An outbreak of Burkholderia cenocepacia bacteremia in immunocompromised oncology patients.
Burkholderia cepacia is a common environmental bacterium that is resistant to disinfectants, and therefore is often encountered as a hospital-acquired pathogen. We describe an outbreak of B. cenocepacia bacteremia among hospitalized oncology patients. A matched case-control study and an extensive environmental investigation were conducted. Species were identified by RFLP of the amplified recA gene. DNA was fingerprinted by pulsed-field gel electrophoresis (PFGE). Between November 2005 and September 2006, B. cenocepacia bacteremia developed in 17 patients with underlying malignancy of whom 14 had tunneled central venous catheters. All patients had fever and chills which subsided following removal of the central catheter and administration of ceftazidime. Extensive epidemiological investigation could not find a common source for the outbreak. Patients were hospitalized in three different buildings with different health care personnel. Medications were prepared in different sites by different personnel. A multivariate analysis demonstrated that the independent risk factors for developing nosocomial B. cenocepacia bacteremia were hospitalization at the center for long-term support (OR 28.8; 95% CI 1.83-453.4) and reduced use of antibiotics during the last month (OR 0.07; 95% CI 0.01-0.40). All isolates had identical antimicrobial susceptibility; PFGE indicated that a complex of closely related strains was involved in the outbreak. All isolates were identified as B. cenocepacia, known to infect cystic fibrosis patients. Strict infection control measures terminated the outbreak. B. cenocepacia is an emerging nosocomial pathogen among oncology patients.


Association of the IL-15 and IL-15Rα genes with celiac disease.
Celiac disease is a chronic autoimmune condition triggered by dietary gluten in genetically predisposed individuals and the treatment is a strict gluten-free diet. The major predisposing genes are HLA-DQA1 and HLA-DQB1, but these are not sufficient for disease development. One of the candidate genes worth studying is interleukin (IL)-15 gene, together with its specific receptor, IL-15Rα, as they participate in promoting lymphocyte signaling and survival, and the establishment of appropriate conditions for villous atrophy, then acting as key players in the immunopathogenesis of CD. Here we analyze IL-15 and IL-15Rα genes in samples from the Spanish Consortium for Genetics of Celiac Disease (CEGEC) collection, identifying two regulatory single-nucleotide polymorphisms (SNP) that might be associated with celiac disease: rs4956400 (p-value 0.0112, OR 1.21, 95% CI 1.04-1.40) and rs11100722 (p-value 0.0087, OR 1.24, 95% CI 1.06-1.45), both located upstream the IL15 gene. When the expression of both genes was assessed, these two SNPs were found to be correlated with IL-15 higher protein expression. Besides, rs8177655 from IL15RA was also associated to mRNA IL-15 expression in CD patients. Finally, three SNPs from IL15RA intronic regions, rs2296141, rs3136614 and rs3181148, and another from its 3'UTR region, rs2229135, could be related to the age of diagnosis of celiac disease patients.


Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors.
The molecular mechanisms contributing to the normal age-related decline of cognitive functions or to pathological learning and memory impairment are largely unknown. We demonstrate here that young mice (6-7 weeks) with a genetic deletion of the cannabinoid CB1 receptor performed as well as WT mice, or often better, in a number of learning and memory paradigms, including animal models of skill-learning, partner recognition, and operant conditioning. In contrast, the performance of mature mice (3-5 months) lacking CB1 receptors was much worse than that of age-matched WT animals. In most tests, these mice performed at the same level as old animals (14-17 months), suggesting that the decline in cognitive functions is accelerated in the absence of CB1 receptors. This rapid decline in CB1-deficient animals is accompanied by a loss of neurons in the CA1 and CA3 regions of the hippocampus.


Axonal transport: a quantitative study of retained and transported protein fraction in the cat.
The fast axonal transport of proteins was studied in the cat sciatic nerve after injection of [3H]leucine into the spinal ganglion or the ventral horn of the seventh lumbar segment. The amount of transported proteins after ganglion injection was linearly related to the amount of label present at the ganglion. At variable intervals after ganglion or spinal cord injection, the sciatic nerves were sectioned in some experiments. The transport of proteins continued in the peripheral nerve stump in a wavelike manner, but the advancing wave leaves a labeled trail behind. A fraction of this trail corresponds to proteins moving at slower velocities than the velocity of proteins in the wave front. Another fraction of the trail corresponds to molecules retained by the axons. Each nerve segment of 5 mm in length retains 1.5% of the transported proteins, and the profile of retained proteins along the sciatic nerves follows a single exponential function. From the proportion of retained proteins, the concentration of transported proteins at the terminals of branching axons as a function of the branching ratio was estimated. In the case of motor axons innervating the soleus muscle of the cat, the concentration of recently transported proteins at the nerve terminals would be approximately 0.83% of the proteins leaving the spinal cord. This low concentration of transported proteins at the nerve terminals may explain the lability of neuromuscular synapses when axonal transport is decreased or interrupted.


Metabolite Profiling of Eastern Teaberry (Gaultheria procumbens L.) Lipophilic Leaf Extracts with Hyaluronidase and Lipoxygenase Inhibitory Activity.
The phytochemical profile and anti-inflammatory activity of Gaultheria procumbens dry lipophilic leaf extracts were evaluated. Forty compounds were identified by GC-MS, representing 86.36% and 81.97% of the petroleum ether (PE) and chloroform (CHE) extracts, respectively, with ursolic acid (28.82%), oleanolic acid (10.11%), methyl benzoate (10.03%), and methyl salicylate (6.88%) dominating in CHE, and methyl benzoate (21.59%), docosane (18.86%), and octacosane (11.72%) prevailing in PE. Three components of CHE were fully identified after flash chromatography isolation and spectroscopic studies as (6S,9R)-vomifoliol (4.35%), 8-demethyl-latifolin (1.13%), and 8-demethylsideroxylin (2.25%). Hyaluronidase and lipoxygenase inhibitory activity was tested for CHE (IC50 = 282.15 ± 10.38 μg/mL and 899.97 ± 31.17 μg/mL, respectively), PE (IC50 = 401.82 ± 16.12 μg/mL and 738.49 ± 15.92 μg/mL), and nine of the main constituents versus heparin (IC50 = 366.24 ± 14.72 μg/mL) and indomethacin (IC50 = 92.60 ± 3.71 μg/mL) as positive controls. With the best activity/concentration relationships, ursolic and oleanolic acids were recommended as analytical markers for the extracts and plant material. Seasonal variation of both markers following foliar development was investigated by UHPLC-PDA. The highest levels of ursolic (5.36-5.87 mg/g DW of the leaves) and oleanolic (1.14-1.26 mg/g DW) acids were observed between August and October, indicating the optimal season for harvesting.


[Expressing plasmid vectors on the basis of Escherichia coli beta-galactosidase gene fragments].
With the use of synthetic DNA fragments, a set of new plasmid vectors has been obtained. The vectors provided high level expression of peptides and small proteins in E. coli as fusions with fragments of beta-galactosidase of various length. These vectors were used to achieve expression of a synthetic gene for a functionally active fragment of bacteriorhodopsin. The yields of hybrid proteins consisting of beta-galactosidase and bacteriorhodopsin fragments were in the range of 5-30% from the total amount of cellular protein.


Isolation of streptonigrin and its novel derivative from Micromonospora as inducing agents of p53-dependent cell apoptosis.
Streptonigrin (1) and its novel natural derivative 7-(1-methyl-2-oxopropyl)streptonigrin (2) were isolated from an actinomycete strain, Micromonospora sp. IM 2670. The inductions for 1 and 2 are more potent in the human neuroblastoma SH-SY5Y cells that contain wild-type p53 than in SH-SY5Y-5.6 cells that overexpress a dominant negative mutant of p53, thus suggesting that they induce apoptosis through a p53-dependent pathway.


Leptin mediates the pathogenesis of severe 2009 pandemic influenza A(H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity.
Obesity is associated with a high circulating leptin level and severe 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) infection. The mechanism for severe lung injury in obese patients and the specific treatment strategy remain elusive. We studied the pathogenesis of A(H1N1)pdm09 infection in a mouse model of diet-induced obesity. Obese mice had significantly higher initial pulmonary viral titer and mortality after challenge with A(H1N1)pdm09, compared with age-matched lean mice. Compared with lean mice, obese mice had heightened proinflammatory cytokine and chemokine levels and more severe pulmonary inflammatory damage. Furthermore, obese mice had a higher preexisting serum leptin level but a lower preexisting adiponectin level. Recombinant mouse leptin increased the interleukin 6 (IL-6) messenger RNA expression in mouse single-lung-cell preparations, mouse macrophages, and mouse lung epithelial cell lines infected with A(H1N1)pdm09. Administration of anti-leptin antibody improved the survival of infected obese mice, with associated reductions in pulmonary levels of the proinflammatory cytokines IL-6 and interleukin 1β but not the pulmonary viral titer. Our findings suggest that preexisting high levels of circulating leptin contribute to the development of severe lung injury by A(H1N1)pdm09 in mice with diet-induced obesity. The therapeutic strategy of leptin neutralization for the reduction of proinflammatory responses and pulmonary damage in obese patients warrants further investigations.


Dispersion stability of colloids in sub- and supercritical water.
Dispersion stability of colloids has been investigated in sub- and supercritical water by measuring the hydrodynamic diffusion coefficients of the particles by means of dynamic light scattering. It is interestingly found that coagulation of the colloids in sub- and supercritical water is a universal phenomenon irrespective of the material of the colloids. Highly charged colloids were found to be more stable in water against high temperature. Numerical analysis reveals that the stability of the colloids at elevated temperature and pressure is primarily governed by the temperature dependence of the dielectric constant of the medium. The effect of the temperature dependence of the ion product of water (pKw) was found to be very little. Surface charge density and Stern potential may change with respect to temperature due to the readjustment of the ion concentration in the diffuse layer through the enhanced ion product and reduced dielectric constant of water. These are the secondary causes of the particle coagulations in sub- and supercritical water.


