Intramedullary spinal cord metastases: visibility on PET and correlation with MRI features.
Studies systematically evaluating the detection of intramedullary spinal cord metastasis with PET are lacking. Our purpose was to evaluate the visibility of intramedullary spinal cord metastasis on PET in a single institutional series and to correlate PET and MR imaging features. Patients were included if pretreatment MR imaging identifying an intramedullary spinal cord metastasis and an [(18)F] FDG-PET examination near the time of MR imaging were available. PET examinations were retrospectively reviewed, with reviewers blinded and then unblinded to the PET report and MR imaging findings. PET intramedullary spinal cord metastasis features were compared with and correlated with previously analyzed MR imaging lesion characteristics. Original clinical PET reports were reviewed. The final study sample was 10 PET examinations in 10 patients with 13 intramedullary spinal cord metastases. In 7 (70%) patients, retrospective blinded review demonstrated convincing evidence of 10 (77%) intramedullary spinal cord metastases. Three MR imaging features correlated with intramedullary spinal cord metastases being visible on PET compared with those nonvisible, respectively: larger lesion enhancement size: mean size: 32.1 mm versus 6.0 mm (P = .038); larger longitudinal extent of T2 signal abnormality: mean 5.6 versus 1.0 segments (P = .0081); and larger ratio of extent of T2 signal abnormality to contrast enhancement: 3.8 versus 1.0 (P = .0069). Intramedullary spinal cord metastasis was confidently reported clinically in 2 (20%) patients, accounting for 5 (38%) intramedullary spinal cord metastases. Most intramedullary spinal cord metastases can be detected on PET when performed near the time of pretreatment MR imaging. However, intramedullary spinal cord metastases may not be clinically reported on PET. Larger lesions with more edema are more likely to be visible. The spinal cord should be specifically and carefully assessed on PET for evidence of intramedullary spinal cord metastases to provide timely diagnosis.


The association between use of a clinical decision support tool and adherence to monitoring for medication-laboratory guidelines in the ambulatory setting.
Stage 2 Meaningful Use criteria require the use of clinical decision support systems (CDSS) on high priority health conditions to improve clinical quality measures. Although CDSS hold great promise, implementation has been fraught with challenges, evidence of their impact is mixed, and the optimal method of content delivery is unknown. The authors investigated whether implementation of a simple clinical decision support (CDS) tool was associated with improved prescriber adherence to national medication-laboratory monitoring guidelines for safety (hepatic function, renal function, myalgias/rhabdomyolysis) and intermediate outcomes for antidiabetic (Hemoglobin A(1c); HbA(1c)) and antihyperlipidemic (low density lipoprotein; LDL) medications prescribed within a diabetes registry. This was a retrospective observational study conducted in three phases of CDS implementation (2008-2009): pre-, transition-, and post-Prescriptions evaluated were ordered from an electronic health record within a multispecialty medical group. Adherence was evaluated within and without applying guideline-imposed time constraints. Forty-thousand prescriptions were ordered over three timeframes. For hepatic and renal function, the proportion of prescriptions for which labs were monitored at any time increased from 52% to 65% (p<0.001); those that met time guidelines, from 14% to 21% (p<0.001). Only 6% of required labs were drawn to monitor for myalgias/rhabdomyolysis, regardless of timeframe. Over 90% of safety labs were within normal limits. The proportion of labs monitored at any time for LDL increased from 56% to 64% (p<0.001); those that met time guidelines from 11% to 17% (p<0.001). The proportion of labs monitored at any time for HbA(1c) remained the same (72%); those that met time guidelines decreased from 45% to 41% (p<0.001). A simple CDS tool may be associated with improved adherence to guidelines. Efforts are needed to confirm findings and improve the timeliness of monitoring; investigations to optimize alerts should be ongoing.


Positive Association of Serum Adiponectin Level With the Vascular Reactivity Index in Kidney Transplant Patients.
Adiponectin has an important role in obesity, insulin resistance, and cardiovascular disease. We investigated the association between serum adiponectin levels and endothelial function in kidney transplant patients. Fasting blood samples were obtained from 70 kidney transplant patients. The vascular reactivity index was measured with a digital thermal monitoring test. Serum adiponectin levels were measured with a commercially available enzyme immunoassay kit. A vascular reactivity index <1.0 was defined as poor, 1.0 or greater but less than 2.0 was intermediate, and 2.0 or greater was good. The results showed that 10 kidney transplant patients (13.3%) were categorized with a vascular reactivity index of poor, 25 (35.7%) were intermediate, and 35 (50%) were good. Increased waist circumference (P = .037), increased serum alkaline phosphatase (P = .026), and lower serum adiponectin (P = .001) were associated with poor vascular reactivity index. Advanced age (r = -0.300; P = .012), waist circumference (r = -0.372; P = .002), serum alkaline phosphatase (r = -0.323; P = .006), and logarithmically transformed serum triglycerides (r = -0.317; P = .007) were negatively correlated with the vascular reactivity index, whereas serum adiponectin (r = 0.332; P = .005) was positively correlated with the vascular reactivity index. Multi variable forward stepwise linear regression analysis showed that waist circumference, serum alkaline phosphatase, and serum adiponectin were significantly and independently associated with the vascular reactivity index. Fasting serum adiponectin levels were positively associated with the vascular reactivity index and negatively associated with endothelial function in kidney transplant patients.


ISABELA studies: plasma exposure and target engagement do not explain the lack of efficacy of ziritaxestat in patients with IPF.
Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor, ziritaxestat, failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162; NCT03733444), two identically designed Phase 3 studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement. Non-linear mixed effect modeling was performed to predict ziritaxestat exposure in individual patients and describe its effect on LPA C18:2 levels. We assessed whether there was a correlation between ziritaxestat and ATX concentration and evaluated the relationship between LPA C18:2 reduction and change from baseline in FVC. Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. In most patients, LPA C18:2 reduction was comparable to that reported in healthy volunteers. ATX concentrations increased over time and correlated weakly with ziritaxestat exposure and LPA C18:2 reduction. No correlation between reduction in LPA C18:2 and change from baseline in FVC was apparent. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro-fibrotic pathway.


