals covering all regions of the Kingdom of Morocco, from patients with suspected meningitis. The results showed the confirmation rate per culture recorded a rate of 33% and the RT-PCR of 70%. Molecular epidemiology is predominant of Neisseria meningitidis followed by Streptococcus pneumoniae and a dramatic reduction in meningitis due to Haemophilus influenzae following the introduction of conjugate vaccine in 2007. Also, the epidemiological profile shows a sex ratio M/F of 1.4 and a median age of 2 years. The national distribution showed a predominant of meningococcal disease followed by pneumococcal disease, especially a dominance of N. meningitidis over S. pneumoniae in two regions and a slight predominance of S. pneumoniae in the other two regions over N. meningitidis. Our research shows that culture in our country has less sensitivity and specificity than RT-PCR in diagnosis of bacterial meningitis and that molecular biology technique at bacteriology laboratories is desirable for diagnosis, early management of meningitis cases and in the context of the surveillance of meningitis in Morocco in parallel with culture.


In vitro ferredoxin-dependent desaturation of fatty acids in cyanobacterial thylakoid membranes.
Thylakoid membranes isolated from the cyanobacterium Synechocystis sp. strain PCC6803 were capable of desaturating the acyl groups in monogalactosyl diacylglycerol. This desaturation reaction required the reduced form of ferredoxin.


Investigating severe neutropenia with a simple bone marrow immunofluorescence test.
Severely neutropenic patients who are suspected of having circulating autoantibodies to neutrophils and/or myeloid precursors present a diagnostic problem. This report describes the use of a simple bone marrow immunofluorescence test (BMIFT) to demonstrate autoantibodies reactive with the patient's own bands, neutrophils and myeloid precursors represented on fresh-frozen bone marrow aspirate smears. Positive results were seen in two of 13 evaluable marrows from children with primary neutropenia and in eight of 44 evaluable marrows from adults with primary or secondary neutropenia. The BMIFT is simple enough to perform in most laboratory environments and provides serological information to support a diagnosis of immune neutropenia when other means of investigation are precluded.


Disinhibition-Induced Delayed Onset of Epileptic Spike-Wave Discharges in a Five Variable Model of Cortex and Thalamus.
Based on a modified neural field network model composed of cortex and thalamus, we here propose a computational framework to investigate the onset control of absence seizure, which is characterized by the spike-wave discharges. Firstly, we briefly demonstrate the existence of various transition types in Taylor's model by increasing the thalamic input. Furthermore, after the disinhibitory function is reasonably introduced into the Taylor's model, we can observe the occurrence of various transition states of firing patterns with different dominant frequencies as the thalamic input is varied under different disinhibitory effects onto the pyramidal neural population. Interestingly, it is found that the onset of spike-wave discharges can be delayed as the disinhibitory input is considered. More importantly, we explore bifurcation mechanism of firing transitions as some key parameters are changed. And also, we observe other dynamical states, such as simple oscillations and saturated discharges with different spatial scales, which are consistent with previous theoretical or experimental findings.


Non-alcoholic fatty pancreas disease as a risk factor for pancreatic cancer based on endoscopic ultrasound examination among pancreatic cancer patients: A single-center experience.
Non-alcoholic fatty pancreas disease (NAFPD) is a disease that ranges from simple steatosis and can further lead to chronic pancreatitis and possible pancreatic cancer development. Its exact pathogenesis and impact on clinical practice are still largely unknown. Pancreatic cancer is still the most lethal malignancy in the world. Studies about the relationship between NAFPD and pancreatic cancer are still lacking. This study aims to find the possible role of endoscopic ultrasound (EUS) examination as a screening tool in NAFPD patients based on EUS examination among pancreatic cancer patients. EUS hospital data were collected within a 2-year period, and all patients who underwent EUS procedures were analyzed. Pancreatic malignancy was diagnosed based on imaging and tumor markers and cytopathology using the endoscopic ultrasound fine needle aspiration (EUS-FNA) procedure. Patients with pre-existing pancreatic diseases, significant alcohol consumption, or other primary cancer with metastasis to the pancreas were excluded. Statistical analysis was performed using SPSS version 23.0. In total, 162 patients (75 females and 87 males) were recruited for database analysis.^ Pancreatic malignancy was found in 43 (26.5%) patients, whereas fatty pancreas was found in 53 (32.7%) patients, and this was commonly found among pancreatic cancer patients.^ Based on logistic regression analysis, factors such as age, gender, diabetes, and chronic pancreatitis were not found to be significant risk factors for pancreatic malignancy where fatty pancreas is the only significant risk factor for pancreatic cancer (odds ratio: 18.027 [95% CI: 7.288-44.588]). Prevalence of NAFPD among pancreatic cancer patients is high. Future studies can be conducted to show whether EUS can be considered a screening tool for the early detection of pancreatic malignancy in NAFPD patients; a cohort prospective study might also be needed to show clear causality between fatty pancreas and pancreatic cancer.


Electromyogram-based method to secure wireless body sensor networks for rehabilitation systems.
Wireless body sensor networks (WBSNs) provide a platform to track and monitor human health status as well as feedback to the user by capturing and processing certain physiological signals. Since WBSNs need to provide efficient health information privacy, their security has been identified as one of the major challenges, especially for rehabilitation systems. Conventionally, the random numbers (RNs) based on the inter-pulse intervals (IPIs) from electrocardiogram (ECG) recordings have been widely used to secure the data in WBSNs. However, this method is limited in real-time applications such as human posture control. In this study, we proposed a novel electromyogram (EMG) based RN generation method to secure the data acquired from WBSNs systems for rehabilitation. The newly proposed security scheme was tested on EMG signals acquired from 15 healthy subjects by using EMG features. These features were coded into 128-bit RNs with entropy values ranging from 0.96 to 1.00, and hamming distances (HDs) that ranged from 41 to 83. These preliminary results showed that randomness and distinctiveness of those RNs are good enough for authentication and encryption. Findings from the current study suggest that the EMG-based RN generation method would be potential in securing the health information in WBSNs.