Expression of insulin-like growth factor-2 can predict the prognosis of human colorectal cancer patients: correlation with tumor progression, proliferative activity and survival.
Expression of insulin-like growth factor-2 (IGF-2) has been reported in tissue specimens and cell lines of human colorectal cancers. However, the effects of IGF-2 in colorectal cancer patients are not well known. In this study, IGF-2 staining was performed on tissue samples from 92 patients with colorectal cancer, and the relationship of IGF-2 staining to clinicopathological variables, proliferating cell nuclear antigen (PCNA) staining and patient survival was analyzed. IGF-2 staining was correlated with tumor progression, PCNA staining and patient survival. Our results suggest that IGF-2 plays an important role in tumor progression and that IGF-2 staining is useful as a prognostic factor in colorectal cancer patients.


Application of the time-driven activity-based costing methodology to a complex patient case management program in Portugal.
The number of people with chronic diseases has increased globally, as has the number of chronic diseases per person. Faced with this reality, the term "complex patient" is current and actual. The healthcare costs associated with these patients are high and are expected to increase since most healthcare systems are not yet ready to provide integrated long-term care. In Portugal, several health institutions have made efforts to provide integrated care: case management models have been implemented to complex patients follow-up. However, studies related to cost of these programs are still limited. Therefore, a qualitative investigation was conducted, approaching the design criteria of a case study research, to design a case management program for complex patients and determine its direct costs, following the Time-Driven Activity-Based Costing methodology, in Local Health Unit setting. The direct costs of providing care to a complex patient involved in a case management program were determined, using the Time-Driven Activity-Based Costing methodology. A map of the complex patient was drawn, considering a standard flow in the program. Times and costs were allocated to the activities on the map, following Portuguese and international practices of case management models. A total of 684,45€/year is spent for each new patient in the case management program, of which 452,65€ corresponds to cost of remuneration of professionals involved; and 663,85€/year, for each patient who is in the case management program (over 1 year), where 432,05€ corresponds to cost of the remuneration of the professionals involved. Follow-up is the most costly phase (80.82%) and where more time is spent (85.62%). The time spent by professionals and resources involved and the costs associated with each patient were obtained. The economic impact of the analysed activities was not studied, however, according to international authors, when well applied and selected, integrated care models lead to cost reduction and improved health outcomes.


Kv3 K+ channels enable burst output in rat cerebellar Purkinje cells.
The ability of cells to generate an appropriate spike output depends on a balance between membrane depolarizations and the repolarizing actions of K(+) currents. The high-voltage-activated Kv3 class of K(+) channels repolarizes Na(+) spikes to maintain high frequencies of discharge. However, little is known of the ability for these K(+) channels to shape Ca(2+) spike discharge or their ability to regulate Ca(2+) spike-dependent burst output. Here we identify the role of Kv3 K(+) channels in the regulation of Na(+) and Ca(2+) spike discharge, as well as burst output, using somatic and dendritic recordings in rat cerebellar Purkinje cells. Kv3 currents pharmacologically isolated in outside-out somatic membrane patches accounted for approximately 40% of the total K(+) current, were very fast and high voltage activating, and required more than 1 s to fully inactivate. Kv3 currents were differentiated from other tetraethylammonium-sensitive currents to establish their role in Purkinje cells under physiological conditions with current-clamp recordings. Dual somatic-dendritic recordings indicated that Kv3 channels repolarize Na(+) and Ca(2+) spikes, enabling high-frequency discharge for both types of cell output. We further show that during burst output Kv3 channels act together with large-conductance Ca(2+)-activated K(+) channels to ensure an effective coupling between Ca(2+) and Na(+) spike discharge by preventing Na(+) spike inactivation. By contributing significantly to the repolarization of Na(+) and especially Ca(2+) spikes, our data reveal a novel function for Kv3 K(+) channels in the maintenance of high-frequency burst output for cerebellar Purkinje cells.


Cerebral toxoplasmosis mimicking subacute meningitis in HIV-infected patients; a cohort study from Indonesia.
HIV-associated subacute meningitis is mostly caused by tuberculosis or cryptococcosis, but often no etiology can be established. In the absence of CT or MRI of the brain, toxoplasmosis is generally not considered as part of the differential diagnosis. We performed cerebrospinal fluid real time PCR and serological testing for Toxoplasma gondii in archived samples from a well-characterized cohort of 64 HIV-infected patients presenting with subacute meningitis in a referral hospital in Indonesia. Neuroradiology was only available for 6 patients. At time of presentation, patients mostly had newly diagnosed and advanced HIV infection (median CD4 count 22 cells/mL), with only 17.2% taking ART, and 9.4% PJP-prophylaxis. CSF PCR for T. Gondii was positive in 21 patients (32.8%). Circulating toxoplasma IgG was present in 77.2% of patients tested, including all in whom the PCR of CSF was positive for T. Gondii. Clinically, in the absence of neuroradiology, toxoplasmosis was difficult to distinguish from tuberculosis or cryptococcal meningitis, although CSF abnormalities were less pronounced. Mortality among patients with a positive CSF T. Gondii PCR was 81%, 2.16-fold higher (95% CI 1.04-4.47) compared to those with a negative PCR. Toxoplasmosis should be considered in HIV-infected patients with clinically suspected subacute meningitis in settings where neuroradiology is not available.


Hemodynamic Correlates of Abnormal Aortic Root Dimension in an Adult Population: The Strong Heart Study.
We evaluated the relationship of aortic root dimension (ARD) with flow output and both peripheral and central blood pressure, using multivariable equations predicting ideal sex-specific ARD at a given age and body height. We measured echocardiographic diastolic ARD at the sinuses of Valsalva in 3160 adults (aged 42±16 years, 61% women) from the fourth examination of the Strong Heart Study who were free of prevalent coronary heart disease, and we compared measured data with the theoretical predicted value to calculate a z score. Central blood pressure was estimated by applanation tonometry of the radial artery in 2319 participants. ARD z scores were divided into tertiles representing small, normal, and large ARD. Participants with large ARD exhibited greater prevalence of central obesity and higher levels of inflammatory markers and lipids (0.05<P<0.0001). Stroke volume, heart rate, and both cuff and central diastolic blood pressure were progressively greater from small to large ARD (all P<0.0001). Pulse pressure was higher in small ARD (P<0.0001). In multivariable analysis, ARD z score was related positively to stroke volume, either cuff or central diastolic blood pressure, and negatively to pulse pressure. Large ARD was also independently correlated to higher waist circumference and percentages of neutrophils and plasminogen activator inhibitor-1 (all P<0.01). Aortic root dilatation is associated with high diastolic blood pressure, high stroke volume, central fat distribution, and inflammatory status. In contrast, at a given diastolic blood pressure and stroke volume, aortic root dilatation is associated with lower pulse pressure and systolic blood pressure.


[Repetitive movements of the upper limbs: results of exposure evaluation and clinical investigation during the sorting and packaging of apples].
In the fruit industry, workers sorting and packing apples perform a job that is characterised by repetitive actions, that require them to remain in an upright position for prolonged periods of time and, occasionally, to manually lift loads of apples. The aim of the study was to detect and provide a preliminary quantification of any possible risks for the musculo-skeletal system, as well as any disorders present among the workers. A risk analysis for WMSDs was performed in an apple packing plant, using video recordings of the job cycles associated with two different tasks (semi-automatic sorting and manual packing). A clinical and anamnestic investigation was carried out in nine plants; a standard questionnaire was distributed to 180 employees, with the purpose of detecting disorders and diseases of the locomotor system. An initial evaluation of the risks for WMSDs indicated that the routine tasks performed by the female apple workers featured a very high frequency of actions, also in view of the fact that the repetitive tasks lasted for the duration of the entire work shift. In the situation examined, the action frequency limits were greatly exceeded; moreover, the recovery times were inadequate in terms both of their duration and distribution. Regarding clinical and anamnestic examination, an overall analysis of the results shows a very high prevalence of spinal and hand-arm disorders. Given these preliminary findings, the authors suggest that the sample population of fruit sorters should undergo clinical and instrumental testing to evaluate the condition of the spine and upper limbs, and that a specific health surveillance programme should be adopted across the industry.


Ultrasonography of the femoral artery in six normal horses and three horses with thrombosis.
Ultrasonography of the femoral artery in the horse, including color, power and spectral Doppler, provides morphologic and dynamic information. This paper describes the use of the techniques in six clinically normal horses and three with femoral artery thrombosis. Useful landmarks for orientation are the saphenous artery and the medial saphenous vein. The lateral circumflex femoral artery can not be visualized. Recognition of the genus descendens artery is complicated due to the presence of multiple distal caudal femoral arteries. The femoral artery feeds a high resistance bed. In normal horses the peak systolic velocity varies between 50-90 cm/sec. Echoic tissue in the femoral artery lumen with stenosis, occlusion and collateral blood flow formation are features encountered in the patients.


Working memory and organizational skills problems in ADHD.
This study tested model-driven predictions regarding working memory's role in the organizational problems associated with ADHD. Children aged 8-13 (M = 10.33, SD = 1.42) with and without ADHD (N = 103; 39 girls; 73% Caucasian/Non-Hispanic) were assessed on multiple, counterbalanced working memory tasks. Parents and teachers completed norm-referenced measures of organizational problems (Children's Organizational Skills Scale; COSS). Results confirmed large magnitude working memory deficits (d = 1.24) and organizational problems in ADHD (d = 0.85). Bias-corrected, bootstrapped conditional effects models linked impaired working memory with greater parent- and teacher-reported inattention, hyperactivity/impulsivity, and organizational problems. Working memory predicted organization problems across all parent and teacher COSS subscales (R2 = .19-.23). Approximately 38%-57% of working memory's effect on organization problems was conveyed by working memory's association with inattentive behavior. Unique effects of working memory remained significant for both parent- and teacher-reported task planning, as well as for teacher-reported memory/materials management and overall organization problems. Attention problems uniquely predicted worse organizational skills. Hyperactivity was unrelated to parent-reported organizational skills, but predicted better teacher-reported task planning. Children with ADHD exhibit multisetting, broad-based organizational impairment. These impaired organizational skills are attributable in part to performance deficits secondary to working memory dysfunction, both directly and indirectly via working memory's role in regulating attention. Impaired working memory in ADHD renders it extraordinarily difficult for these children to consistently anticipate, plan, enact, and maintain goal-directed actions.