Accident or osteoporosis?: Survey of community follow-up after low-trauma fracture.
To describe the postfracture osteoporosis management of at-risk patients presenting with low-trauma fracture in a suburban community hospital setting. Telephone survey. Hospital emergency department serving a retirement community in White Rock and South Surrey, BC. Men and women older than 40 years of age who presented with low-trauma fracture between October 1, 2004, and April 30, 2005. The prevalence of bone mineral density testing, osteoporosis medication prescriptions, referrals to fall prevention programs, and calcium and vitamin D supplementation within 6 months of the index fracture, as well as patient perceptions of future risk of fracture and sources of osteoporosis information. A total of 181 people met the eligibility criteria and 161 were contacted; 84 (52%) people responded, of whom 53 were interviewed. At the time of their index fractures, 79% (42 of 53) of patients surveyed were not taking osteoporosis medication. After the index fracture, 30% (16 of 53) received new bone mineral density testing, and 8% (4 of 53) were starting courses of new osteoporosis medication. Sixty-eight percent (36 of 53) of all patients were taking calcium supplements and 50% (26 of 53) were taking vitamin D supplements. Eight percent (4 of 53) of patients were referred to a fall prevention program and 9% (5 of 53) were prescribed hip protectors; 19% (10 of 53) of patients thought they were at risk of having another fracture. Osteoporosis management of patients after low-trauma fracture in this community was suboptimal; the role of the media, family and friends, and allied health professionals to prevent fractures in at-risk individuals needs to be further explored.


Rapid Turbidimetric Assay to Determine the Potency of Daptomycin in Lyophilized Powder.
Daptomycin is an important antimicrobial for clinical practice, mainly because it remains very active against Gram-positive resistant strains, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Development of microbiological methods for the analysis of antimicrobials is highly recommended, since they can provide important information about their biological activities, which physicochemical methods are not able to provide. Considering that there are no studies in the literature describing microbiological methods for the analysis of daptomycin, the aim of this work was to validate a microbiological method for the quantitation of daptomycin by the turbidimetric assay. Staphylococcus aureus was used as the test microorganism, and the brain heart infusion broth was used as the culture medium. The validation of the method was performed according to the ICH guidelines, and it was shown to be linear, precise, robust, accurate and selective, over a concentration range of 8.0 to 18.0 µg mL-1. Student's t-test showed the interchangeability of the proposed method with a previously-validated HPLC method. The developed turbidimetric method described in this paper is a convenient alternative for the routine quality control of daptomycin in its pharmaceutical dosage form.


Shwachman-Diamond Syndrome in a Child Presenting With Chronic Diarrhea: A Rare Case in Family Medicine Practice.
Diarrhea remains an important cause of morbidity and mortality worldwide. Chronic diarrhea often represents a diagnostic challenge for family medicine and pediatric physicians because of its broad spectrum of possible etiologies. The differential diagnoses can be narrowed by taking a detailed history and performing an appropriate physical examination. In general, chronic diarrhea can be due to osmotic, secretory, inflammatory, or dysmotility-related pathologies. We present the case of a 30-month-old male who was brought to the family medicine clinic with a complaint of abdominal bloating and persistent diarrhea after every feeding for four months. His stools were foul-smelling and occurred more than four times a day. The patient was below the second standard deviations for weight and height. He appeared pale, and there was no scleral icterus. The patient underwent upper endoscopy, which showed no abnormal gross findings. A dedicated abdominal computed tomography scan was performed to evaluate the pancreas for any structural abnormalities. The scan demonstrated complete replacement of the pancreatic parenchyma by fatty tissue. The diagnosis of Shwachman-Diamond syndrome was established as the analysis revealed a mutation in the SBDS gene. The patient was treated with pancreatic enzyme replacement therapy. After two months of follow-up, the parents reported that the patient had significant improvement in diarrhea. Shwachman-Diamond syndrome is a very rare inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. Despite its rarity, clinicians should keep a high index for this condition when they encounter a child with unexplained chronic diarrhea.


Dissecting cellular states of infiltrating microenvironment cells in melanoma by integrating single-cell and bulk transcriptome analysis.
Cellular states of different immune cells can affect the activity of the whole immune microenvironment. Here, leveraging reference profiles of microenvironment cell states that were constructed based on single-cell RNA-seq data of melanoma, we dissected the composition of microenvironment cell states across 463 skin cutaneous melanoma (SKCM) bulk samples through CIBERSORT-based deconvolution of gene expression profiles and revealed high heterogeneity of their distribution. Correspondence analysis on the estimated cellular fractions of melanoma bulk samples was performed to identify immune phenotypes. Based on the publicly available clinical survival and therapy data, we analyzed the relationship between immune phenotypes and clinical outcomes of melanoma. By analysis of the relationships among those cell states, we further identified three distinct tumor microenvironment immune phenotypes: "immune hot/active", "immune cold-suppressive" and "immune cold-exhausted". They were characterized by markedly different patterns of cell states: most notably the CD8 T Cytotoxic state, CD8 T Mixed state, B non-regulatory state and cancer-associated fibroblasts (CAFs), depicting distinct types of antitumor immune response (or immune activity). These phenotypes had prognostic significance for progression-free survival and implications in response to immune therapy in an independent cohort of anti-PD1 treated melanoma patients. The proposed strategy of leveraging single-cell data to dissect the composition of microenvironment cell states in individual bulk tumors can also extend to other cancer types, and our results highlight the importance of microenvironment cell states for the understanding of tumor immunity.


Multifunctional chitin nanogels for simultaneous drug delivery, bioimaging, and biosensing.
In this work, we developed biodegradable chitin nanogels (CNGs) by controlled regeneration method. For multifunctionalization, we have conjugated CNGs with MPA-capped-CdTe-QDs (QD-CNGs) for the in vitro cellular localization studies. In addition, the Bovine Serum Albumin (BSA) was loaded on to QD-CNGs (BSA-QD-CNGs). The CNGs, QD-CNGs, and BSA-QD-CNGs were well-characterized by SEM and AFM, which shows that the nanogels are in the range of <100 nm. These were further characterized by FT-IR and Cyclic Voltametry. The cytocompatibility assay showed that the nanogels are nontoxic to L929, NIH-3T3, KB, MCF-7, PC3, and VERO cells. The cell uptake studies of the QD-CNGs were analyzed, which showed retention of these nanogels inside the cells (L929, PC3, and VERO). In addition, the protein loading efficiency of the nano gels has also been analyzed. Our preliminary studies reveal that these multifunctionalized nanogels could be useful for drug delivery with simultaneous imaging and biosensing.


Tasimelteon: A Review in Non-24-Hour Sleep-Wake Disorder in Totally Blind Individuals.
Tasimelteon (Hetlioz(®)) is a dual melatonin receptor agonist indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) (free-running disorder). In two randomized, double-masked, multicentre, phase III trials, totally blind individuals with Non-24 who received oral tasimelteon 20 mg once nightly were significantly more likely than those receiving placebo to entrain the circadian pacemaker (the SET trial) and maintain entrainment (the RESET trial). Sleep/wake parameters and functioning were also improved with tasimelteon. Oral tasimelteon was generally well tolerated in totally blind patients with Non-24. In conclusion, tasimelteon is a useful drug for the treatment of Non-24 in totally blind individuals.