In vitro and in vivo assessment of a novel ultra-flexible ventriculoamniotic shunt for treating fetal hydrocephalus.
Fetal aqueductal stenosis (AS) is one of the most common causes of congenital hydrocephalus, which increases intracranial pressure due to partial or complete obstruction of cerebrospinal fluid (CSF) flow within the ventricular system. Approximately 2-4 infants per 10,000 births develop AS, which leads to progressive hydrocephalus, which enlarges the head often necessitating delivery by cesarean section. Most babies born with AS are severely neurologically impaired and experience a lifetime of disability. Therefore, a new device technology for venticuloamniotic shunting is urgently needed and has been studied to ameliorate or prevent fetal hydrocephalus development, which can provide a significant impact on patients and their family's quality of life and on the decrease of the healthcare dollars spent for the treatment. This study has successfully validated the design of shunt devices and demonstrated the mechanical performance and valve functions. A functional prototype shunt has been fabricated and subsequently used in multiple in vitro tests to demonstrate the performance of this newly developed ventriculoamniotic shunt. The shunt contains a main silicone-nitinol composite tube, a superelastic 90° angled dual dumbbell anchor, and an ePTFE valve encased by a stainless-steel cage. The anchor will change its diameter from 1.15 mm (collapsed state) to 2.75 mm (deployed state) showing up to 1.4-fold diameter change in human body temperature. Flow rates in shunts were quantified to demonstrate the valve function in low flow rates mimicking the fetal hydrocephalus condition showing "no backflow" for the valved shunt while there is up to 15 mL/h flow through the shunt with pressure difference of 20 Pa. In vivo ovine study results show the initial successful device delivery and flow drainage with sheep model.


catena-Poly[(E)-4,4'-(ethane-1,2-di-yl)dipyridinium [[bis-(thio-cyanato-κN)ferrate(II)]-di-μ-thio-cyanato-κN:S;κS:N]].
In the crystal structure of the title compound, {(C(12)H(14)N(2))[Fe(NCS)(4)]}(n), the iron(II) cation is coordinated by four N-bonded and two S-bonded thio-cyanate anions in a distorted octa-hedral coordination mode. The asymmetric unit consists of half an iron(II) cation and half a protonated (E)-4,4'-(ethane-1,2-di-yl)dipyridinium dication, each located on a centre of inversion. In addition, there are two thio-cyanate anions in general positions. The crystal structure consists of Fe-(NCS)(2)-Fe chains in which each iron(II) cation is additionally coordinated by two terminal N-bonded thio-cyanate anions. Non-coordinating dipyridinium dications are present between the thiocyanatoferrate(II) chains and are connected to the anions via N-H⋯N and N-H⋯S hydrogen-bond interactions.


Current Status of Air Toxics Management and Its Strategies for Controlling Emissions in Taiwan.
Since the 1970s, hazardous air pollutants (HAPs), so-called air toxics, have been of great concern because they can cause serious human health effects and have adverse effects on the environment. More noticeably, some of them are known to be human carcinogens. The objective of this paper is to investigate the regulatory systems and human health effects of air toxics which have been designated by the Taiwan government under the Air Pollution Control Act. These toxic air pollutants include acutely toxic gas (i.e., ammonia, chlorine, fluorides, hydrochloric acid, hydrogen cyanide, hydrogen sulfide, nitric acid, phosphoric acid and sulfuric acid), gas containing heavy metals, and carcinogenic chemicals (including formaldehyde, vinyl chloride, asbestos and matter containing asbestos, dioxins and furans, volatile organic compounds, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls). In line with international concern about the carcinogenic risk and environmental persistence of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs/PCDFs) and heavy metals in recent years, the current status in monitoring and reducing the emissions of PCDDs/PCDFs from stationary sources was analyzed as a case study in the present study. Furthermore, the control strategies for reducing emissions of air toxics from stationary sources in Taiwan were also addressed.


Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study.
Eosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co-occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20-80 mg/day), methotrexate (6-10 mg/week), cyclosporin (100-150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first-line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.


Evaluating peptide repertoires within the context of thymocyte development.
The process of antigen presentation by MHC molecules allows T cells to sample the proteins expressed within a particular cell. This sampling is in the form of short peptides bound within the grooves of MHC molecules displayed on the surface of cells. In the context of immune surveillance, this presentation allows the identification of infected cells by displaying peptides originating from foreign proteins within the cell. However, MHC-bound peptides play additional roles beyond serving as antigenic stimuli during an immune response. In fact, it has become clear that MHC-bound peptides derived from self proteins are critically involved in the development of T cells during selective events in the thymus. In this review we will discuss the nature of the population of MHC-bound peptides as it relates to thymocyte development, with particular emphasis on the recent finding that peptide-MHC complexes present at low levels can drive the positive selection of thymocytes.


Establishment of three heterogeneous subtypes and a risk model of low-grade gliomas based on cell senescence-related genes.
Cellular senescence is a key element in the occurrence and progression of a variety of tumors. As a result, cellular senescence-related markers can be categorized based on the prognosis status of patients. Due to the heterogeneity and the complexity of the tumor microenvironment (TME), the long-term effectiveness of low-grade glioma (LGG) treatment remains a clinical challenge. Consequently, developing and refining effective treatment approaches to aid with LGG management is critical. Based on the expressions of cell senescence-related genes (CSRGs) acquired from the cellAge database, consensus clustering was utilized to identify stable molecular subtypes. Clinical features, immune infiltration, route modifications, and genetic changes of various subtypes were also assessed. Following that, the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis were used for developing the cell senescence-related risk score (CSRS) model. Finally, a correlation study of the CSRS model with molecular, immunological, and immunotherapy parameters was performed. C1, C2, and C3, are the three senescence-related subtypes that were identified. Patients belonging to the C1 subtype had poor prognoses and a substantial proportion of them was in the grade G3. The differentially expressed genes (DEGs) among the three subtypes were used to develop the CSRS model. In both the training and independent validation cohort, the model had a high area under the receiver operating characteristic (ROC) curve in predicting the overall survival (OS) of patients. As a result, this model can predict clinical features and responses to immunotherapy in a variety of patients and it is a potential independent prognostic factor for LGG. This research discovered three LGG subtypes related to cell senescence and created a CSRS model for six genes. Cell senescence was highly associated with unfavorable prognosis in LGG. The CSRS model can be used to predict the prognosis of patients and identify patients who would benefit from immunotherapy.