[Reliability and effectiveness of monitoring the stroke and minute volume of the heart by Kubicek's rheographic method].
Simultaneous measurements by the Fick direct method and the Kubicek rheographic method of cardiac output of 20 men with ischemic heart disease have shown that both methods are well correlated (r = 0.76, k = 0.92, n = 41). The reproducibility of the Kubicek data was slightly better than the Fick data (on the average +/- 6% instead of +/- 9-10%). An attempt of increasing the correlation of the Kubicek data with the Fick data by correcting the specific resistance with respect to the hematocrit data and the chest perimeter failed. In order to provide the necessary accuracy of the Kubicek method, it is required that the procedure be stringent and the five variables in the formula for calculating cardiac output be precisely measured. The cardiac output values determined simultaneously by the Kubicek method and by x-ray contrast ventriculography showed a better correlation (r = 0.88, k = 0.97, n = 15).


A new target for autoantibodies in patients with rheumatoid arthritis.
Early treatment of rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs can achieve a better disease outcome and reduce the severity of joint damage. The presence of autoantibodies in patient sera can precede onset of the disease and thus be predictive of the development of RA. To date, known autoantibodies in RA are positive in only 50-60% of RA patients at onset of disease and even less before the onset of any RA symptom. The aim of this study was to identify new antibodies that could be useful for the diagnosis of RA using synovial membrane proteins, which represent the best source of candidate RA autoantigens. The humoral reactivity of sera from RA patients was explored using immunoblotting on extracted proteins obtained from synovial membranes from RA after synovectomy or arthroplasty. A new target protein with a molecular weight of 26 kDa was found to be recognized by autoantibodies in RA sera. This protein was identified using MALDI-TOF mass spectrometry and two-dimensional electrophoresis as carbonic anhydrase III with a high level of confidence. In conclusion, this study demonstrates new autoantibodies in RA patients that are directed against carbonic anhydrase III. The sensitivity and specificity of these new autoantibodies for RA have to be further evaluated.


Protective effects of berberine on doxorubicin-induced hepatotoxicity in mice.
Doxorubicin, a very potent and often used anti-cancer drug, is largely limited due to the dose-related toxic effects. The present study investigated whether berberine, a natural product alkaloid, can reduce the liver injury induced by doxorubicin. Mice of either gender were randomly divided into four groups: the control group, doxorubicin group, berberine group, and berberine+doxorubicin group. In the tests, body weight, general condition and mortality of the mice were observed, and serum alanine aminotransferase and aspartate transaminase levels were determined to evaluate liver function. Furthermore, the liver was excised for determination of the weight changes, as well as histopathological analysis in the tissues. Mortality rate and significant decline in body weight, and increased plasma alanine aminotransferase and aspartate transaminase activities were observed in doxorubicin-treated mice. These changes were significantly prevented by pretreatment with berberine. Histopathological studies showed that doxorubicin caused structural injuries, such as vascular congestion, inflammatory cell infiltration, hepatocellular degeneration and necrosis, fibrosis in the liver. These histopathological changes were largely attenuated by berberine pretreatment. These findings indicate that berberine has the hepatoprotective effect on doxorubicin-induced liver injury in mice.


[Spontaneous rupture of the esophagus (presentation of a case)].
The authors describe the case of a 67-year-old patient with spontaneous rupture of the middle third of the oesophagus, occurring apparently without any involvement of intraluminal hypertension. The surgical treatment consisted in the execution of an aspiration drainage of the left pleural cavity, followed by a right thoracotomy with exploration of the mediastinum. A gastrostomy according to Witzel was also performed. Total parenteral nutrition was instituted in the post-operative period. Healing of the oesophageal lesion was confirmed radiologically 2 months after admission to our department.


Long-term exposure to environmentally relevant doses of methyl-tert-butyl ether causes significant reproductive dysfunction in the zebrafish (Danio rerio).
Methyl-tert-butyl ether (MTBE), an anthropogenic chemical used as a gasoline additive, is being detected at an increasing frequency in the environment. The acute lethal concentration that kills 50% of the fish test population and the chronic effects of exposure to MTBE were investigated in the zebrafish (Danio rerio). Chronic exposure over three weeks to effective MTBE conceritrations as low as 0.11 mg/L induced a significant increase in the vitellogenin concentration of male fish. The impact of a chronic, eight-week exposure at effective concentrations ranging from 0.44 to 220 mg/L had no significant effect on fecundity, fertilization, or hatch rate but highly significant impacts on sperm motility. Spermatozoa of all MTBE-exposure groups showed a significantly lower straight-line velocity and lower average path velocity compared to those of the nonexposed group. These results suggest that chronic exposure to MTBE negatively affects fish sperm motility at concentrations that are environmentally relevant and several orders of magnitude lower than concentrations inducing acute effects.


[A case of isolated lung contusion].
A case of the isolated lung contusion is presented. A possibility of such a trauma in young individuals with elastic thoracic covers has been noted. The necessity of chest X-rays within short period following trauma to detect a source of contusion is stressed because of the dynamic changes in the contused lung tissue. Proper treatment produces a remission of pathologic lesions in lung parenchyma within 4-10 days.


Hepatoxicity induced by clozapine: Case report and brief review.
Antipsychotics are drugs that can produce transient elevations of hepatic enzymes. Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia and there is evidence that it can produce elevations of hepatic transaminases, expression of liver damage in a hepatocellular pattern. Case report and non-systematic review of the relevant literature. A 39-year-old woman with a diagnosis of paranoid schizophrenia attended the emergency department of a general hospital for nausea, vomiting and jaundice that appeared after the initiation of clozapine. There was no clinical improvement during hospitalisation, and death occurred after 44 days. Clozapine can increase the liver enzyme levels transiently and asymptomatically; however, there are clinical criteria that recommend the withdrawal of the antipsychotic. This is the third case reported in the literature of a fatal outcome of clozapine-induced hepatotoxicity.


Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway.
Dysfunctional high density lipoprotein (HDL) is implicated in the pathogenesis of cardiovascular disease, but the underlying pathways remain poorly understood. One potential mechanism involves covalent modification by reactive carbonyls of apolipoprotein A-I (apoA-I), the major HDL protein. We therefore determined whether carbonyls resulting from lipid peroxidation (malondialdehyde (MDA) and hydroxynonenal) or carbohydrate oxidation (glycolaldehyde, glyoxal, and methylglyoxal) covalently modify lipid-free apoA-I and inhibit its ability to promote cellular cholesterol efflux by the ABCA1 pathway. MDA markedly impaired the ABCA1 activity of apoA-I. In striking contrast, none of the other four carbonyls were effective. Liquid chromatography-electrospray ionization-tandem mass spectrometry of MDA-modified apoA-I revealed that Lys residues at specific sites had been modified. The chief adducts were MDA-Lys and a Lys-MDA-Lys cross-link. Lys residues in the C terminus of apoA-I were targeted for cross-linking in high yield, and this process may hinder the interaction of apoA-I with lipids and ABCA1, two key steps in reverse cholesterol transport. Moreover, levels of MDA-protein adducts were elevated in HDL isolated from human atherosclerotic lesions, suggesting that lipid peroxidation might render HDL dysfunctional in vivo. Taken together, our observations indicate that MDA damages apoA-I by a pathway that generates lysine adducts at specific sites on the protein. Such damage may facilitate the formation of macrophage foam cells by impairing cholesterol efflux by the ABCA1 pathway.


Crohn's disease presenting with acute pancreatitis.
Crohn's disease is often accompanied by extraintestinal inflammation. Acute pancreatitis can be a rare manifestation of Crohn's disease. The present report describes a patient who developed two episodes of pancreatitis before the diagnosis of Crohn's disease. Clinical and laboratory evaluation excluded other causes of pancreatitis, confirming a direct association of the pancreatitis with Crohn's disease. This case report supports the hypothesis that acute pancreatitis may precede the clinical manifestations and diagnosis of the underlying inflammatory bowel disease.


RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 down-regulation of transforming growth factor β signaling.
The activity of the E3 ligase, SMURF2, is antagonized by an intramolecular, autoinhibitory interaction between its C2 and Hect domains. Relief of SMURF2 autoinhibition is induced by TGFβ and is mediated by the inhibitory SMAD, SMAD7. In a proteomic screen for endomembrane interactants of the RING-domain E3 ligase, RNF11, we identified SMURF2, among a cohort of Hect E3 ligases previously implicated in TGFβ signaling. Reconstitution of the SMURF2·RNF11 complex in vitro unexpectedly revealed robust SMURF2 E3 ligase activity, with biochemical properties previously restricted to the SMURF2·SMAD7 complex. Using in vitro binding assays, we find that RNF11 can directly compete with SMAD7 for SMURF2 and that binding is mutually exclusive and dependent on a proline-rich domain. Moreover, we found that co-expression of RNF11 and SMURF2 dramatically reduced SMURF2 ubiquitylation in the cell. This effect is strictly dependent on complex formation and sorting determinants that regulate the association of RNF11 with membranes. RNF11 is overexpressed in certain tumors, and, importantly, we found that depletion of this protein down-regulated gene expression of several TGFβ-responsive genes, dampened cell proliferation, and dramatically reduced cell migration in response to TGFβ. Our data suggest for the first time that the choice of binding partners for SMURF2 can sustain or repress TGFβ signaling, and RNF11 may promote TGFβ-induced cell migration.