Pharmacokinetics of isoflurane: uptake in the brain.
We studied the effect of the inspired isoflurane concentration (C(I)iso) on the pharmacokinetics of isoflurane uptake in the brain by comparing the isoflurane concentration in internal jugular-bulb blood (Jiso) with that in arterial blood (Aiso), and analyzed this by gas chromatography. Sixteen patients (aged 43-76 years) undergoing colorectal surgery were enrolled, and anesthesia was maintained with a constant C(I)iso of either 1% (group 1, n = 8) or 2% (group 2, n = 8) during the 1st hour of isoflurane anesthesia. Under constant volume-controlled ventilation, we measured the C(I)iso and the end-tidal isoflurane concentration (C(E)iso) at the mouthpiece by infrared analysis. Our results demonstrate that it takes 40 min for the brain tissue concentration to equal Aiso for 1% C(I)iso, and 50 min for 2% C(I)iso. The Aiso (and/or Jiso) for 2% C(I)iso was approximately double when compared to that for 1% C(I)iso. Except during the initial wash-in period of the functional residual capacity in the first 3 min, the differences between C(I)iso and C(E)iso revealed that the body uptake of isoflurane for 2% C(I)iso was twice that for 1% C(I)iso. These results demonstrate that the pharmacokinetics of isoflurane uptake in the brain is time-dependent for Jiso to equal Aiso, and the midpoint between Aiso and Jiso (likely representing the isoflurane concentration in brain tissue) was dependent on C(I)iso.


Effects of vasopressin on epithelial transport.
Vasopressin increases the permeability of responsive epithelia for a variety of chemical species, such as sodium, urea, water, and lipophilic molecules. The analysis of the mechanisms leading to the stimulation of water transport (hydrosmotic action) is the main topic of this review. A model implying the quantal insertion of water channels into the apical epithelial membrane by an exocytosislike process is discussed with reference to biophysical, biochemical, and ultrastructural results obtained in the past few years. It is also shown that, in nonexcitable cells, insertion of transport units packed in intracytoplasmic structures may be a rather general mechanism for controlling membrane transport rates.


Biocompatibility, Surface Morphology, and Bacterial Load of Dental Implant Abutments following Decontamination Protocols: An In-Vitro Study.
The long-term success of dental implant rehabilitation depends significantly on proper peri-implant soft tissue integration. Therefore, decontamination of abutments prior to their connection to the implant is beneficial to enhance soft tissue attachment and to aid in maintaining marginal bone around the implant. Consequently, different implant abutment decontamination protocols were evaluated regarding biocompatibility, surface morphology, and bacterial load. The protocols evaluated were autoclave sterilization, ultrasonic washing, steam cleaning, chlorhexidine chemical decontamination, and sodium hypochlorite chemical decontamination. The control groups included: (1) implant abutments prepared and polished in a dental lab without decontamination and (2) unprepared implant abutments obtained directly from the company. Surface analysis was performed using scanning electron microscopy (SEM). Biocompatibility was evaluated using XTT cell viability and proliferation assays. Biofilm biomass and viable counts (CFU/mL) (n = 5 for each test) were used for surface bacterial load evaluation. Surface analysis revealed areas of debris and accumulation of materials, such as iron, cobalt, chromium, and other metals, in all abutments prepared by the lab and with all decontamination protocols. Steam cleaning was the most efficient method for reducing contamination. Chlorhexidine and sodium hypochlorite left residual materials on the abutments. XTT results showed that the chlorhexidine group (M = 0.7005, SD = 0.2995) had the lowest values (p < 0.001) (autoclave: M = 3.6354, SD = 0.1510; ultrasonic: M = 3.4077, SD = 0.3730; steam: M = 3.2903, SD = 0.2172; NaOCl: M = 3.5377, SD = 0.0927; prep non-decont.: M = 3.4815, SD = 0.2326; factory: M = 3.6173, SD = 0.0392). Bacterial growth (CFU/mL) was high in the abutments treated with steam cleaning and ultrasonic bath: 2.93 × 109, SD = 1.68 × 1012 and 1.83 × 109, SD = 3.95 × 1010, respectively. Abutments treated with chlorhexidine showed higher toxicity to cells, while all other samples showed similar effects to the control. In conclusion, steam cleaning seemed to be the most efficient method for reducing debris and metallic contamination. Bacterial load can be reduced using autoclaving, chlorhexidine, and NaOCl.


Dynamic morphing of 3D curved laser traps for all-optical manipulation of particles.
The development of optical manipulation techniques focused on the confinement and transport of micro/nano-particles has attracted increased interest in the last decades. In particular the combination of all-optical confinement and propelling forces, respectively arising from high intensity and phase gradients of a strongly focused laser beam, is promising for optical transport. The recently developed freestyle laser trap exploits this manipulation mechanism to achieve optical transport along arbitrary 3D curves. In practice, reconfigurable 3D optical transport of numerous particles is a challenging problem because it requires the ability to easily adapt the trajectory in real time. In this work, we introduce and experimentally demonstrate a strategy for on-task adaptive design of freestyle laser traps based on a dynamic morphing technique. This provides programmable smooth transformation of the 3D shape of the curved laser trap with independent control of the propelling forces along it, that can be configured according to the considered application. Dynamic morphing, proven here on the example of colloidal dielectric micro-particles, significantly simplifies the important problem of real-time reconfigurable 3D optical transport and opens up routes for other sophisticated optical manipulation tasks.


p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition.
Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery (i.e., 'bounce-back') of proteasome activity. We previously demonstrated that the transcription factor Nrf1/NFE2L1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded promptly by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol. DOI: http://dx.doi.org/10.7554/eLife.01856.001.


2,4,5-Trichlorophenol degradation using a novel TiO2-coated biofilm carrier: roles of adsorption, photocatalysis, and biodegradation.
Intimate coupling of photocatalysis and biodegradation (ICPB) offers potential for degrading biorecalcitrant and toxic organic compounds. This study reports on a novel sponge-type, TiO(2)-coated biofilm carrier that showed significant adherence of TiO(2) and ability to accumulate biomass in its interior. This carrier was tested for ICPB in a continuous-flow photocatalytic circulating-bed biofilm reactor (PCBBR) to mineralize 2,4,5-trichlorophenol (TCP), which is biorecalcitrant. Four mechanisms possibly acting in ICPB were tested separately: TCP adsorption to the carrier, UV photolysis, UV photocatalysis, and biodegradation by biofilm inside the carrier. The carrier exhibited strong TCP adsorption that followed a Freundlich isotherm with an exponent near 2. Whereas UV photolysis was negligible, photocatalysis produced TCP-degradation products that could be mineralized, and the strong adsorption of TCP to the carrier enhanced biodegradation by relieving toxicity. Validating the ICPB concept, biofilm was protected inside the carriers, although biomass originally on the outer surface of the carriers was eliminated. ICPB significantly lowered the diversity of the bacterial community, but five genera known to biodegrade chlorinated phenols (Ralstonia, Bradyrhizobium, Methylobacterium, Cupriavidus, and Pandoraea) were markedly enriched.