Zero-point corrections and temperature dependence of HD spin-spin coupling constants of heavy metal hydride and dihydrogen complexes calculated by vibrational averaging.
Vibrational corrections (zero-point and temperature dependent) of the H-D spin-spin coupling constant J(HD) for six transition metal hydride and dihydrogen complexes have been computed from a vibrational average of J(HD) as a function of temperature. Effective (vibrationally averaged) H-D distances have also been determined. The very strong temperature dependence of J(HD) for one of the complexes, [Ir(dmpm)Cp*H2]2 + (dmpm = bis(dimethylphosphino)methane) can be modeled simply by the Boltzmann average of the zero-point vibrationally averaged JHD of two isomers. For this complex and four others, the vibrational corrections to JHD are shown to be highly significant and lead to improved agreement between theory and experiment in most cases. The zero-point vibrational correction is important for all complexes. Depending on the shape of the potential energy and J-coupling surfaces, for some of the complexes higher vibrationally excited states can also contribute to the vibrational corrections at temperatures above 0 K and lead to a temperature dependence. We identify different classes of complexes where a significant temperature dependence of J(HD) may or may not occur for different reasons. A method is outlined by which the temperature dependence of the HD spin-spin coupling constant can be determined with standard quantum chemistry software. Comparisons are made with experimental data and previously calculated values where applicable. We also discuss an example where a low-order expansion around the minimum of a complicated potential energy surface appears not to be sufficient for reproducing the experimentally observed temperature dependence.


Transferable imipenem resistance in Pseudomonas aeruginosa.
We isolated an imipenem-resistant strain, GN17203, of Pseudomonas aeruginosa. The strain produced a beta-lactamase that hydrolyzed imipenem. The beta-lactamase was encoded by a 31-MDa plasmid, pMS350, which belongs to incompatibility group P-9. The plasmic conferred resistance to beta-lactams, gentamicin, and sulfonamide and was transferable by conjugation to P. aeruginosa but not to Escherichia coli. The molecular weight of the purified enzyme was estimated to be 28,000, and the isoelectric point was 9.0. The enzyme showed a broad substrate profile, hydrolyzing imipenem, oxyiminocephalosporins, 7-methoxycephalosporins, and penicillins. The enzyme activity was inhibited by EDTA, iodine, p-chloromercuribenzoate, CuSO4, and HgCl2 but not by clavulanic acid or sulbactam.


Treatment of PTSD by eye movement desensitization reprocessing (EMDR) improves sleep quality, quality of life, and perception of stress.
The impact of posttraumatic stress disorder (PTSD) on the sleep of patients is widely reported. However, the parameters that can be altered are not the same for all patients. Some studies report an impairment of sleep maintenance and recurrent nightmares, while others failed to find such alterations. Among the many treatments, the eye movement desensitization reprocessing (EMDR) is a therapy used specifically to treat PTSD and general trauma. The purpose of this study was to examine whether EMDR treatment can improve PTSD symptoms, such as sleep, depression, anxiety, and poor quality of life.


Large Tunneling Magnetoresistance in VSe2/MoS2 Magnetic Tunnel Junction.
Two-dimensional (2D) van der Waals (vdW) materials provide the possibility of realizing heterostructures with coveted properties. Here, we report a theoretical investigation of the vdW magnetic tunnel junction (MTJ) based on VSe2/MoS2 heterojunction, where the VSe2 monolayer acts as a ferromagnet with room-temperature ferromagnetism. We propose the concept of spin-orbit torque (SOT) vdW MTJ with reliable reading and efficient writing operations. The nonequilibrium study reveals a large tunneling magnetoresistance of 846% at 300 K, identifying significantly its parallel and antiparallel states. Thanks to the strong spin Hall conductivity of MoS2, SOT is promising for the magnetization switching of VSe2 free layer. Quantum-well states come into being and resonances appear in MTJ, suggesting that the voltage control can adjust transport properties effectively. The SOT vdW MTJ based on VSe2/MoS2 provides desirable performance and experimental feasibility, offering new opportunities for 2D spintronics.


Solvent based hydrogen bonding: impact on poly(3-hexylthiophene) nanoscale morphology and charge transport characteristics.
We demonstrate that supramolecular assembly and subsequent enhancement of charge transport characteristics of conjugated polymers can be facilitated simply by adding small amounts of a more volatile poor solvent, which can hydrogen bond with the majority solvent. Addition of up to 2 vol % acetone to a precursor solution of poly(3-hexylthiophene) (P3HT) in chloroform leads to approximately a 4-fold increase in P3HT field-effect mobility. The improvement is associated with hydrogen bonding interactions between acetone and chloroform which decrease the evaporation rate of the mixed solvent. P3HT is less soluble in the binary solvent than in the more readily vaporized chloroform component, and this characteristic enables the supramolecular assembly of P3HT chains at the nanoscale. Two-dimensional molecular ordering of the polymer film was controlled by varying the quantity of poor solvent added to the precursor solution, and the correlation between field-effect mobility and molecular ordering was investigated. Hansen solubility parameters were used to systematically understand how the solvent mixture enhances the alignment and assembly of polymer chains and influences subsequent thin film properties. The value of the relative energy difference (RED) of the solvent with respect to P3HT increased from less than 1 to more than 1 during film formation, which indicates that the solvent characteristics are initially those of a good solvent but transform into those of a poor dissolution medium. A mechanistic illustration of the molecular ordering process during film formation is postulated.


Gene therapy for head and neck cancer.
Head and neck cancer continues to present a major therapeutic challenge to physicians. Recent advances in molecular or gene therapy have allowed us to reassess these malignancies and consider novel strategies for their management. Since the first clinical trial 5 years ago, it has become apparent that gene transfer is no longer a speculative approach for treating malignancies. Gene therapy involves the introduction of genetic material (DNA) into host cells to induce the expression of the therapeutic product of that gene. This review summarizes the most recent data concerning the use of gene therapy as a treatment strategy for head and neck solid malignancies. A brief overview of the basic concepts of gene therapy as well as future potential applications is also discussed.