Focusing subwavelength grating coupler for mid-infrared suspended membrane germanium waveguides.
We present a focusing subwavelength grating (SWG) for efficient coupling of mid-infrared (mid-IR) light into suspended membrane Ge photonic integrated circuits (PICs) that enable mid-IR applications in the entire fingerprint region. By virtue of their wide spectral transparency window and air-cladding device configuration, the suspended membrane Ge PICs are expected to be effective for mid-IR applications over the spectral region covering from 2 to 15 μm. Specifically, we demonstrate the maximum coupling efficiency of -11 dB with a 1-dB bandwidth of ∼58 nm at the SWG's center wavelength of 2.37 μm. Our focusing SWG is expected to advance the development of on-chip long-wavelength mid-IR applications such as biochemical sensing, thermal imaging, and nonlinear optics in the fingerprint region.


Prednisone monotherapy in asymptomatic hormone refractory prostate cancer.
Patients with advanced prostate cancer eventually cease to respond to hormonal therapy and thus progress to hormone refractory prostate cancer (HRPC). Prednisone has been used in this setting; however, limited data is available for this monotherapy in the asymptomatic HRPC population. To evaluate the PSA response rate to prednisone in asymptomatic patients with hormone refractory prostate cancer (HRPC). Secondary objectives were to determine toxicity, predictors of response, and to determine overall survival of this population. Patients with asymptomatic HRPC that were treated with low dose prednisone from April 1998 to 2003 were identified from the British Columbia Cancer Agency patient and pharmacy registries. Inclusion criteria were an ECOG Performance Status of 2 at the time of prednisone initiation, prior medical or surgical orchidectomy, a rising PSA, and no symptoms from prostate cancer. Demographic data, lab values, serial PSAs, and survival data were collected. Univariate analyses were performed to evaluate potential predictors of response. Forty-nine patients met the inclusion criteria. There was a 22.4% response rate to prednisone as defined by a 50% PSA decline. An additional 16.3% of patients had a PSA decline of < 50%. Ninety percent of patients had no documented side effects. PSA responders were more likely to have bony metastases (9/11 versus 17/38, p = 0.03) and lived longer (24.7 versus 15.4 months median survival p = 0.02). The median duration of response in the PSA responders was 4.3 months (0.89-30). Of all PSA responders, 27% had a time to progression greater than 1 year and 45% did not require chemotherapy for the duration of the study. Prednisone monotherapy is well tolerated and is associated with a clinically relevant response rate in patients with asymptomatic HRPC. Prolonged time to progression and thus avoidance of more toxic chemotherapy is possible in some patients.


Development and validation of frailty and malnutrition knowledge assessment scale for community-dwelling older adults.
There is a lack of reliable tools to assess the knowledge of frailty and malnutrition in community-dwelling older adults. To develop and validate reliable frailty and malnutrition knowledge assessment scales for this population, two scales were developed and validated through five phases. Phase 1: the item pools were constructed through a literature review and research panel based on the symptom interpretation model. Phase 2: the expert consultation was performed to select the items. Phase 3: a pilot survey was conducted to assess the clarity of the items and further revise the scales. Phase 4: 242 older adults were surveyed to finalize the items. Phase 5: 241 older adults were surveyed to test the psychometric properties. The two scales each comprise 3 dimensions (symptoms, risk factors, and management strategies) and 11 items. They had good construct validity, with all indicators of correlation analysis and confirmatory factor analysis meeting their specific criteria. The reliability of the frailty and malnutrition knowledge assessment scales was good, with composite reliability coefficients all >0.60, Cronbach's alpha being 0.81 and 0.83, and the Spearman-Brown coefficient being 0.74 and 0.80, respectively. Their acceptability was good, with both having a completion rate of 92.18% and an average completion time of 3 min. The two scales are reliable tools to assess the knowledge of frailty and malnutrition among community-dwelling older adults, especially for large-scale surveys. They can help identify knowledge gaps in older adults and provide a basis for developing targeted educational interventions.


[Feasibility of applying ornamental plants in contaminated soil remediation].
Phytoremediation is one of the effective ways in resolving problems of contaminated soils, but limited hyperaccumulation plant species were reported and documented. This shortage could be offset if remediation plants can be screened out from various ornamental plants. In addition, such doing can beautify the environment while bring some economic effects. Starting from the importance of phytoremediation, this paper generalized the characters and standards of remediation plants. Through describing the resources of ornamental plants and their functions on environmental protection, particularizing their superiorities to other plants, and analyzing their endurance, accumulation traits and remediation types, the feasibility of applying ornamental plants in the practices of contaminated soil remediation was discussed. To screening out hyperaccumulators from ornamental plants would be an entirely new research area in the remediation of contaminated soils.


Imaging of complicated frontal sinusitis.
Complications occur in 3% of the cases of frontal sinusitis. These are mainly oculo-orbital, intracranial and osteomyelitis. Our aim is to describe the contribution of different imaging modalities in the diagnosis of these complications and their post-treatment monitoring. within a 15 years period (2000-2014), 10 patients with complicated frontal sinusitis were included into this retrospective study. 10 patients (9 males) aged 9 to 70 year old (mean 28). Two of these patients (20%) had a history of craniofacial trauma. Frontal headache was present in all cases (100%), frontal swelling in 8 cases (80%) and unilateral palpebral edema in 3 cases (30%). A CT scan of the face and brain was performed in all cases and revealed frontal osteomyelitis in 6 cases (60%), extradural empyema in 3 cases (33%), intracranial frontal abscess in 2 cases (20%) and occulo-orbital complications in 3 cases (30%). Magnetic resonance imaging was performed in one patient and demonstrated thrombosis of the upper longitudinal sinus. 40% of our patients associated 2 complications. Cross-sectional imaging is important in early and accurate diagnosis of complicated frontal sinusitis.


Preparation and evaluation of self-microemulsifying drug delivery system containing vinpocetine.
The main purpose of current investigation is to prepare a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of vinpocetine, a poorly water-soluble drug. Suitable vehicles were screened by determining the solubility of vinpocetine in them. Certain surfactants were selected according to their emulsifying ability with different oils. Ternary phase diagrams were used to identify the efficient self-microemulsifying region and to screen the effect of surfactant/cosurfactant ratio (K(m)). The optimized formulation for in vitro dissolution and bioavailability assessment was oil (ethyl oleate, 15%), surfactant (Solutol HS 15, 50%), and cosurfactant (Transcutol P, 35%). The release rate of vinpocetine from SMEDDS was significantly higher than that of the commercial tablet. Pharmacokinetics and bioavailability of SMEDDS were evaluated. It was found that the oral bioavailability of vinpocetine of SMEDDS was 1.72-fold higher as compared with that of the commercial tablet. These results obtained demonstrated that vinpocetine absorption was enhanced significantly by employing SMEDDS. Therefore, SMEDDS might provide an efficient way of improving oral bioavailability of poorly water-soluble drugs.


Assessing The Role Of Education In Adult Women's Knowledge And Awareness Of Human Papillomavirus And Human Papillomavirus Vaccine.
Awareness and knowledge of Human Papillomavirus (HPV) and HPV vaccine among women are not satisfactory in developing countries. The aim of this study was to assess the role of education in adult women about knowledge and awareness of human papillomavirus (HPV) and HPV vaccine. This cross-sectional study was carried out in women aged 19- 50 years attending the out-patient waiting area of a tertiary care hospital in Karachi from August 2014 to August 2015. Convenience sampling was applied. After their written consent, a selfadministered questionnaire was used to obtain information regarding role of education and awareness, knowledge of human papillomavirus (HPV) and HPV vaccine. A total of 600 women completed the questionnaire. Mean age of the study participants was 39±10.7 years. About 68% (n=405) had an education level intermediate or less, while 33% (n=195) had a bachelors or higher degree. A total of 56.3% (n=338) women were aged less than 40 years. Awareness among women varies with the level of education acquired. As shown by results, a lesser proportion of undergraduate women were aware about HPV and its related diseases as compared women at graduate level. Moreover, our study identifies significant gaps in knowledge about sexually transmitted infections, HPV, cervical cancer and its prevention. There is an urgent need to develop public awareness programs targeting the adolescent and young adult women of our country.


[Neuro-AIDS].
Various findings prove the neurotropism of the human immune deficiency virus (HIV). Besides an aseptic meningitis at the time of seroconversion and polyradiculoneuropathies clinical and neuropathological studies focus on subacute encephalitis leading to dementia and focal neurological complications. Therapeutic strategies, various considerations concerning the pathogenesis of other subacute, chronic and slow virus infections of the nervous system as well as prophylactic implications become more and more important.


Reintroduction and Post-Release Survival of a Living Fossil: The Chinese Giant Salamander.
Captive rearing and reintroduction / translocation are increasingly used as tools to supplement wild populations of threatened species. Reintroducing captive-reared Chinese giant salamanders may help to augment the declining wild populations and conserve this critically endangered amphibian. We released 31 captive-reared juvenile giant salamanders implanted with VHF radio transmitters at the Heihe River (n = 15) and the Donghe River (n = 16) in the Qinling Mountains of central China. Salamanders were monitored every day for survival from April 28th 2013 to September 3rd 2014. We attempted to recapture all living individuals by the end of the study, measured their body mass and total body length, and checked for abnormalities and presence of external parasites. Two salamanders at the Heihe River and 10 animals at the Donghe River survived through the project timeline. Nine salamanders were confirmed dead, while the status of the other 10 animals was undetermined. The annual survival rate of giant salamanders at the Donghe River (0.702) was 1.7-fold higher than that at the Heihe River (0.405). Survival increased as individuals were held longer following surgery, whereas body mass did not have a significant impact on survival rate. All salamanders recaptured from the Donghe River (n = 8) increased in mass (0.50 ± 0.13 kg) and length (5.5 ± 1.5 cm) after approximately 11 months in the wild, and they were only 7% lighter than wild animals of the same length (mean residual = -0.033 ± 0.025). Our results indicate that captive-reared Chinese giant salamanders can survive in the wild one year after release and adequate surgical recovery time is extremely important to post-release survival. Future projects may reintroduce older juveniles to achieve better survival and longer monitoring duration.