Corneal sub-basal nerve plexus microneuromas in individuals with and without dry eye.
An objective marker is needed to detect when corneal nerve abnormalities underlie neuropathic corneal pain (NCP), as symptoms often overlap with those of dry eye (DE). This study evaluated microneuroma (MN) frequency in various populations and investigated relationships between MN presence and DE clinical features in individuals with DE symptoms but without a history of refractive surgery, in order to eliminate refractive surgery as a potential confounder of nerve abnormalities. This was a retrospective study that included individuals with and without DE symptoms who underwent a clinical evaluation for DE (symptom surveys and ocular surface evaluation) and in vivo confocal microscopy imaging. DE clinical features (including those suggestive of neuropathic pain) were compared based on MN presence using t-tests, χ2 analyses and Pearson's correlation coefficients with 0.05 alpha level. MN frequencies did not significantly differ between individuals with DE symptoms (Dry Eye Questionnaire 5 score ≥6) and a history of refractive surgery (n=1/16, 6%), individuals with DE symptoms without a history of refractive surgery (n=26/119, 22%) and individuals without DE symptoms (n=2/18, 11%, p=0.22). Among individuals with DE symptoms without a history of refractive surgery, DE clinical features, including those indicative of NCP (burning sensation and sensitivity to light, wind and extreme temperatures), did not significantly differ based on MN presence (p>0.05). MN frequencies did not significantly differ between individuals with and without DE symptoms. Their presence alone could not distinguish between DE subtypes, including features of NCP in our study population.


Sii-Mobility: An IoT/IoE Architecture to Enhance Smart City Mobility and Transportation Services.
The new Internet of Things/Everything (IoT/IoE) paradigm and architecture allows one to rethink the way Smart City infrastructures are designed and managed, but on the other hand, a number of problems have to be solved. In terms of mobility the cities that embrace the sensoring era can take advantage of this disruptive technology to improve the quality of life of their citizens, also thanks to the rationalization in the use of their resources. In Sii-Mobility, a national smart city project on mobility and transportation, a flexible platform has been designed and here, in this paper, is presented. It permits one to set up heterogeneous and complex scenarios that integrate sensors/actuators as IoT/IoE in an overall Big Data, Machine Learning and Data Analytics scenario. A detailed and complex case-study has been presented to validate the solution in the context of a system that dynamically reverse the traveling direction of a road segment, with all the safety conditions in place. This case study composes several building blocks of the IoT platform, which demonstrate that a flexible and dynamic set-up is possible, supporting security, safety, local, cloud and mixed solutions.


[The discrepancy between ACTH and 11-deoxycortisol levels in a single dose metyrapone test].
Five healthy men were given 1.0 gr of metyrapone p.o. (MTP test) with and without 0.5 gr of 1- dopa p.o. (DOPA-MTP test) or 10 mg of metoclopramide p.o. (MTC-MTP test) and plasma 11-deoxycortisol, cortisol, ACTH and pregnenolone (only in MTP test) were determined before and hourly after the drug administrating for 6 hrs. In the MTP test, plasma 11-deoxycortisol increased significantly at 1 hr with peak at 5 hrs, whereas the significant increases of pregnenolone and ACTH were not seen until 2 hrs, although plasma cortisol levels were reduced definitely at 1 hr. Thus, the increase of 11-deoxycortisol in the MTP test should be divided into two phases; the increase in the phase II (later than 3 hrs) is due to pituitary ACTH reserve, and that in the phase I (until 2 hrs) is due to unknown mechanism other than pituitary reserve. In the DOPA-MTP test, the 11-deoxycortisol rise was significantly larger than that in the MTP test. The increases in 11-deoxycortisol at 4 hrs and 5 hrs in the MTC-MTP test were significantly smaller than those in the MTP test. The cortisol/(cortisol + 11-deoxycortisol) ratio reached its lowest point at 3 hrs in the MTP test and at 2 hrs (a 1 hr advance) in the DOPA-MTP and MTC-MTP tests. However, there were no significant differences in the responses of cortisol and ACTH to metyrapone in these tests. This provides evidence for a discrepancy between plasma 11-deoxycortisol and ACTH responses in a single dose metyrapone test, as disclosed by the simultaneous administration of dopamine agonist or antagonist with metyrapone.


Effects of local single and fractionated X-ray doses on rat bone marrow blood flow and red blood cell volume.
Time and dose dependent changes in blood flow and red blood cell volume were studied in the locally irradiated bone marrow of the rat femur after single and fractionated doses of X-rays. With the single dose of 10 Gy the bone marrow blood flow although initially reduced returned to the control levels by seven months after irradiation. With doses greater than or equal to 15 Gy the blood flow was still significantly reduced at seven months. The total dose levels predicted by the nominal standard dose equation for treatments in three, six or nine fractions produced approximately the same degree of reduction in the bone marrow blood flow seven months after the irradiation. However, the fall in the red blood cell volume was from 23 to 37% greater in the three fractions groups compared with that in the nine fractions groups. Using the red blood cell volume as a parameter the nominal standard dose formula underestimated the severity of radiation damage in rat bone marrow at seven months for irradiation with small numbers of large dose fractions.


[Biochemical markers in diagnosis and prognosis of obturative jaundice].
The results of complex examination and treatment of 175 patients with obturative jaundice of different genesis were analyzed Especial attention have been devoted to interaction of specific enzymes: aminotransferases, alkali phosphatase and gamma-glutamiletranspeptidase. It was established some connection of the activity of these enzymes in obturative jaundice and liver functionally-morphologic state. This had been confirmed by facts of laboratory investigations date. Comparison of these indexes will promote the increase of diagnostic informativity, that can be used as one of diagnostic and prognostic criterions.


The effect of urbanization on helminth communities in the Eurasian blackbird (Turdus merula L.) from the eastern part of the Czech Republic.
In the present study we investigated two ecologically distinct populations of T. merula for the presence of helminths. We wished to determine whether urban populations of blackbirds had reduced helminth fauna compared to birds from forest habitats. Birds were caught in two ecologically distinct sites located in the eastern part of the Czech Republic. A total of 320 birds were examined. The first site was located in Prerov where the birds were obtained from a typical urban population, and the second site was Zahlinice, which constitutes a typical forest area. As a result of parasitological examination, 30 helminth species belonging to Digenea, Cestoda, Nematoda and Acanthocephala were recorded from both sites: 29 species were found in the forested site and 15 in the urban site. The overall prevalence of infection was 93.1% and differed significantly between the sites (Zahlinice 97.2%, Prerov 85.1%). The mean species richness was almost three times higher in the forest population (3.37 ± 0.10) than in the urban one (1.78 ± 0.11). The clear qualitative and quantitative differences in the helminth community of T. merula obtained from two ecologically disparate localities show that urbanization leads to a significant reduction in the helminth fauna of a bird which is highly adapted to synanthropic habitats, while still remaining common in its original forest habitat.