[Iodine deficiency and pregnancy].
Iodine availability for maternal thyroid during pregnancy results from a combination of specific factors (increased urinary iodine loss, fetal-placental unit competition) and is critically reduced by the nutritional deficiency. Hyperestrogenism is associated with increased circulating thyroxine-binding globulin (TBG) levels and a higher binding capacity for T4 and T3, because of a reduced clearance rate of the protein. Our study carried out in a moderately iodine deficiency area from North-Eastern Sicily in pregnant women showed a inadequate synthesis of T4 not proportional to the increased TBG levels. The progressive decrease T4/TBG molar ratio implies the reduction of serum FT4 and the consequently increase of serum TSH. At delivery, about 70% of women showed a critical and transient biochemical hypothyroidism. Mental impairment and neurosensorial and neuromuscular disorders were observed in children born from those women. Therefore, short-term iodine prophylaxis with iodized salt in pregnant women does not correct nor prevent maternal hypothyroxinemia. L-T4 treatment is thus often required.


(11)CH4 molecule production using a NaBH4 target for (11)C ion acceleration.
Solid-state materials suitable for use as proton irradiation targets were investigated for producing high-purity (11)CH4 molecules for heavy-ion cancer therapy. The radioactivity of gas produced by proton irradiation was measured for several target materials. Also, the radioactive molecular species of the produced gas were analyzed by radio gas chromatography. We found that 5 × 10(12) (11)C molecules could be collected by proton irradiation on a NaBH4 target. We also found that the (11)CH4 molecules were produced and collected directly from the irradiated target, owing to the hydrogen atoms bound in the solid-state NaBH4.


The 'horns' of a medical dilemma: Alexander the Great.
Retrospective 'diagnosis' of clinical disorders of famous historical figures has been of medical interest. In the absence of a patient's 'body', the validity of 'physical symptoms' and their interpretation by contemporary diagnostic criteria are questionable. When the symptoms have been gleaned from the patients's effigy which, as in the case of Alexander the Great, is submerged in legend, the enterprise becomes inherently hazardous. In the present paper, some of the conceptual problems underlying retrospective diagnoses will be identified. Then the use of iconographic records, such as numismatics and sculpture, to provide evidence of clinical symptoms will be shown to be highly misleading.


Diet and cognition in chronic liver disease.
The spectrum of neurocognitive impairment in cirrhosis spans a continuum of minimal hepatic encephalopathy (MHE) to overt hepatic encephalopathy (OHE), the pathophysiology of which remains incompletely understood. The current available evidence, however, suggests that nutrition plays an important role in its development and points to the fact that malnutrition increases the morbidity and mortality of patients with cirrhosis. This review incorporates recent findings published in the last 2 years within the evolution of evidence regarding the role dietary manipulation can play in the comprehensive management of patients with cirrhosis and cognitive dysfunction. In patients with cirrhosis it is important to prevent starvation physiology which occurs after few hours of caloric deprivation as compared to 3 days in noncirrhotics. This can be accomplished by making sure that cirrhotic patients have daily breakfast and a late evening snack. In addition, probiotics and symbiotics are well tolerated and improve cognitive function in patients with MHE. The long-time held belief that protein restriction is needed to improve encephalopathy has no scientific basis but remains widely practiced. Branched-chain amino acids supplement may be helpful in patients who continue to suffer from OHE despite treatment of precipitating events and pharmacologic treatment with lactulose and rifaximin. Preventing starvation physiology and supplementing the diet with prebiotics and symbiotics are helpful in patients with MHE.


Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection.
Glycogen synthase kinase-3beta (GSK-3beta) is a central component in many critical intracellular signaling mechanisms. These include the phosphatidylinositol 3-kinase/Akt cell survival pathway, which inhibits GSK-3beta activity. GSK-3beta itself inhibits the activation of several transcription factors, which are important cell survival factors, such as heat shock factor 1. These factors likely contribute to the recent revelation that GSK-3beta is a pro-apoptotic enzyme. Recently, lithium has been identified as a selective and direct inhibitor of GSK-3beta. Based on these findings, we have proposed that part of the neuroprotectant properties of lithium is due to its ability to inhibit GSK-3beta, and thus block the facilitation of apoptosis produced by GSK-3beta. Since several anticonvulsants recently have been shown to be effective mood stabilizers, we examined if these agents are capable of protecting cells from GSK-3beta-facilitated apoptosis. In addition to lithium, both valproic acid and lamotrigine, but not carbamazepine, provided protection from GSK-3beta-facilitated apoptosis in human neuroblastoma SH-SY5Y cells. These results demonstrate that several drugs therapeutic for bipolar disorder can provide neuroprotection by inhibiting the pro-apoptotic effects of GSK-3beta, providing new evidence that dysregulation of GSK-3beta may contribute to the pathophysiology of bipolar disorder.


Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy.
In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.


Crystal structure of a transcription factor, GerE (PaGerE), from spore-forming bacterium Paenisporosarcina sp. TG-14.
In cold and harsh environments such as glaciers and sediments in ice cores, microbes can survive by forming spores. Spores are composed of a thick coat protein, which protects against external factors such as heat-shock, high salinity, and nutrient deficiency. GerE is a key transcription factor involved in spore coat protein expression in the mother cell during sporulation. GerE regulates transcription during the late sporulation stage by directly binding to the promoter of cotB gene. Here, we report the crystal structure of PaGerE at 2.09 Å resolution from Paenisporosarcina sp. TG-14, which was isolated from the Taylor glacier. The PaGerE structure is composed of four α-helices and adopts a helix-turn-helix architecture with 68 amino acid residues. Based on our DNA binding analysis, the PaGerE binds to the promoter region of CotB to affect protein expression. Additionally, our structural comparison studies suggest that DNA binding by PaGerE causes a conformational change in the α4-helix region, which may strongly induce dimerization of PaGerE.


Evaluation of transplacental treatment for fetal congenital bradyarrhythmia: – nationwide survey in Japan –.
There are few large studies of fetal congenital bradyarrhythmia. The aim of the present study was to investigate the effects and risks of transplacental treatment for this condition. Using questionnaires, 128 cases of fetal bradyarrhythmia were identified at 52 Japanese institutions from 2002 to 2008. Of the 128 fetuses, 90 had structurally normal hearts. Among these 90 fetuses, 61 had complete atrioventricular block (CAVB), 16 had second-degree AVB, 8 had sinus bradycardia, and 5 had other conditions. The 61 CAVB fetuses were divided into those who did (n = 38) and those who did not (n = 23) receive transplacental medication. Monotherapy with β-sympathomimetics, steroid monotherapy, and combination therapy with these agents was given in 11, 5 and 22 cases, respectively. Beta-sympathomimetics improved bradycardia (P<0.001), but no medication could significantly improve the survival rate. Fetal hydrops was associated with a 14-fold increased risk of perinatal death (P = 0.001), and myocardial dysfunction was a significant risk factor for poor prognosis (P = 0.034). Many adverse effects were observed with steroid treatment, with fetal growth restriction increasing significantly after >10 weeks on steroids (P = 0.043). Treatment with β-sympathomimetics improved bradycardia, but survival rate did not differ significantly in fetuses with and without transplacental medication. It is recommended that steroid use should be limited to <10 weeks to avoid maternal and fetal adverse effects, especially fetal growth restriction and oligohydramnios.