The clinical and histological features of transitional cell carcinoma of the bladder with microcysts: analysis of 12 cases.
To describe the clinical course and histological features of transitional cell carcinoma (TCC) of the bladder with microcysts. Among 940 patients with bladder TCC diagnosed at our institution during a 5 year period. 12 (1.2%; eight men and four women, mean age 71.1 years, range 52-85) were diagnosed histologically as having microcystic TCC. Sections of the tumours were stained with haematoxylin and eosin, periodic acid-Schiff and Alcian blue and clinical data obtained from the patients' records. Of the 12 patients with bladder TCC with microcysts, three had tumours confined to the epithelium, six had tumour invasion of the lamina propria and three had muscle invasion. One patient had low-grade TCC and 11 had high-grade TCC; six patients had a second primary tumour; three had a colon carcinoma, one a villous adenoma of the caecum, one a locally advanced carcinoma of the prostate and the last a squamous cell carcinoma of the uterine cervix. Microcystic TCC was associated with high-stage and high-grade bladder tumours and with other primary tumours, especially of the colon. Screening these patients for asymptomatic tumours of the colon is suggested.


Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation.
Second-hand smoke (SHS) is associated with 20-30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL (p < 0.001), lung (p < 0.05), and bladder mucosa (p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair (p < 0.01) and base excision repair (p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly (p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers.


Early heparin administration after traumatic brain injury: Prolonged cognitive recovery associated with reduced cerebral edema and neutrophil sequestration.
Early administration of unfractionated heparin (UFH) after traumatic brain injury (TBI) reduces early in vivo circulating leukocytes (LEUs) in peri-injury penumbral brain tissue, enhancing cognitive recovery 2 days after injury. It remains unclear how long this effect lasts and if this is related to persistently accumulating LEUs in penumbral brain tissue. We hypothesized that UFH reduces LEU brain tissue sequestration resulting in prolonged cognitive recovery. CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. Unfractionated heparin (75 or 225 U/kg) or vehicle was repeatedly administered after TBI. Neurologic function (Garcia Neurological Test [maximum score = 18]) and body weight loss ratios were evaluated at 24 hours to 96 hours after TBI. Brain and lung wet-to-dry ratios, hemoglobin levels, and brain LEU sequestration (Ly6G immunohistochemistry) were evaluated 96 hours postmortem. Analysis of variance with Bonferroni correction determined significance (p < 0.05). Compared with untreated CCI animals (24 hours, 14.7 ± 1.0; 48 hours, 15.5 ± 0.7; 72 hours, 15.0 ± 0.8; 96 hours, 16.5 ± 0.9), UFH75 (24 hours, 16.0 ± 1.0, p < 0.01; 48 hours, 16.5 ± 0.7, p < 0.05; 72 hours, 17.1 ± 0.6, p < 0.01; 96 hours, 17.4 ± 0.7, p < 0.05) increased cognitive recovery throughout the entire observation period after TBI. At 48 hours, UFH225 significantly worsened body weight loss (10.2 ± 4.7%) as compared with uninjured animals (5.5 ± 2.9%, p < 0.05). Both UFH75 (60.8 ± 40.9 PMNs per high-power field [HPF], p < 0.05) and UFH225 (36.0 ± 17.6 PMNs/HPF, p < 0.01) significantly decreased brain neutrophil sequestration found in untreated CCI animals (124.2 ± 44.1 PMNs/HPF) 96 hours after TBI. Compared with untreated CCI animals (78.8 ± 0.8%), UFH75 (77.3 ± 0.6%, p = 0.04) reduced cerebral edema to uninjured levels (77.4 ± 0.6%, p = 0.04 vs. CCI). Only UFH225 (10.6 ± 1.2 g/dL) resulted in lower hemoglobin than in uninjured animals (13.0 ± 1.2 g/dL, p < 0.05). Heparin after TBI reduces tissue LEU sequestration and edema in injured brain for up to 4 days. This is associated with persistent improved cognitive recovery, but only when low-dose UFH is given. Early administration of UFH following TBI may blunt LEU-related cerebral swelling and slow progression of secondary brain injury.


Diagnostic value of liver biopsy in alcoholic liver disease.
Because it remains debatable whether all patients with a clinical diagnosis of alcoholic liver disease should have a liver biopsy to help confirm the diagnosis, we evaluated the diagnostic value of liver biopsy in alcoholic liver disease. Studied were 108 consecutive patients who had a percutaneous liver biopsy for the first time. In all cases the patient's clinical diagnosis recorded before biopsy was compared with the histological diagnosis of an experienced histopathologist. Prebiopsy clinical data (reported alcohol intake, signs of chronic liver disease) and laboratory data (liver function tests, mean corpuscular volume, ferritin, hepatitis B serology) were reviewed. We found that a prebiopsy clinical diagnosis of alcoholic liver disease (n = 35) was confirmed by biopsy in all but one case. The prebiopsy diagnosis of alcoholic liver disease was significantly associated with a histological diagnosis of alcoholic liver disease (specificity 98%, sensitivity 79%). Individually, alcohol intake, signs of chronic liver disease, the alanine aminotransferase (ALT), the aspartate aminotransferase to ALT ratio, and the mean corpuscular volume were significantly associated with a histological diagnosis of alcoholic liver disease. When clinical and laboratory parameters were considered jointly using stepwise logistic regression, only reported alcohol intake and mean corpuscular volume were significant. Liver biopsy may not always be necessary for the identification of that broad group of patients with alcoholic liver disease.


Optimization of high-frequency oscillatory ventilation for the treatment of experimental pneumothorax.
To determine the effect of frequency, amplitude, inspiratory time, and mean airway pressure on gas flow through a chest tube in an animal model of pneumothorax treated with high-frequency oscillatory ventilation (HFOV). Observational study. Animal laboratory. Neonatal piglets (n = 12). After saline lavage, a model of experimental pneumothorax was created by selective right mainstem intubation and manual ventilation at high-peak inspiratory pressure. A chest tube was placed, and gas flow through the chest tube was measured with a pneumotachometer during HFOV with the SensorMedics 3100A. The effects of frequency, inspiratory time, amplitude, and mean airway pressure on chest tube gas flow were determined. Gas flow through the chest tube was significantly higher (p <.001) at 5 Hz (601 +/- 23 mL/min) than at 10 Hz (464 +/- 64 mL/min) or 15 Hz (400 +/- 11 mL/min), while mean airway pressure, inspiratory time, and PaCO2 were kept constant. Gas flow was higher at an inspiratory time of 50% compared with one of 30% (645 +/- 49 vs. 436 +/- 36 mL/min, respectively). Gas flow was directly related to amplitude (284 mL/min at an amplitude of 10 cm H2O, increasing to 877 mL/min at an amplitude of 80 cm H2O) when a 3.5-mm endotracheal tube was used; however, gas flow was attenuated at amplitudes of >40 cm H2O when smaller endotracheal tubes were used. Gas flow increased significantly with the increase of mean airway pressure from 92 mL/min at 15 cm H2O to 1433 mL/min at 30 cm H2O. In a neonatal piglet model of pneumothorax treated with HFOV, with amplitude adjusted to maintain constant alveolar ventilation, gas flow through the chest tube was significantly lower at 15 Hz compared with either 10 Hz or 5 Hz. Chest tube gas flow increased with increasing inspiratory time, amplitude, and mean airway pressure. These findings support the use of higher frequencies, short inspiratory times, low amplitudes, and low mean airway pressures for healing air leak with HFOV.


Epidemiological analysis of coronavirus disease (COVID-19) patients on ships arriving at Busan port in Korea, 2020.
Quarantine played an important role in preventing the spread of infectious diseases between countries in the early stages of the COVID-19 outbreak. In particular, in ports, infection during transit can cause a large number of patients on board ships and can flow into the community. In this study investigated cause of the cause of transmission in ships and suggested the way of preventing secondary transmission by analyzing clinical and epidemiological characteristics of COVID-19 patients identified at Busan Port (South Korea) in 2020. During the study period, out of 19,396 ships that arrived at Busan Port, 50 ships had COVID-19 confirmed cases. Among the 50 ships, type of deep-sea fishing vessels (24 ships, 48.0%), ships weighing less than 5,000 tons (31 ships, 62.0%), and ships from Russia (41 ships, 82.0%) had the highest positivity rates. Total 283 of the 25,450 arrivals tested positive for COVID-19 (a positivity rate of 1.1%), and 270 (95.4%) were asymptomatic. Moreover, the number of COVID-19 patients increased with the duration of the waiting period between arrival and sample collection (12.7% to 37.4%), and the positivity rate was significantly higher for those working as stewards (64.3%). These results indicate secondary transmission was active on board ships and that infection among stewards importantly contributed to group outbreaks. In addition, onboard residence time after arrival significantly elevated to COVID-19 positivity rates, indicating that rapid isolation, as determined using various screening techniques, might be effective at preventing onboard transmission and subsequent community outbreaks.


Editorial: biodegradable materials.
This Special Issue "Biodegradable Materials" features research and review papers concerning recent advances on the development, synthesis, testing and characterisation of biomaterials. These biomaterials, derived from natural and renewable sources, offer a potential alternative to existing non-biodegradable materials with application to the food and biomedical industries amongst many others. In this Special Issue, the work is expanded to include the combined use of fillers that can enhance the properties of biomaterials prepared as films. The future application of these biomaterials could have an impact not only at the economic level, but also for the improvement of the environment.


Genome resource banking for wildlife conservation: promises and caveats.
The value of cryopreserved germplasm in agriculture, aquaculture and medicine was recognized in the mid-twentieth century following the discovery in the late 1940s of a method for recovering viable spermatozoa after freeze-thawing. Sir Alan Parkes (a founder of cryobiology as a discipline) remarked that "time and space has been abolished for cattle breeding", a phrase that continues to summarise the potential value of the Genetic Resource Bank (GRB) concept for all species. The underlying principle behind these remarks was based on the recognition that spermatozoa could remain viable for many years, and still achieve pregnancies even long after the semen donor had died. Nowadays, live mammalian embryos, amphibian spermatozoa and cultured somatic cells can also be stored for future use in conservation breeding programmes, where the overarching aim is to mitigate the deleterious impacts of inbreeding on the fitness and survival of populations. Revolutionary advances in the cryobiology of coral spermatozoa, embryos and larvae are also helping to counter the damaging effects of climate change and toxic chemicals on coral reefs. In this article we review the ways in which GRBs can contribute to global conservation activities, noting that species-specific biological differences can limit the success of standard animal breeding technologies such as artificial insemination and embryo transfer. These limitations mean that there is still a need for the development of novel, and possibly species-specific, GRB technologies.


Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.
Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.


[Progress in research of safety, efficiency and vaccination status of influenza vaccine in populations at high risk].
This paper reviews the domestic and foreign studies published in 2020 on the application of influenza vaccine in populations at high risk. The importance of influenza vaccination in population at high risk has been proved by larger sample, multicentre, high-quality evidence-based studies. Influenza vaccination is the most cost-effective measure to prevent influenza. However, the coverage rate of influenza vaccine is very low in China, it is necessary to strengthen the health education to promote influenza vaccination in different populations. It is recommended to give influenza vaccination to the population in whom influenza vaccination has been proven safe and effective before influenza season. Research of the safety, efficiency and cost-effectiveness of influenza vaccine should be accelerated for the populations in whom such data are lacking or insufficient.


ABL1-Directed Inhibitors for CML: Efficacy, Resistance and Future Perspectives.
The introduction of tyrosine kinase inhibitors (TKIs) directed against the catalytic activity of the ABL tyrosine kinase has considerably improved the outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease. Indeed, these individuals currently show a life-expectancy comparable to those of healthy subjects. Currently, five TKIs (imatinib, dasatinib, nilotinib, bosutinib and ponatinib) are approved for the treatment of CML and can be used as first, second or further lines of treatment according to disease risk scores, patient comorbidities and the presence of known TKI resistance mechanisms. In fact, 15-20% of all CML patients fail to achieve optimal responses according to the current definitions of the European Leukemia Network and will require sequential TKI treatment to avoid disease progression. In this review, we present the state of art in several crucial areas of CML management by briefly: i) depicting the domain structure of the BCR-ABL1 oncoprotein; ii) describing pivotal data concerning TKI efficacy; iii) illustrating the diverse molecular mechanisms causing TKI resistance; and iv) summarizing new ABL1-directed therapeutic approaches that are presently under investigation.


[Possible use of saliva in the diagnostics and treatment--review of the literature].
In recent years increasingly more attention has been devoted to the possibilities of saliva analysis in laboratory diagnostics. The article discusses issues associated with the production of saliva, and contemporary possibilities of its use in the diagnostics and treatment. The benefits of diagnostic application of saliva for laboratory tests instead of blood serum are presented, and current possibilities of its application in the diagnostics of hereditary disorders, autoimmune diseases, infectious diseases, endocrine disorders, as well as in the assessment of therapeutic drug levels and the monitoring of stimulants.


Ezrin/radixin/moesin proteins are high affinity targets for ADP-ribosylation by Pseudomonas aeruginosa ExoS.
Pseudomonas aeruginosa ExoS is a bifunctional type III-secreted cytotoxin. The N terminus (amino acids 96-233) encodes a GTPase-activating protein activity, whereas the C terminus (amino acids 234-453) encodes a factor-activating ExoS-dependent ADP-ribosyltransferase activity. The GTPase-activating protein activity inactivates the Rho GTPases Rho, Rac, and Cdc42 in cultured cells and in vitro, whereas the ADP-ribosylation by ExoS is poly-substrate-specific and includes Ras as an early target for ADP-ribosylation. Infection of HeLa cells with P. aeruginosa producing a GTPase-activating protein-deficient form of ExoS rounded cells, indicating the ADP-ribosyltransferase domain alone is sufficient to elicit cytoskeletal changes. Examination of substrates modified by type III-delivered ExoS identified a 70-kDa protein as an early and predominant target for ADP-ribosylation. Matrix-assisted laser desorption ionization mass spectroscopy identified this protein as moesin, a member of the ezrin/radixin/moesin (ERM) family of proteins. ExoS ADP-ribosylated recombinant moesin at a linear velocity that was 5-fold faster and with a K(m) that was 2 orders of magnitude lower than Ras. Moesin homologs ezrin and radixin were also ADP-ribosylated, indicating the ERMs collectively represent high affinity targets of ExoS. Type III delivered ExoS ADP-ribosylated moesin and ezrin (and/or radixin) in cultured HeLa cells. The ERM proteins contribute to cytoskeleton dynamics, and the ability of ExoS to ADP-ribosylate the ERM proteins links ADP-ribosylation with the cytoskeletal changes associated with ExoS intoxication.


Hyolaryngeal Movement During Normal and Effortful Swallows Determined During Ultrasonography.
This study investigated (a) the effects of the effortful swallow under two different instructions (tongue emphasis vs. pharyngeal squeezing) on hyoid displacement and hyoid-larynx approximation, (b) the association between tongue pressure and hyolaryngeal movement during normal swallowing and the effortful swallow produced with tongue emphasis, and (c) age-related differences in hyolaryngeal movement during normal and effortful swallows (tongue emphasis vs. pharyngeal squeezing) in healthy individuals. Forty healthy adults (20 younger and 20 older) swallowed their saliva as they normally do (normal swallow) and performed the effortful swallow with tongue emphasis and pharyngeal squeezing. Tongue-to-palate pressure during swallowing was measured using the Iowa Oral Performance Instrument, hyolaryngeal movement was measured using ultrasonography, and submental surface electromyography was used to track swallows. Results revealed differences in hyolaryngeal movement across swallowing types. Both types of effortful swallows showed greater hyolaryngeal movement than normal swallows. Additionally, hyolaryngeal movement was greater during the effortful swallow with tongue emphasis than the effortful swallow with pharyngeal squeezing. Age-related differences were found only in hyoid-larynx approximation during the effortful swallow with tongue emphasis (younger > older adults). Furthermore, moderate positive correlations were identified between tongue pressure and hyolaryngeal movement during normal swallows and the effortful swallow with tongue emphasis. The findings show that varying instructions of the effortful swallow affect hyolaryngeal movement differently, suggesting that clinicians may need to individualize the effortful swallow instruction according to the physiological impairments of each patient. Additionally, natural age-related changes in swallowing physiology do not seem to affect an individual's ability to perform the effortful swallow or to impact hyolaryngeal movement. Finally, the association between tongue pressure and hyolaryngeal movement during normal swallows and the effortful swallow with tongue emphasis suggests that the tongue plays a critical role in swallowing, priming subsequent swallowing events.


Show me the pragmatic contribution: a developmental investigation of contrastive inference.
An utterance such as 'Show me the large rabbit' potentially generates a contrastive inference, i.e., the article the and the adjective large allow listeners to pragmatically infer the existence of other entities having the same noun (e.g. a small rabbit). The primary way to measure children's ability to carry out this pragmatic inference has been through tasks that measure infelicity detection. We argue that such studies are not as revealing as one might assume because they force children to adopt a metalinguistic stance and they consider infelicity detection as tantamount to contrastive inference-making. To address these concerns, we develop a game-like situation in which all utterances remain felicitous. Moreover, we make a distinction between responses that are revealing of a pragmatic interpretation and responses that are revealing of a reliance on the utterance's linguistically encoded meaning (i.e., a lack of contrastive inference). Three experiments with seven-year-olds, ten-year-olds, and adults show that pragmatic interpretations do not emerge among seven-year-olds, that ten-year-olds do not show adult-like performance, and that adults are not at ceiling. We conclude that contrastive inference-making is an effortful process and that the ability to detect such gains-in-information through language increases with age.


Effect of microclimate on bacterial count and airborne emission from dairy barns on the environment.
The main microclimate parameters, i.e. bacterial count and airborne emission to the immediate environment, were analyzed in a dairy barn. Air temperature, relative humidity and air flow velocity were measured on an attested Testo 400 device (Testo Inc., Germany). Air samples were collected by use of a Merck MAS-100 device (Merck KgaA, Darmstadt, Germany) onto a commercially available nutrient Columbia agar (Biolife, Milan, Italy) and incubated for 24 h in an incubator at 37 degrees C work temperature. Measurements were carried out once a week in the morning, at noon, and in the evening during October and November 2002. In the barn, measurements were performed in the animal housing area along the feedlot, and outside the barn at a distance of 5 m, 25 m and 50 m eastward and westward from the barn. The measured dairy barn temperature ranged from 11.2 degrees C to 13.1 degrees C, relative humidity from 71.3-78.6 %, and air flow velocity from 0.09-0.11 m/s. The mean value of total bacterial count in the barn air ranged from 2.82 x 10 (4) cfu/m(3) at noon to 7.76 x 10(4) cfu/m(3) in the evening. Bacterial count decreased at particular measuring sites outside the barn, with Wilcoxon matched pair test showing statistical significance (p < 0.05) at a distance of 5 m eastward and 5 m westward of the barn.


Active squamous metaplasia of the cervical epithelium is associated with subsequent acquisition of human papillomavirus 16 infection among healthy young women.
Vulnerability of younger women to human papillomavirus 16 (HPV16) infection has been attributed to the predominance of ectocervical columnar epithelia in this age group. However, squamous metaplastic tissue may be more influential. We examined the extent of ectopy and metaplastic activity as risks for HPV16 acquisition in a prospective cohort. Participants were HPV16 negative at the first two visits. Follow-up occurred every 4 months. Ectopy was quantitatively measured on colpophotographs. We calculated metaplastic rate as the difference in ectopy between visits. Cox proportional hazards models were constructed, adjusting for several covariates. Analyses included 198 women (mean baseline age 17 years) for 1734 visits. Mean follow-up was 4.4 years. Incident HPV16 was detected in 36 (18%) women. Metaplastic rate between the two visits before HPV16 detection was significantly associated with incident infection (hazard ratio [HR], 1.17; confidence interval [CI], 1.02-1.33; P = .02). However, ectopy was not significant, whether measured before or concurrent to HPV16 detection (HR range, 0.99-1.00; CI range, .97-1.02; P range, .47-.65). Dynamic metaplasia rather than the sheer extent of ectopy appears to increase risk for incident HPV16 in healthy young women. This in vivo observation is consistent with the HPV life cycle, during which host cell replication and differentiation supports viral replication.