Ionic liquid clusters: structure, formation mechanism, and effect on the behavior of ionic liquids.
The microstructure of ionic liquids (ILs) has attracted much attention due to their relevance in physiochemical properties and behavior of ILs. The existence of clusters (or microheterogeneous structure) is one of the main features for many ILs, which provides fundamental information for understanding the performance of ILs in their applications. This perspective concentrates on the recent progresses in IL clusters research. Firstly, we give a brief introduction on the structure of clusters in neat ILs and IL solutions. Secondly, the possible formation mechanism of the IL clusters is described. Then, the effects of the clusters on the physicochemical properties, interfacial properties, confined geometry and assembly processes of ILs are discussed. Finally, we address the associated challenges and prospects on the future study of IL clusters.


Engineering thick tissues--the vascularisation problem.
The ability to create thick tissues is a major tissue engineering challenge, requiring the development of a suitable vascular supply. Current trends are seeing the utilization of cells seeded into hybrid matrix/scaffold systems to create in vitro vascular analogues. Approaches that aim to create vasculature in vitro include the use of biological extracellular matrices such as collagen hydrogels, porous biodegradable polymeric scaffolds with macro- and micro-lumens and micro-channels, co-culture of cells, incorporation of growth factors, culture in dynamic bioreactor environments, and combinations of these. Of particular interest are those approaches that aim to create bioengineered tissues in vitro that can be readily connected to the host's vasculature following implantation in order to maintain cell viability.


Chimeric mice carrying 'regional' targeted deletion of the angiotensin type 1A receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells.
We have developed chimeric mice carrying 'regional' null mutation of the angiotensin type 1A (AT1A) receptor, the AT1 receptor subtype exclusively present in mouse juxtaglomerular (JG) cells. The chimeric mouse (Agtr1a -/- <--> +/+) is made up of wild-type (Agtr1a +/+) cells or cells homozygous for Agtr1a deletion (Agtr1a -/-). In the latter, the AT1A coding exon was replaced with a reporter gene, lacZ. In Agtr1a -/- <--> +/+ mice, these two clones of cells are found to be clustered and display patchy distributions in the kidney and heart. Tracking of lacZ activities in hetero- (Agtr1a +/-) and homozygous (Agtr1a -/-) deletion mutant offspring from Agtr1a -/- <--> +/+ mice revealed that the promoter activity of Agtr1a is localized in JG cells, afferent arteriolar walls, glomerular mesangial region and endothelial cells, and apical and basolateral proximal tubule membranes. The JG apparatuses of Agtr1a -/- mice are markedly enlarged with intense expression of renin mRNA and protein. In Agtr1a -/- <--> +/+ mice, these changes were proportional to the degree of chimerism. Within a given Agtr1a -/- <--> +/+ mouse, however, the degree of JG hypertrophy/hyperplasia and the expression of renin mRNA and protein were identical between Agtr1a +/+ and Agtr1a -/- cells. Thus, in the in vivo condition tested, the local interaction between angiotensin and the AT1 receptor on the JG cells has little functional contribution to the feedback regulation of JG renin synthesis.


Poly(ester-ether)s: II. Properties of electrospun nanofibres from polydioxanone and poly(methyl dioxanone) blends and human fibroblast cellular proliferation.
This article deals with an in-depth study of the thermal, mechanical and degradation behaviours of nanofibres from polydioxanone (PDX) and polydl-3-methyl-1,4-dioxan-2-one (PMeDX) and a comparison with their blend films. Varying ratios of both polymers were blended and electrospun from solution. Electrospun fibres exhibited a melting transition at 109 °C independently of the PMeDX content, which corresponds to the melting of PDX nanofibres. As a result of the drawing process, PMeDX had a reduced plasticizing effect on PDX. In general, it was observed that overall crystallinity of the fibres decreased from 53% to 36% with increasing PMeDX content and this impacted on their mechanical properties. The Young's moduli decreased as the PMeDX content of the fibres increased. However, an increase in strain at break and peak stress was noted as a result of a decrease in the fibre diameter. AFM images of the electrospun fibres showed an increasing degree of morphological heterogeneity with increasing PMeDX content. Thermal degradation studies showed that electrospun mats were thermally more stable than blend films, as confirmed by a two-fold increase in activation energy. The hydrolytic degradation of the electrospun mats conducted in phosphate buffer solution at 37 °C showed that the degradation followed a surface erosion mechanism as opposed to bulk degradation observed for blend films. Degradation of fibres was found to be mainly dependent on their diameter. On the other hand, the degradation of blend films depended on the overall crystallinity of the blends. Electrospun PDX/PMeDX nanofibrous scaffolds were also subjected to cell viability studies with human dermal fibroblasts, in which they did not show illicit response and demonstrated excellent cell attachment and proliferation.


Classification of bladder cancer cell lines according to regulon activity.
Bladder cancer is one of the most frequent cancers and causes more than 150.000 deaths each year. During the last decade, several studies provided important aspects about genomic characterization, consensus subgroup definition, and transcriptional regulation of bladder cancer. Still, much more research needs to be done to characterize molecular signatures of this cancer in depth. At this point, the use of bladder cancer cell lines is quite useful for the identification and test of new signatures. In this study, we classified the bladder cancer cell lines according to the activities of regulons implicated in the regulation of primary bladder tumors. Our regulon gene expression-based classification revealed three groups, neuronal-basal (NB), luminal-papillary (LP), and basal-squamous (BS). These regulon gene expression-based classifications showed a quite good concordance with the consensus subgroups assigned by the primary bladder cancer classifier. Importantly, we identified FGFR1 regulon to be involved in the characterization of the NB group, where neuroendocrine signature genes were significantly upregulated, and further β-catenin was shown to have significantly higher nuclear localization. LP groups were mainly driven by the regulons ERBB2, FOXA1, GATA3, and PPARG, and they showed upregulation of the genes involved in epithelial differentiation and urogenital development, while the activity of EGFR, FOXM1, STAT3, and HIF1A was implicated for the regulation of BS group. Collectively, our results and classifications may serve as an important guide for the selection and use of bladder cancer cell lines for experimental strategies, which aim to manipulate regulons critical for bladder cancer development.