Near-Infrared Photothermal Catalysis for Enhanced Conversion of Carbon Dioxide under Mild Conditions.
Enhanced conversion of carbon dioxide (CO2) for cycloaddition with epoxide derivatives is highly desired in organic synthesis and green chemistry, yet it is still a challenge to obtain satisfactory activity under mild reaction conditions of temperature and pressure. For this purpose, an unexploited strategy is proposed here by incorporating near-infrared (NIR) photothermal properties into multicomponent catalysts. Through the electrostatic adsorption of Co- or Ce-substituted polyoxometalate (POM) clusters on the surface of graphene oxide (GO) with covalently grafted polyethyleneimine (PEI), a series of composite catalysts POMs@GO-PEI are prepared. The structural and property characterizations demonstrate the synergistic advantages of the catalysts bearing Lewis acids and bases and local NIR photothermal heating from the GO matrix for dramatically enhanced CO2 cycloaddition. Noticeably, while the turnover frequency increases up to 2718 h-1, the heterogeneous catalysts exhibit photothermal stability and recyclability. With this method, the onsite NIR photothermal transformation becomes extendable to more green reaction processes.


Simultaneous analysis of cardiolipin and lipid A from Helicobacter pylori by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Cardiolipin (CL) is an anionic tetraacylphospholipid found in mammalian tissues, inner membrane of mitochondria and in the cytoplasmic membrane of Gram-positive and -negative bacteria. Lipid A is the principal structural component responsible for the range of biological activities of lipopolysaccharides. Here we report a MALDI-MS-based method for the sensitive simultaneous analysis of CL and lipid A from Helicobacter pylori cells. The sensitivity was demonstrated by the analysis of CL and lipid A from a single bacterial colony of in vitro grown H. pylori strain NCTC 11637 (ATCC 43504). We then characterized the CL and lipid A structures in H. pylori cells grown under three different conditions, on agar-horse blood plates, in liquid culture and ex vivo. The results revealed the presence of high amounts of myristic (C14:0) and 19-carbon cyclopropane (C19:0cyc) fatty acids. Alterations in CL structure were observed in H. pylori cells cultivated on plates as compared with the bacteria grown in broth culture. Furthermore, significant changes in lipid A acylation pattern were detected in H. pylori cells during formation of coccoids. In contrast, structural analysis of CL from ex vivo H. pylori cells recovered from the stomachs of infected Mongolian gerbils demonstrated only minor changes in acyl chain combination. This is the first report of simultaneous analysis of CL and lipid A from ex vivo cells of H. pylori.


The immune response to implant materials in humans.
The etiology of aseptic loosening of prosthetic joint replacement components is unclear. Implant materials have been considered biologically inert, but recently studies indicate that inflammatory reactions directed against the implanted materials may contribute to aseptic loosening. Data suggesting a progression from a simple inflammatory reaction to complex immune responses against the biomaterials are reviewed. The cellular responses to particles of polymethylmethacrylate, ultrahigh molecular weight polyethylene, and alloys of cobalt-chromium and titanium were assayed in vitro to determine cell proliferation in patients with underlying diagnoses of osteoarthrosis, rheumatoid arthritis, and avascular necrosis who had joint replacement. Control populations were provided by patients with similar diagnoses who were preoperative surgical candidates. The underlying diagnoses did not seem to influence responses to particle stimulation. Elevated responses to both acrylic and cobalt-chromium were observed in patients with aseptically loosened prostheses. These findings suggest that the development of a cellular response to particulate debris may be significant in the pathogenesis of aseptic loosening.


Primary chemotherapy: the future for the management of advanced ovarian cancer?
Primary surgery for advanced ovarian cancer has been the standard practice for more than 30 years. A survival benefit is principally seen in patients who have optimal cytoreduction with no or small-volume residual disease after surgery. In everyday clinical practice, many patients are not able to undergo optimal tumor debulking. Modern preoperative imaging and assessment can identify most of these patients. Through developments in platinum-based chemotherapy, a high proportion of patients can be expected to respond to primary (neoadjuvant) chemotherapy. A recent clinical trial has shown that the survival of patients with operable disease is not disadvantaged by neoadjuvant chemotherapy followed by surgery. Thus, complete tumor cytoreduction could be achieved in a greater percentage of patients, if primary chemotherapy is used in women in whom optimal primary surgery would be difficult. Furthermore, delayed surgery provides more knowledge about the biological behavior of the tumor, and this could be used to tailor treatment more effectively.


Changes in the localization of the rat canalicular conjugate export pump Mrp2 in phalloidin-induced cholestasis.
Administration of phalloidin, one of the toxic peptides of the mushroom Amanita phalloides, leads to rapid and sustained cholestasis in rats. Although attributed to the interaction of phalloidin with microfilaments, the events leading to cholestasis are incompletely understood. The adenosine triphosphate (ATP)-dependent, apical conjugate export pump, termed multidrug resistance protein 2 (Mrp2) or canalicular multispecific organic anion transporter, is the major driving force for bile salt-independent bile flow. We investigated the role of Mrp2 in phalloidin-induced cholestasis. Bile flow decreased to 53% and 31% of control at 15 and 30 minutes after phalloidin (0.5 mg/kg), respectively. Mrp2-mediated [3H]leukotriene excretion into bile during the initial 45 minutes was reduced to 44% of control when [3H]LTC4 was injected 15 minutes after phalloidin treatment. Mrp2 was progressively lost from the hepatocyte canalicular membrane and detected predominantly on intracellular membrane structures together with other canalicular proteins including P-glycoproteins, ecto-ATPase, and dipeptidyl-peptidase IV. By contrast, structures involved in intercellular adhesion (zonula occludens, zonula adhaerens, and desmosomes) as well as intermediate filaments of the cytokeratin type appeared largely unaffected within 30 minutes after phalloidin. In line with the immunofluorescence analysis, immunoblots indicated a loss of Mrp2 and P-glycoproteins from the canalicular membrane and a 3- and 4.6-fold increase of these transport proteins in the microsomal fraction, respectively. Our results indicate that phalloidin induces marked alterations of the hepatocyte canalicular architecture and a loss of Mrp2 together with other proteins from the canalicular membrane. The resulting cholestasis can therefore be explained in part by the loss of export pumps, including Mrp2, from the canalicular membrane.