Carcinogen metabolism, DNA damage repair and oral head and neck squamocellular carcinoma (HNSCC). A review.
Head and neck squamocellular carcinoma (HNSCC) has now become the 6th most common cancer among men in the developed world and affects the oral cavity, salivary glands, larynx and pharynx. Tobacco chewing, alcohol consumption and last but not least, smoking seem to be the most important risk factors. In particular in non-drinkers, smoke increases the relative risk (RR) of developing HNSCC of the oral cavity and pharynx from 2 to 20 fold; especially in the oral cavity, the association between alcohol and smoke could have a multiplier effect. Cancer arises from damage to DNA of genes located at various points of the short (p) and long (q) arms of a number of chromosomes, caused by exposure to various carcinogens. Thus, the carcinogenic process requires continuous exposure to environmental carcinogens (i.e., longstanding history of smoking and drinking), an increased susceptibility to carcinogens (induced by xenobiotic metabolizing enzyme polymorphism) and an impaired DNA repair capacity (both inherited and acquired). Our purpose in this paper is to review advances in the understanding of the role of the European or Caucasian genetic aberrations that affect carcinogen metabolism and DNA repair genes in oral HNSCC development: we consider that those abnormalities will be useful in assessing individuals at risk.


D-1 agonist, SKF 38393, but not a D-2 agonist, produces a cholinergically mediated analeptic effect in rabbits.
SKF 38393 (2-15 mg/kg, IV), but not quinpirole, shortened the duration of loss of righting reflex produced in pentobarbital-narcotized rabbits. This effect was blocked by atropine (2-5 mg/kg, IV), but not by atropine methylbromide, suggesting that a central cholinergic mechanism was involved. The analeptic effect was also blocked by SCH 23390 (0.1 mg/kg, IV) or raclopride (5 mg/kg, IV). These results indicate that SKF 38393 activates central cholinergic neurons, which in turn initiate the analeptic effect. However, the fact that raclopride also blocked the SKF 38393 analeptic effect, but quinpirole did not exert any analeptic effect, suggests that a D-1/D-2 modulation of cholinergic systems may be involved in the SKF 38393-induced analeptic effect. These results also support our earlier findings and view that cocaine-induced analeptic activity is mediated by a dopaminergic-cholinergic mechanism.


Predictive value of ACE I/D genetic polymorphism for 12-month all-cause mortality in patients with acute myocardial infarction.
The prognostic role of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genetic polymorphism in patients with acute myocardial infarction (AMI) is controversial and inconsistent across various study populations. This study evaluated the predictive validity of the ACE I/D variant based on 12-month all-cause mortality in Vietnamese patients after AMI. This was an observational, prospective study conducted among AMI patients at Cho Ray Hospital between January 2020 and September 2021. All participants were identified for ACE I/D polymorphism using the polymerase chain reaction method, with follow-up on survival status at 12 months from the date of admission. The proportions of II, ID, and DD genotypes of the ACE I/D variant were 49.5%, 35.9%, and 14.6%, respectively. All-cause mortality after 12 months occurred in 58 cases (10.6%). The ACE I/D polymorphism did not affect all-cause mortality in the dominant (P = .196), recessive (P = .827), homozygous (P = .515), and heterozygous (P = .184) models. A subgroup analysis by usage status of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) showed that in the non-ACEI/ARB group, patients with the DD genotype had a lower cumulative survival probability than patients with the II/ID genotypes (hazard ratio [HR] = 3.97, 95% confidence interval [CI]: 1.21-13.04; P = .023). Among patients with Global Registry of Acute Coronary Events (GRACE) scores below the median (153.5 points), those with DD genotype had a higher risk of mortality than those with the II/ID genotypes (HR = 3.35, 95% CI: 1.01-11.11; P = .049). The ACE I/D genetic polymorphism was found not to be associated with 12-month all-cause mortality in Vietnamese patients with AMI. However, it was associated with mortality in patients who did not use ACEI/ARB and also whose GRACE scores were below 153.5 points.


A pilot study examining measures of balance and mobility in children with unilateral lower-limb amputation.
Individuals with unilateral lower-limb amputation (LLA) have altered structure and physiology of their lower limbs which impairs their balance, mobility, physical function and participation in physical activities. As part of (re)habilitation, focus is given to improving gait and balance in order to enhance overall mobility, function, self-efficacy, and independence. However, the relationships amongst body impairments and physical activity limitations remain unclear, particularly in the pediatric population. To provide an examination of the relationships among balance and mobility measures in children with unilateral lower-limb amputation and able-bodied children. Cross-sectional prospective comparative pilot study. Spatiotemporal gait parameters and standing postural control were evaluated in children with lower-limb amputation (n = 10) and age-matched able-bodied children (n = 10) in a laboratory-based setting. Clinical tests for mobility and balance consisted of the 10-m walk test, the 6-min walk test, and the Community Balance and Mobility scale. Energy expenditure was estimated during the 6-min walk test using the Physiological Cost Index. Analysis included comparing variables between able-bodied and lower-limb amputation groups, as well as examining the correlations among them. Walking speed, distance, and functional balance (p < 0.05) were significantly diminished in children with lower-limb amputation compared to able-bodied children. For children with lower-limb amputation, reduced energy expenditure was associated with narrower step width and more symmetrical gait; better postural control and balance were associated with faster walking speeds (p < 0.05). A greater clinical understanding of gait and balance deficits in this population may help to improve rehabilitation outcomes and overall functional mobility. Improved understanding of deficits in children with lower-limb amputation (LLA) may lead to more targeted interventions and facilitate clinical decision-making in rehabilitation settings for this population. The findings contribute to the limited literature and provide a basis to further examine suitable clinical outcome measures to be used in children with LLA.


Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle.
Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through hetero-oligomerization with α1-adrenoceptors. Here, we show that ACKR3 also regulates arginine vasopressin receptor (AVPR)1A. We observed that ACKR3 agonists inhibit arginine vasopressin (aVP)-induced inositol trisphosphate (IP3) production in human vascular smooth muscle cells (hVSMCs) and antagonize aVP-mediated constriction of isolated arteries. Proximity ligation assays, co-immunoprecipitation and bioluminescence resonance energy transfer experiments suggested that recombinant and endogenous ACKR3 and AVPR1A interact on the cell surface. Interference with ACKR3 : AVPR1A heteromerization using siRNA and peptide analogues of transmembrane domains of ACKR3 abolished aVP-induced IP3 production. aVP stimulation resulted in β-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit β-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced β-arrestin 2 recruitment to AVPR1A. AVPR1A and ACKR3 co-internalized upon agonist stimulation in hVSMC. These data suggest that AVPR1A : ACKR3 heteromers are constitutively expressed in hVSMC, provide insights into molecular events at the heteromeric receptor complex, and offer a mechanistic basis for interactions between the innate immune and vasoactive neurohormonal systems. Our findings suggest that ACKR3 is a regulator of vascular smooth muscle function and a possible drug target in diseases associated with impaired vascular reactivity.


GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon.
Activated regulatory T (Treg) cells express the surface receptor glycoprotein-A repetitions predominant (GARP), which binds and activates latent TGFβ. How GARP modulates Treg function in inflammation and cancer remains unclear. Here we demonstrate that loss of GARP in Treg cells leads to spontaneous inflammation with highly activated CD4+ and CD8+ T cells and development of enteritis. Treg cells lacking GARP were unable to suppress pathogenic T-cell responses in multiple models of inflammation, including T-cell transfer colitis. GARP-/- Treg cells were significantly reduced in the gut and exhibited a reduction in CD103 expression, a colon-specific migratory marker. In the colitis-associated colon cancer model, GARP on Treg cells dampened immune surveillance, and mice with GARP-/- Treg cells exhibited improved antitumor immunity. Thus, GARP empowers the functionality of Treg cells and their tissue-specific accumulation, highlighting the importance of cell surface TGFβ in Treg function and GARP as a potential therapeutic target for colorectal cancer therapy.Significance: These findings uncover functions of membrane-bound TGFβ and GARP that tune the activity of Treg cells, highlighting a potential treatment strategy in autoimmune diseases and cancer.


IMPROVING MAGNETIC RESONANCE RESOLUTION WITH SUPERVISED LEARNING.
Despite ongoing improvements in magnetic resonance (MR) imaging (MRI), considerable clinical and, to a lesser extent, research data is acquired at lower resolutions. For example 1 mm isotropic acquisition of T1-weighted (T1-w) Magnetization Prepared Rapid Gradient Echo (MPRAGE) is standard practice, however T2-weighted (T2-w)-because of its longer relaxation times (and thus longer scan time)-is still routinely acquired with slice thicknesses of 2-5 mm and in-plane resolution of 2-3 mm. This creates obvious fundamental problems when trying to process T1-w and T2-w data in concert. We present an automated supervised learning algorithm to generate high resolution data. The framework is similar to the brain hallucination work of Rousseau, taking advantage of new developments in regression based image reconstruction. We present validation on phantom and real data, demonstrating the improvement over state-of-the-art super-resolution techniques.


Water-induced degradation of polymer solar cells studied by H2(18)O labeling.
Water-induced degradation of polymer photovoltaics based on the active materials poly(3-hexylthiophene) (P3HT) or poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEHPPV) was studied. The solar cell devices comprised a bulk heterojunction formed by the active material and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) in a standard device geometry. The use of H2(18)O in conjunction with time-of-flight secondary ion mass spectrometry enabled mapping of the parts of the device that were induced by water. A comparison was made between the two active materials and between devices that were kept in the dark and devices that had been subjected to illumination under simulated sunlight. Devices that were exposed to ambient humidity were compared to devices exposed to saturated humidity. Finally, a comparison was made between results obtained using H2(18)O and earlier work involving 18O2. Water was found to have behavior similar to but not identical with molecular oxygen.


Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs.
Positional cloning has already produced the sequences of more than 70 human genes associated with specific diseases. In addition to their medical importance, these genes are of interest as a set of human genes isolated solely on the basis of the phenotypic effect of the respective mutations. We analyzed the protein sequences encoded by the positionally cloned disease genes using an iterative strategy combining several sensitive computer methods. Comparisons to complete sequence databases and to separate databases of nematode, yeast, and bacterial proteins showed that for most of the disease gene products, statistically significant sequence similarities are detectable in each of the model organisms. Only the nematode genome encodes apparent orthologs with conserved domain architecture for the majority of the disease genes. In yeast and bacterial homologs, domain organization is typically not conserved, and sequence similarity is limited to individual domains. Generally, human genes complement mutations only in orthologous yeast genes. Most of the positionally cloned genes encode large proteins with several globular and nonglobular domains, the functions of some or all of which are not known. We detected conserved domains and motifs not described previously in a number of proteins encoded by disease genes and predicted functions for some of them. These predictions include an ATP-binding domain in the product of hereditary nonpolyposis colon cancer gene (a MutL homolog), which is conserved in the HS90 family of chaperone proteins, type II DNA topoisomerases, and histidine kinases, and a nuclease domain homologous to bacterial RNase D and the 3'-5' exonuclease domain of DNA polymerase I in the Werner syndrome gene product.


Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.
Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH(2)-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856-68. (c)2010 AACR.


Silver-releasing bioactive glass nanoparticles for infected tissue regeneration.
Bacterial infections represent a formidable challenge, often leaving behind significant bone defects post-debridement and necessitating prolonged antibiotic treatments. The rise of antibiotic-resistant bacterial strains further complicates infection management. Bioactive glass nanoparticles have been presented as a promising substitute for bone defects and as carriers for therapeutic agents against microorganisms. Achieving consistent incorporation of ions into BGNs has proven challenging and restricted to a maximum ion concentration, especially when reducing the particle size. This study presents a notable achievement in the synthesis of 10 nm-sized Ag-doped bioactive glass nanoparticles (Ag-BGNs) using a modified yet straightforward Stöber method. The successful incorporation of essential elements, including P, Ca, Al, and Ag, into the glass structure at the intended concentrations (i.e., CaO wt% above 20 %) was confirmed by EDS, signifying a significant advancement in nanoscale biomaterial engineering. While exhibiting a spherical morphology and moderate dispersity, these nanoparticles tend to form submicron-sized aggregates outside of a solution state. The antibacterial effectiveness against MRSA was established across various experimental conditions, with Ag-BGNs effectively sterilizing planktonic bacteria without the need for antibiotics. Remarkably, when combined with oxacillin or fosfomycin, Ag-BGNs demonstrated a potent synergistic effect, restoring antibacterial capabilities against MRSA strains resistant to these antibiotics when used alone. Ag-BGNs exhibited potential in promoting human mesenchymal stromal cell proliferation, inducing the upregulation of osteoblast gene markers, and significantly contributing to bone regeneration in mice. This innovative synthesis protocol holds substantial promise for the development of biomaterials dedicated to the regeneration of infected tissue.


A new method for monitoring personal exposure to ethylene oxide in the occupational environment.
A novel method for monitoring occupational exposure to ethylene oxide was developed. Ethylene oxide was collected on Columbia JXC activated carbon, desorbed with carbon disulfide, and analyzed by gas chromatography using a TERGITOL TMN or UCON LB55OX column. Several parameters such as selection of adsorbent and column; effects of humidity, sampling rate and volume; shelf-life; interference from ten contaminants; desorption technique and calibration curve were investigated. The lower detection limit of the method is 0.15 ppm in ten liters of air. The method was evaluated statistically and by conducting a round-robin interlaboratory study.


[Leaf photosynthetic potential in canopy layers of un-thinned and thinned apple orchards].
Through the comparison of leaf photosynthetic potential and of photosynthetically active radiation (PAR), leaf nitrogen concentration (Nl), and mass per unit leaf area (Ml) in different canopy layers of un-thinned orchard (UOD) and thinned orchard (TOD), this paper studied the effects of UOD rebuilding on the use efficiencies of PAR and nitrogen, and their relationships to the fruit yield and quality. Thinning obviously improved the radiation environment in canopy. The radiation distribution in TOD canopy was more uniformly than that in UOD canopy, and the invalid space with relative PAR (PARr) less than 30% in TOD approached to zero, while the minimum mean PARr in UOD was 17%, and the space under 0. 3 of relative canopy height was invalid. The leaf photosynthetic efficiency in TOD was notably improved. Comparing with that in UOD, the photsynthetic rate (Pn) at the middle and bottom of the canopy in TOD was increased by 7.8% and 10.2%, respectively. Meanwhile, the photosynthetic potential parameters such as maximum carboxylation rate (Vmax) and maximum electron transfer rate (Jmax) also increased remarkably in TOD. The leaf photosynthetic potential had significant correlation with Nl, and the Nl was strongly correlated with PARr. As a result, leaf photosynthetic potential and PARr could be estimated according to the spatial distribution of relative leaf nitrogen concentration (Nlr).


MicroRNAs of Equine Amniotic Mesenchymal Cell-derived Microvesicles and Their Involvement in Anti-inflammatory Processes.
Cell-derived microvesicles (MVs) are a recently discovered mechanism of cell-to-cell communication. Our previous data show that MVs secreted by equine amniotic mesenchymal-derived cells (AMCs) are involved in downregulation of proinflammatory genes in lipopolysaccharide-stressed equine tendon and endometrial cells. The aim of the present study was to evaluate whether AMC-MVs contain selected microRNAs (miRNAs) involved in inflammation. Two pools of cells, derived from 3 amniotic membranes each, and their respective MVs were collected. Small RNAs were extracted and deep sequenced, followed by miRNA in silico detection. The analysis identified 1,285 miRNAs, which were quantified both in AMCs and MVs. Among these miRNAs, 401 were classified as Equus caballus miRNAs, 257 were predicted by homology with other species (cow, sheep, and goat), and 627 were novel candidate miRNAs. Moreover, 146 miRNAs differentially expressed (DE) in AMCs and MVs were identified, 36 of which were known and the remaining were novel. Among the known DE miRNAs, 17 showed higher expression in MVs. Three of these were validated by real time polymerase chain reaction: eca-miR-26, eca-miR-146a, and eca-miR-223. Gene ontology analysis of validated targets showed that the DE miRNAs in cells and MVs could be involved both in immune system regulation by modulating interleukin signaling and in the inflammatory process. In conclusion, this study suggests a significant role of AMCs in modulating immune response through cell-cell communication via MV-shuttling miRNAs.


Searching for Scalar Dark Matter with Compact Mechanical Resonators.
Ultralight scalars are an interesting dark matter candidate that may produce a mechanical signal by modulating the Bohr radius. Recently it has been proposed to search for this signal using resonant-mass antennas. Here, we extend that approach to a new class of existing and near term compact (gram to kilogram mass) acoustic resonators composed of superfluid helium or single crystal materials, producing displacements that are accessible with opto- or electromechanical readout techniques. We find that a large unprobed parameter space can be accessed using ultrahigh-Q, cryogenically cooled centimeter-scale mechanical resonators operating at 100 Hz-100 MHz frequencies, corresponding to 10^{-12}-10^{-6} eV scalar mass range.


[Growth and gene expression of leukemia cell after treated with methylation inhibitor 5-aza-2'-deoxycytidine].
To investigate the mechanism of demethylation therapy of leukemia by 5-aza-2'-deoxycytidine (5-aza-CdR). By using MTT test, NBT reduction reaction and DNA agarose gel electrophoresis, changes in proliferation, differentiation and apoptosis were observed in K562, HL-60 and fresh leukemia cells after treated with 5-aza-CdR. The mRNA expressions of DNMTs, p15, p53 and bcl-2 were measured by RT-PCR. The status of p15(INK4B) gene methylation was examined by methylation-specific PCR (MSP-PCR). The growth inhibition of K562, HL-60 and fresh leukemia cells displayed a dose and time-dependent manner after treated by 5-aza-CdR. The differentiation-inducing ability on HL-60 cells was obvious at 0.5 micromol/L of 5-aza-CdR. The up-regulation of p15 mRNA and p53 mRNA expression and down-regulation of bcl-2 mRNA expression were obvious as compared with the control, but the DNMTs expression was not significantly different from the control. The methylation status of p15 gene in fresh leukemia cells decreased gradually with increasing concentration of 5-aza-CdR. The proliferation of leukemia cells was obviously inhibited by 5-aza-CdR, its mechanism maybe related to the up-regulation of p15 and p53 genes and down-regulation of bcl-2 gene. The decrease of p15 gene methylation was associated with the competitive inhibition of 5-aza-CdR.


The Antigen-Presenting Potential of Vγ9Vδ2 T Cells During Plasmodium falciparum Blood-Stage Infection.
During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function, compromising effective antimalarial adaptive immunity. Human Vγ9Vδ2 T cells can act in vitro as antigen-presenting cells (APCs) and induce αβ T-cell activation. However, the relevance of this activity in vivo has remained elusive. Because Vγ9Vδ2 T cells are activated during the early immune response against P. falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P. falciparum-infected patients, Vγ9Vδ2 T cells presented increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, Vγ9Vδ2 T cells upregulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83, and CD86, induced naive αβ T-cell responses, and cross- presented soluble prototypical protein to antigen-specific CD8+ T cells. Our findings qualify Vγ9Vδ2 T cells as alternative APCs, which could be harnessed for therapeutic interventions and vaccine design.


Unbiased global optimization of Lennard-Jones clusters for N < or =201 using the conformational space annealing method.
We apply the conformational space annealing method to the Lennard-Jones clusters and find all known lowest energy configurations up to 201 atoms, without using extra information of the problem such as the structures of the known global energy minima. In addition, the robustness of the algorithm with respect to the randomness of initial conditions of the problem is demonstrated by ten successful independent runs up to 183 atoms. Our results indicate that this method is a general and yet efficient global optimization algorithm applicable to many systems.