Failure of Centers for Disease Control criteria to identify hepatitis B infection in a large municipal obstetrical population.
The Centers for Disease Control (CDC) has recommended screening pregnant women from high-risk populations for hepatitis B surface antigen (HBsAg). To assess the adequacy of the risk criteria, all women presenting for delivery to a large municipal hospital were screened. Sera from 5356 women were tested, and questionnaires designed to identify women at high risk were completed by 78% of these patients. Sixty-four women were found to be HBsAg seropositive (1.2%). If the CDC criteria had been applied for screening, 30 of the seropositive mothers (47%) would not have been identified. Women from some Latin American and Caribbean countries not recommended for screening were found to have a relatively high prevalence of hepatitis B infection. Reluctance to give a history of venereal disease or illicit drug use may be another factor in the failure of the CDC screening strategy. To achieve effective immunoprophylaxis of newborns, all pregnant women should be screened for HBsAg carriage.


Cytotoxic Effects of Resveratrol, Rutin and Rosmarinic Acid on ARH-77 Human (Multiple Myeloma) Cell Line.
Multiple myeloma (MM) cancers are 10% of hematological cancers. Leukemia ARH-77 is a malignancy like MM with a worse course of disease and the survival rate from it is very low. Therefore, ARH-77 is a commonly used model for antitumor agent studies. Polyphenolic compounds, such as resveratrol, rutin and rosmarinic acid, have many protective roles, but there is no comparative study about these three polyphenolic compounds on ARH-77. In the present study, we investigated the cytotoxic effects of resveratrol, rutin and rosmarinic acid on ARH-77. Toxic concentration ranges were determined by the brine shrimp lethality test on Artemia salina. In addition, for determination of their cytotoxic effects, MTT and NR methods were used for ARH-77. Resveratrol caused significant reduction in both mitochondrial and lysosomal activities compared with the control group. Maximum inhibition values were detected on mitochondrial and lysosomal activity with 200 pM concentrations after 48 hours. After a 24 hours incubation period, rutin showed cytotoxic effects, particularly with 50, 100 and 200 lM concentrations. Rosmarinic acid also decreased the mitochondrial activity with the same concentrations. Resveratrol showed higher cytotoxic effects than rutin and rosmarinic acid. According to our study, polyphenolic compounds such as rutin, resveratrol and rosmarinic acid may hold promise in multiple myeloma treatment with further investigations.


[Gougerot Sjögren syndrome and hepatitis C virus: what relation?].
The incidence of Sjogrëns syndrome (SS) in patients with chronic liver disease and that of hepatitis C in mixed cryoglobulinemia strongly-suggest a link between the hepatitis C virus (HCV) and SS. A recent report has also demonstrated typical lymphocyte sialadenitis in HCV-positive subjects, raising a question concerning the classical definition of SS. Do patients with HCV and lymphocyte sialadenitis have SS? If the problem of variable diagnostic criteria can be overcome (for example by using the criteria established by the European study group) it can be concluded that the proportion of HCV+ patients with SS is related to female sex, age (perimenopause period in women), and liver histology rather than fibrosis, but not with duration of the liver disease, nor cirrhosis or viral genotype. The second question is to determine whether the observed focal lymphocyte infiltration of the salivary glands is typical of SS. As routine biopsy results lack specificity and sensitivity, immunohistochemistry is required to identify T8 predominance distinctive of SS. Results obtained to date suggest that the T8 sialadenitis might result from an autoimmune mechanism and consequently that the SS-HCV association might either be a coincidence between the two relatively frequent diseases or on the contrary that HCV plays a pathogenic role in SS. The major argument for the latter hypothesis would be the demonstration of HCV within the salivary gland epithelial cells. As HCV-positive immunohistochemistry tests on salivary biopsies may simply indicate presence of HCV in the blood stream at the time of biopsy, more sophisticated in situ PCR methods are currently being applied in an attempt to obtain objective evidence which could incriminate HCV infection of the salivary glands as a causal agent in Sjogrëns syndrome.


Integrating the "new" with the "traditional": an innovative education model.
In 1998 the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta, Canada, introduced a new elective semester course entitled "The Pain Module" for pharmacy students in their final year of undergraduate training. The aim was to build on the existing theoretical content related to areas such as pharmacology and therapeutics and to generate opportunities for skill and attitude development, including those related to the management of cancer-related pain. Traditional formats such as classroom-based seminars were integrated with innovative methods such as computer-mediated discussions and conferencing (CMC) and academic bus rounds. The CMC component of the course served to provide continuity of discussion between weekly classroom discussions, gave students access to content experts on an ongoing basis and furthered learning initiated in the classroom. Students were given the opportunity to meet palliative care patients being cared for at home and in hospices. A total of 21 students participated in all the course activities. By the end of the course, there appeared to be a greater appreciation for end-of-life care issues. This highlights the need to incorporate end-of-life care into the undergraduate curriculum of disciplines other than medicine and nursing. Evaluation of the course identified several benefits and limitations of CMC. There was increased access to content experts and increased interaction between students. Limitations of CMC included increased time commitments and an open-ended nature that was uncomfortable for some learners. Other benefits and limitations are described further in this article. Future attempts at integrating new instructional technologies should be systematically evaluated.


Morphological and physiological changes during reproduction and their relationships to reproductive performance in a capital breeder.
Current reproductive effort typically comes at a cost to future reproductive value by altering somatic function (e.g., growth or self-maintenance). Furthermore, effects of reproduction often depend on both fecundity and stage of reproduction, wherein allocation of resources into additional offspring and/or stages of reproduction results in increased costs. Despite these widely accepted generalities, interindividual variation in the effects of reproduction is common-yet the proximate basis that allows some individuals to mitigate these detrimental effects is unclear. We serially measured several variables of morphology (e.g., musculature) and physiology (e.g., antioxidant defenses) in female Children's pythons (Antaresia childreni) throughout reproduction to examine how these traits change over the course of reproduction and whether certain physiological traits are associated with reduced effects of reproduction in some individuals. Reproduction in this capital breeder was associated with changes in both morphology and physiology, but only morphological changes varied with fecundity and among specific reproductive stages. During reproduction, we detected negative relationships between morphology and self-maintenance (e.g., increased muscle allocation to reproduction was related to reduced immune function). Additionally, females that allocated resources more heavily into current reproduction also did so during future reproduction, and these females assimilated resources more efficiently, experienced reduced detriments to self-maintenance (e.g., lower levels of oxidative damage and glucocorticoids) during reproduction, and produced clutches with greater hatching success. Our results suggest that interindividual variation in specific aspects of physiology (assimilation efficiency and oxidative status) may drive variation in reproductive performance.