[Bridged nucleic acids (BNAs) as a basic material for genome technology].
The completion of the human genome sequencing project will greatly accelerate the development of novel and practical technologies for genome-analysis, diagnostics or therapeutics. Oligonucleotides are playing an important role in these genome technologies, because of their sequence-specific hybridization ability toward the complementary strand. Besides the sequence-specific duplex formation, oligonucleotides are able to form stable triplex structures, which is fundamental to the antigene strategy to regulate gene expression in a living cell. However, two major drawbacks are known in the triplex formation by a natural oligonucleotide: low stability of the triplex and limitations of the target DNA sequence. One promising strategy to overcome these problems is chemical modification of the oligonucleotides. We have developed various bridged nucleic acids (BNAs), and found that the oligonucleotides containing 2'-O,4'-C-methylene bridged nucleic acid (2',4'-BNA) modification form a stable parallel motif triplex with the double-stranded DNA target under physiological conditions. Some nucleobase analogues to extend the target DNA sequence were designed, synthesized and incorporated into the 2',4'-BNA structure. The obtained 2',4'-BNA derivatives containing modified nucleobases effectively recognized a pyrimidine-purine interruption. Some other examples of nucleic acid analogues to overcome the two major drawbacks in the triplex-forming oligonucleotides are also summarized.


Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death.
Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease that has a pro-apoptotic function in mammalian cells. Upon induction of apoptosis, Omi translocates to the cytoplasm and participates in caspase-dependent apoptosis by binding and degrading inhibitor of apoptosis proteins. Omi can also initiate caspase-independent apoptosis in a process that relies entirely on its ability to function as an active protease. To investigate the mechanism of Omi-induced apoptosis, we set out to isolate novel substrates that are cleaved by this protease. We identified HS1-associated protein X-1 (HAX-1), a mitochondrial anti-apoptotic protein, as a specific Omi interactor that is cleaved by Omi both in vitro and in vivo. HAX-1 degradation follows Omi activation in cells treated with various apoptotic stimuli. Using a specific inhibitor of Omi, HAX-1 degradation is prevented and cell death is reduced. Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity. Degradation of HAX-1 is an early event in the apoptotic process and occurs while Omi is still confined in the mitochondria. Our results suggest that Omi has a unique pro-apoptotic function in mitochondria that involves removal of the HAX-1 anti-apoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins.


The explanatory role of events in causal and temporal reasoning in medicine.
The logic of time and the way we reason about time is intrinsically connected with the way we reason about causality. In this paper, we focus our attention on some of the less obvious ways in which reasoning about time and causality interact. It is explained why in temporal reasoning a firm distinction has to be made between the ontology, i.e., what happens, and the way we describe the ontology. Temporal events need to be redescribed in such a way that they causally explain why some of the events are followed by the others. While building a temporal/causal theory, certain events may be omitted, not because they do not play a causal role, but because they do not play an explanatory role. In doing so, it is possible to eliminate the distinction between theories representing time as dense, and theories that represent time as discrete.


Product inhibition of potato tuber pyrophosphate:fructose-6-phosphate phosphotransferase by phosphate and pyrophosphate.
The product inhibition of potato (Solanum tuberosum) tuber pyrophosphate:fructose-6-phosphate phosphotransferase by inorganic pyrophosphate and inorganic phosphate has been studied. The binding of substrates for the forward (glycolytic) and the reverse (gluconeogenic) reaction is random order, and occurs with only weak competition between the substrate pair fructose-6-phosphate and pyrophosphate, and between the substrate pair fructose-1,6-bisphosphate and phosphate. Pyrophosphate is a powerful inhibitor of the reverse reaction, acting competitively to fructose-1,6-biphosphate and noncompetitively to phosphate. At the concentrations needed for catalysis of the reverse reaction, phosphate inhibits the forward reaction in a largely noncompetitive mode with respect to both fructose-6-phosphate and pyrophosphate. At higher concentrations, phosphate inhibits both the forward and the reverse reaction by decreasing the affinity for fructose-2,6-bisphosphate and thus, for the other three substrates. These results allow a model to be proposed, which describes the interactions between the substrates at the catalytic site. They also suggest the enzyme may be regulated in vivo by changes of the relation between metabolites and phosphate and could act as a means of controlling the cytosolic pyrophosphate concentration.


Exploring real-time in vivo redox biology of developing and aging Caenorhabditis elegans.
Reactive oxygen species (ROS) are no longer considered merely toxic by-products of the oxidative metabolism. Tightly controlled concentrations of ROS and fluctuations in redox potential may be important mediators of signaling processes. Understanding the role of ROS and redox status in physiology, stress response, development, and aging requires their nondisruptive, spatiotemporal, real-time quantification in a living organism. We established Caenorhabditis elegans strains bearing the genetically encoded fluorescent biosensors HyPer and Grx1-roGFP2 for the detection of hydrogen peroxide (H(2)O(2)) and the glutathione redox potential, respectively. Although, given its transparency and genetic tractability, C. elegans is perfectly suitable as a model organism for such approaches, they have never been tried before in this nematode. We found that H(2)O(2) treatment clearly induces a dose-dependent, reversible response of both biosensors in the living worms. The ratio of oxidized to reduced glutathione decreases during postembryonic development. H(2)O(2) levels increase with age and this effect is delayed when life span is extended by dietary restriction. In young adults, we detected several regions with distinct redox properties that may be linked to their biological function. Our findings demonstrate that genetically encoded biosensors can reveal previously unknown details of in vivo redox biology in multicellular organisms.