Identification of the biological processes, immune cell landscape, and hub genes shared by acute anaphylaxis and ST-segment elevation myocardial infarction.
Background: Patients with anaphylaxis are at risk for ST-segment elevation myocardial infarction (STEMI). However, the pathological links between anaphylaxis and STEMI remain unclear. Here, we aimed to explore shared biological processes, immune effector cells, and hub genes of anaphylaxis and STEMI. Methods: Gene expression data for anaphylactic (GSE69063) and STEMI (GSE60993) patients with corresponding healthy controls were pooled from the Gene Expression Omnibus database. Differential expression analysis, enrichment analysis, and CIBERSORT were used to reveal transcriptomic signatures and immune infiltration profiles of anaphylaxis and STEMI, respectively. Based on common differentially expressed genes (DEGs), Gene Ontology analysis, cytoHubba algorithms, and correlation analyses were performed to identify biological processes, hub genes, and hub gene-related immune cells shared by anaphylaxis and STEMI. The robustness of hub genes was assessed in external anaphylactic (GSE47655) and STEMI (GSE61144) datasets. Furthermore, a murine model of anaphylaxis complicated STEMI was established to verify hub gene expressions. The logistic regression analysis was used to evaluate the diagnostic efficiency of hub genes. Results: 265 anaphylaxis-related DEGs were identified, which were associated with immune-inflammatory responses. 237 STEMI-related DEGs were screened, which were involved in innate immune response and myeloid leukocyte activation. M0 macrophages and dendritic cells were markedly higher in both anaphylactic and STEMI samples compared with healthy controls, while CD4+ naïve T cells and CD8+ T cells were significantly lower. Enrichment analysis of 33 common DEGs illustrated shared biological processes of anaphylaxis and STEMI, including cytokine-mediated signaling pathway, response to reactive oxygen species, and positive regulation of defense response. Six hub genes were identified, and their expression levels were positively correlated with M0 macrophage abundance and negatively correlated with CD4+ naïve T cell abundance. In external anaphylactic and STEMI samples, five hub genes (IL1R2, FOS, MMP9, DUSP1, CLEC4D) were confirmed to be markedly upregulated. Moreover, experimentally induced anaphylactic mice developed impaired heart function featuring STEMI and significantly increased expression of the five hub genes. DUSP1 and CLEC4D were screened as blood diagnostic biomarkers of anaphylaxis and STEMI based on the logistic regression analysis. Conclusion: Anaphylaxis and STEMI share the biological processes of inflammation and defense responses. Macrophages, dendritic cells, CD8+ T cells, and CD4+ naïve T cells constitute an immune cell population that acts in both anaphylaxis and STEMI. Hub genes (DUSP1 and CLEC4D) identified here provide candidate genes for diagnosis, prognosis, and therapeutic targeting of STEMI in anaphylactic patients.


Obesity May Provide Pro-ILC3 Development Inflammatory Environment in Asthmatic Children.
The prevalence of obesity in children has dramatically increased in the last few decades, and obesity has also emerged as an important risk factor for asthma. Innate mechanisms have been shown to be involved in both diseases, particularly through the recently described innate lymphoid cells (ILCs), in which ILC3s have been linked to obesity both in human and in murine models. The aim of this study was to explore whether being overweight in asthmatic children was associated with elevated circulating ILC3 or elevated messenger RNA (mRNA) levels of RORC, IL-17A, and IL-22. Our results showed significantly elevated ILC3 frequencies in overweight asthmatic children compared with nonoverweight controls based on the detection of Lin+CD127+IL-23R+ cells by flow cytometry. Moreover, elevated ILC3 frequencies positively correlated with the mRNA expression of RORC which has been identified as a transcription factor of ILC3s. The relative mRNA expression level of IL-17A was also upregulated in overweight compared to nonoverweight children, as was the relative mRNA level of IL-22. However, there were no correlations between ILC3 frequencies or the expressions of RORC, IL-17A, and IL-22 and asthma severity. These results suggested that childhood obesity is an independent factor that is associated with an elevated frequency of circulating ILC3s and higher expressions of RORC, IL-22, and IL-17A.


Effect of pH and oxygen tension on staphylococcal growth and enterotoxin formation in fermented sausage.
Commercial fermented 0sausages that contained significant numbers of viable coagulase-positive staphylococci were found to have the growth localized in the outermost areas of the sausage where oxygen tension was highest. Staphylococci were found to be more acid-tolerant aerobically than anaerobically. With chemical acidulation of sausage, growth could be controlled both aerobically and anaerobically with approximately 1.5% glucono delta lactone. Biological acidulation with a high inoculum of Pediococcus cerevisiae inhibited anaerobic staphylococcal growth but failed to suppress aerobic growth completely. A staphylococcal count of approximately 4 x 10(7) cells/g of sausage appeared to be necessary to produce detectable enterotoxin A within 24 hr in sausage. A minor difference existed in the relative rates of production of the different types of enterotoxin. Detectable enterotoxin A was produced in 24 hr in sausage held in atmospheres containing 10, 15, and 20% oxygen. In an atmosphere containing 5% oxygen, toxin was detected after 48 hr of incubation. No toxin was detected after 120 hr under anaerobic conditions. Most staphylococcal strains tested initiated growth and produced detectable enterotoxin aerobically at a pH of 5.1 in broth media. Anaerobically, however, most strains failed to produce detectable enterotoxin below pH 5.7.


False confessions, expert testimony, and admissibility.
The confession of a criminal defendant serves as a prosecutor's most compelling piece of evidence during trial. Courts must preserve a defendant's constitutional right to a fair trial while upholding the judicial interests of presenting competent and reliable evidence to the jury. When a defendant seeks to challenge the validity of that confession through expert testimony, the prosecution often contests the admissibility of the expert's opinion. Depending on the content and methodology of the expert's opinion, testimony addressing the phenomenon of false confessions may or may not be admissible. This article outlines the scientific and epistemological bases of expert testimony on false confession, notes the obstacles facing its admissibility, and provides guidance to the expert in formulating opinions that will reach the judge or jury. We review the 2006 New Jersey Superior Court decision in State of New Jersey v. George King to illustrate what is involved in the admissibility of false-confession testimony and use the case as a starting point in developing a best-practice approach to working in this area.


Thiopurine methyltransferase activity in red blood cells of dogs.
Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurine medications such as azathioprine. In humans, activity varies widely among individuals, primarily because of genetic polymorphisms. Low TPMT activity increases the risk of myelosuppression from azathioprine and 6-mercaptopurine, whereas high TPMT activity is associated with poor drug efficacy. The purpose of this study was to determine whether dogs also show a wide range of TPMT activity. Heparinized blood samples were obtained from 177 dogs associated with a veterinary teaching hospital. Red blood cell (RBC) TPMT activity was measured by means of a modification of a radiochemical method as established for use in people. TPMT activity varied across a 9-fold range (7.9-71.8 U of RBC per milliliter; median, 21.7). Variation in TPMT activity was not associated with age, sex, or neutering status. Giant Schnauzers had much lower TPMT activity (7.9-20 U of RBC per milliliter; median, 13.1; P < .001) than did other breeds, and Alaskan Malamutes had much higher TPMT activity (22.7-71.8 U of RBC per milliliter; median, 36.0; P < .001) than did other breeds. Such variations in TPMT activity in the canine population and within groups of related dogs could affect thiopurine drug toxicity and efficacy in canine patients.