Social work leadership development through international exchange.
Social workers in large bureaucratic settings face the pressure to define their service in relation to other professional disciplines and to maintain a quality service despite conflicting mandates and economic restraints. Few strategies exist for providing training and education to senior social workers in order to help them develop leadership roles in multidisciplinary environments. This paper examines the characteristics and qualities necessary to provide social work leadership in a complex hospital environment. The ideas emerged from an international leadership exchange program with The Mount Sinai Medical Center in New York City. Aspects of this experience are used to illustrate leadership roles.


Ear biometrics for patient identification in global health: a cross-sectional study to test the feasibility of a simplified algorithm.
One of the greatest public health challenges in low- and middle-income countries (LMICs) is identifying people over time and space. Recent years have seen an explosion of interest in developing electronic approaches to addressing this problem, with mobile technology at the forefront of these efforts. We investigate the possibility of biometrics as a simple, cost-efficient, and portable solution. Common biometrics approaches include fingerprinting, iris scanning and facial recognition, but all are less than ideal due to complexity, infringement on privacy, cost, or portability. Ear biometrics, however, proved to be a unique and viable solution. We developed an identification algorithm then conducted a cross sectional study in which we photographed left and right ears from 25 consenting adults. We then conducted re-identification and statistical analyses to identify the accuracy and replicability of our approach. Through principal component analysis, we found the curve of the ear helix to be the most reliable anatomical structure and the basis for re-identification. Although an individual ear allowed for high re-identification rate (88.3%), when both left and right ears were paired together, our rate of re-identification amidst the pool of potential matches was 100%. The results of this study have implications on future efforts towards building a biometrics solution for patient identification in LMICs. We provide a conceptual platform for further investigation into the development of an ear biometrics identification mobile application.


Evidence for intracellular down-regulation of the epidermal growth factor (EGF) receptor during adenovirus infection by an EGF-independent mechanism.
We have reported previously that human group C adenoviruses down-regulate the epidermal growth factor (EGF) receptor (EGF-R) (C. R. Carlin, A. E. Tollefson, H. A. Brady, B. L. Hoffman, and W. S. M. Wold, Cell 57:135-144, 1989). Expression of a 13.7-kDa protein encoded by a gene in the E3 transcription unit is necessary and sufficient for this effect (Carlin et al., Cell, 1989; B. L. Hoffman, A. Ullrich, W. S. M. Wold, and C. R. Carlin, Mol. Cell. Biol. 10:5521-5524, 1990). We show here that EGF-R down-regulation is accelerated in cells which overexpress the receptor when these cells are infected with virus mutants that overproduce the 13.7-kDa protein compared with wild-type virus. This is in contrast to EGF stimulation, for which others have shown that high concentrations of ligand are associated with low rates of receptor internalization in EGF-R-overexpressing cells (D. Kuppuswamy and L. J. Pike, J. Biol. Chem. 264:3357-3363, 1989; H. S. Wiley, J. Cell Biol. 107:801-810, 1988). We also show that the E3 protein is not present in media conditioned by infected cells and that it does not induce secretion of an EGF-like autocrine factor. Moreover, while mature membrane-bound EGF-R is down-regulated, the precursor of the membrane-bound form is not. Adenovirus infection also does not affect receptor-related molecules expressed in the secretory pathway. Interestingly, adenovirus-induced down-regulation is not regulated by concentrations of EGF associated with a slow rate of internalization in A431 cells. This suggests that 13.7-kDa protein expression triggers receptor entry by a novel ligand-independent pathway or, alternatively, that it compensates for a cellular factor that may be rate limiting during EGF-mediated endocytosis.


Contribution of chemical water properties to the differential responses of bacterioneuston and bacterioplankton to ultraviolet-B radiation.
The surface microlayer (SML) is characterized by different physicochemical properties from underlying waters (UW). However, whether these differences in abiotic factors underlie the distinct sensitivity of bacterioneuston (i.e. SML bacteria) and bacterioplankton to environmental stressors remains to be addressed. We investigated the contribution of abiotic factors to the UV-B sensitivity of bacterioneuston and bacterioplankton. Nutrients (especially nitrogen and phosphate) emerged as important determinants of bacterial UV-B sensitivity. The role of particles, nutrients, and dissolved organic components on bacterial UV-B sensitivity was further evaluated using dilution cultures. Filtered samples were twofold more UV sensitive than unfiltered samples, suggesting a UV-protective effect of particles. High nutrient concentrations attenuated bacterial UV-B sensitivity (up to 40%), compared with unamended conditions, by influencing bacterial physiology and/or community composition. Suspending cells in natural water, particularly from the SML, also attenuated UV-B sensitivity (up to 23%), compared with suspension in an artificial mineral solution. Bioassays using Pseudomonas sp. strain NT5I1.2B revealed that chemical water properties influence UV-induced oxidative damage. UV-B sensitivity was associated with high cell-specific activities. The chemical environment of the SML and UW influences UV-B effects on the corresponding bacterial communities. Maintaining low cell activities might be advantageous in stressful environments, like the SML.


Corticotropin releasing factor activity of CRF 41 in normal man is potentiated by angiotensin II and vasopressin but not by desmopressin.
Multiple hypothalamic factors seem to influence ACTH release. In vitro and/or in vivo animal models have shown that angiotensin II, vasopressin and some of its analogs are ACTH secretagogues capable of potentiating the corticotropin releasing activity of CRF41. Since these effects are controversial in man, we investigated in 3 groups of volunteers the corticotropin releasing activity of a 2h-infusion of angiotensin II (7 ng/kg/min), vasopressin (1 ng/kg/min) and desmopressin (1 ng/kg/min) given alone or in combination with a bolus injection of 100 micrograms CRF41 by measuring plasma concentrations of ACTH, cortisol, dehydroepiandrosterone and delta 4-androstenedione. Given alone angiotensin II and desmopressin had no significant effect in contrast to vasopressin which increased significantly the ACTH and steroid levels. Angiotensin II and vasopressin were both able to potentiate the corticotropin releasing activity of CRF41, whereas desmopressin was unable to produce such a potentiation. These results suggest that in man vasopressin and angiotensin II may well regulate the responsiveness of the pituitary-adrenal axis in various physiological or pathophysiological situations.


Changes in stroke volume with beta-blockade before and after 10 days of exercise training in men and women.
We sought to determine whether 10 days of training would be a sufficient stimulus for cardiac adaptations that would allow a greater compensatory stroke volume during beta-blockade. We also sought to determine whether men and women had a similar cardiac reserve capacity for increasing stroke volume with beta-blockade during submaximal exercise. Eight men (age 29 +/- 2 yr, mean +/- SE) and eight women (25 +/- 2 yr) cycled at 65% of peak O2 consumption (unblocked) under placebo-control and beta-blockade (100 mg atenolol) conditions performed on separate days. These tests were repeated at the same power output after training (10 consecutive days, 1 h of cycling per day). Before training, beta-blockade significantly (P < 0.05) decreased heart rate (HR) and cardiac output and increased stroke volume in both men and women. After training, the increase in stroke volume and decrease in HR with beta-blockade was significantly less while cardiac output was reduced more. There were no gender differences in the effects of beta-blockade on HR, stroke volume, or cardiac output. These data indicate that, during exercise with beta-blockade, exercise training for 10 days does not enhance the compensatory increase in stroke volume and that men and women have a similar cardiac reserve capacity for increasing stroke volume.


Incidence, patient characteristics and predictors of aborted myocardial infarction in patients undergoing primary PCI: prospective study comparing pre- and in-hospital abciximab pretreatment.
This study was performed to assess the incidence, patient characteristics and predictors of aborted myocardial infarction (MI) in patients with ST-segment elevation MI (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We enrolled 179 consecutive patients with STEMI within a fixed protocol for PPCI (Leiden MISSION! project); 90 patients received abciximab bolus in the hospital (in-hospital group) and 89 patients received abciximab bolus in the ambulance (pre-hospital group). Thirty-two patients (18%) fulfilled the criteria for an aborted MI. The incidence of aborted MI was four times higher in the pre-hospital abciximab group compared to the in-hospital group (OR = 4.2, 95% CI = 1.7-10.3). The median time between symptoms onset and abciximab bolus administration was significantly shorter in the aborted MI compared to established MI patients (70 vs. 115 min, p = 0.005). Multivariable analysis identified prehospital abciximab administration as the main predictor of aborted MI (OR = 2.86, 95% CI = 1.1-7.5). In patients with STEMI treated with PPCI, the incidence of aborted MI was 18%. Pre-hospital abciximab administration was the main predictor of aborted MI, and this effect was related to the initiation of treatment within the first two hours after symptoms onset and to the higher infarct related artery patency at presentation.


Similar molecular determinants on Rem mediate two distinct modes of inhibition of CaV1.2 channels.
Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like GTPases that potently inhibit all high-voltage-gated calcium (CaV1/CaV2) channels and are, thus, well-positioned to tune diverse physiological processes. Understanding how RGK proteins inhibit CaV channels is important for perspectives on their (patho)physiological roles and could advance their development and use as genetically-encoded CaV channel blockers. We previously reported that Rem can block surface CaV1.2 channels in 2 independent ways that engage distinct components of the channel complex: (1) by binding auxiliary β subunits (β-binding-dependent inhibition, or BBD); and (2) by binding the pore-forming α1C subunit N-terminus (α1C-binding-dependent inhibition, or ABD). By contrast, Gem uses only the BBD mechanism to block CaV1.2. Rem molecular determinants required for BBD CaV1.2 inhibition are the distal C-terminus and the guanine nucleotide binding G-domain which interact with the plasma membrane and CaVβ, respectively. However, Rem determinants for ABD CaV1.2 inhibition are unknown. Here, combining fluorescence resonance energy transfer, electrophysiology, systematic truncations, and Rem/Gem chimeras we found that the same Rem distal C-terminus and G-domain also mediate ABD CaV1.2 inhibition, but with different interaction partners. Rem distal C-terminus interacts with α1C N-terminus to anchor the G-domain which likely interacts with an as-yet-unidentified site. In contrast to some previous studies, neither the C-terminus of Rem nor Gem was sufficient to inhibit CaV1/CaV2 channels. The results reveal that similar molecular determinants on Rem are repurposed to initiate 2 independent mechanisms of CaV1.2 inhibition.


Drugs for Parkinson's disease.
Levodopa combined with carbidopa is still the most effective treatment for symptoms of Parkinson's disease. Dopamine agonists, the next most effective class of drugs, can be used alone before the introduction of levodopa or as an adjunct to levodopa.Addition of a peripherally-acting COMT inhibitor or an MAO-B inhibitor to levodopa can reduce motor fluctuations in patients with advanced disease.Amantadine may have mild symptomatic benefit and can decrease levodopa-induced dyskinesias.Anticholinergics are rarely used because of their adverse effects, but can be a useful addition to levodopa for control of tremor and drooling.Subcutaneous apomorphine should be available for rescue use in patients with 'off' episodes. Deep brain stimulation is an option for patients with levodopa-induced motor complications and relatively intact cognition.


Fabrication and Characterization of Alveolus-Like Scaffolds with Control of the Pore Architecture and Gas Permeability.
The micrometer scale sac-like alveoli are the most important and essential unit for gas exchange in the lung. Thus, design and fabrication of scaffolds for alveoli regeneration by tissue engineering approach should meet a few topography and functional requests such as large surface area, flexibility, and high gas permeability to their native counterpart. Testing the gas permeability of scaffolds through a fast and simple technique is also highly demanded to assist new scaffold development. This study fabricated alveolus-like scaffolds with regular pore shape, high pore connectivity, and high porosity produced by inverse opal technique alongside randomly distrusted porous scaffolds by salt leaching technique from two different materials (polyurethane and poly(L-lactic acid)). The scaffold surface was modified by immobilization of VEGF. A facile and new technique based on the bubble meter principle enabling to measure the gas permeability of porous scaffolds conveniently has been developed specifically. The cellular response of the scaffolds was assessed by culturing with bone marrow mesenchymal stem cells and coculturing with lung epithelial NL20 and endothelial HUVECs. Our results showed that the newly designed gas permeability device provided rapid, nondestructive, reproducible, and accurate assessment of gas permeability of different scaffolds. The porous polyurethane scaffolds made by inverse opal method had much better gas permeability than other scaffolds used in this study. The cellular work indicated that with VEGF surface modification, polyurethane inverse opal scaffolds induced alveolus-like tissues and have promising application in lung tissue engineering.