Progressive muscle relaxation in persons with schizophrenia: a systematic review of randomized controlled trials.
The aim of this systematic review was to assess the effectiveness of progressive muscle relaxation on psychological distress and anxiety symptoms and on response/remission for people with schizophrenia. Randomized controlled trials were considered if they investigated progressive muscle relaxation in patients with schizophrenia. EMBASE, PsycINFO, PubMed, ISI Web of Science, CINAHL, PEDro and Cochrane Library were searched. The selection of studies, data extraction and quality assessment were performed independently by two reviewers. Three randomized controlled trials involving 146 patients met the inclusion criteria. Progressive muscle relaxation can acutely reduce state anxiety and psychological distress and improve subjective well-being. No studies investigated the evidence for progressive muscle relaxation as an add-on treatment for general psychopathology and for positive or negative symptoms. Also, no studies assessed the value of progressive muscle relaxation in longer-term treatment and for relapse prevention. There were no data to draw any conclusions about progressive muscle relaxation in comparison with other treatment modalities. None of the studies encountered adverse events. Dose-response relationships could not be determined. Progressive muscle relaxation might be a useful add-on treatment to reduce state anxiety and psychological distress and improve subjective well-being in persons with schizophrenia.


The evaluation of hospital laboratory information management systems based on the standards of the American National Standard Institute.
Nowadays, modern laboratories are faced with a huge volume of information. One of the goals of the Laboratory Information Management System (LIMS) is to assist in the management of the information generated in the laboratory. This study intends to evaluate the LIMS based on the standards of the American National Standard Institute (ANSI). This research is a descriptive-analytical study, which had been conducted in 2011, on the LIMSs in use, in the teaching and private hospitals in Isfahan. The data collecting instrument was a checklist, which was made by evaluating three groups of information components namely: 'System capabilities', 'work list functions,' and 'reporting' based on LIS8-A. Data were analyzed using the SPSS 20. Data were analyzed using (relative) frequency, percentage. To compare the data the following statistical tests were used: Leven test, t-test, and Analysis of Variance (ANOVA). The results of the study indicated that the LIMS had a low conformity (30%) with LIS8-A (P = 0.001), with no difference between teaching and private hospitals (P = 0.806). The ANOVA revealed that in terms of conformity with the LIS8-A standard, there was a significant difference between the systems produced by different vendors (P = 0.023). According to the results, a Kowsar system with more than %57 conformity in the three groups of information components had a better conformity to the standard, compared to the other systems. This study indicated that none of the LIMSs had a good conformity to the standard. It seems that system providers did not pay sufficient attention to many of the information components required by the standards when designing and developing their systems. It was suggested that standards from certified organizations and institutions be followed in the design and development process of health information systems.


Guidance on the management of left ventricular assist device (LVAD) supported patients for the non-LVAD specialist healthcare provider: executive summary.
The accepted use of left ventricular assist device (LVAD) technology as a good alternative for the treatment of patients with advanced heart failure together with the improved survival of patients on the device and the scarcity of donor hearts has significantly increased the population of LVAD supported patients. Device-related, and patient-device interaction complications impose a significant burden on the medical system exceeding the capacity of LVAD implanting centres. The probability of an LVAD supported patient presenting with medical emergency to a local ambulance team, emergency department medical team and internal or surgical wards in a non-LVAD implanting centre is increasing. The purpose of this paper is to supply the immediate tools needed by the non-LVAD specialized physician - ambulance clinicians, emergency ward physicians, general cardiologists, and internists - to comply with the medical needs of this fast-growing population of LVAD supported patients. The different issues discussed will follow the patient's pathway from the ambulance to the emergency department, and from the emergency department to the internal or surgical wards and eventually back to the general practitioner.


Terrain Model Reconstruction from Terrestrial LiDAR Data Using Radial Basis Functions.
The presence of vegetation and the terrain topography itself generate strong occlusions causing large gaps in terrestrial laser scanning (TLS) data at the ground level as well as a risk of integrating above-ground objects. This article introduces a surface-approximation algorithm dedicated to extracting digital terrain models (DTMs) from terrestrial TLS data acquired in forest areas. The proposed method is based on the combination of a quadtree subdivision of space guided by the local density and distribution of data together with a surface modeling via radial basis functions, which are used as partitions of unity for merging local quadratic approximating patches.


Effects of caffeine ingestion on dynamic visual acuity: a placebo-controlled, double-blind, balanced-crossover study in low caffeine consumers.
Acute caffeine ingestion has been associated with improvements in cognitive performance and visual functioning. The main objective of this study was to determine the effects of caffeine intake on dynamic visual acuity (DVA). Twenty-one low caffeine consumers (22.5 ± 1.6 years) took part in this placebo-controlled, double-blind, and balanced crossover study. In two different days and following a random order, participants ingested either caffeine (4 mg/kg) or placebo, and DVA was measured after 60 min of ingesting the corresponding capsule. A recently developed and validated software (moV& test, V&mp Vision Suite, Waterloo, Canada) was used to assess DVA. We found a greater accuracy for both the horizontal and random motion paths of DVA after caffeine ingestion (p < 0.001 and p = 0.002, respectively). In regard to the speed of the response, our data revealed that caffeine intake was associated with a faster reaction time for horizontally (p = 0.012) but not for randomly (p = 0.846) moving targets. Also, participants reported higher levels of perceived activation after consuming caffeine in comparison to placebo (p < 0.001). Our data suggest that caffeine intake (i.e., a capsule containing 4 mg/kg) has an ergogenic effect on DVA, which may be of special relevance in real-word contexts that require to accurately and rapidly detect moving targets (e.g., sports, driving, or piloting).


[Complex diagnosis of fragment injuries of the eye and orbit].
The paper presents data on the prevalence and pattern of fragment injuries of the eye and orbit in the Sverdlovsk Region in 2000-2004. It describes the authors' system for complex diagnosis of metallic foreign bodies, which is based on the wide use of electron location in combination with other clinical, instrumental, and special studies. The comparative results of treating patients with the standard and proposed system, which demonstrate the advantages of the latter in small-sized fragments in particular, are given.


Role of chromatin accessibility in the occupancy and transcription of the insulin gene by the pancreatic and duodenal homeobox factor 1.
The pancreatic and duodenal homeobox factor 1 (Pdx-1) is a Hox-like transcription factor that is responsible for the activation of the insulin gene. Previous studies have demonstrated the interaction in vitro of Pdx-1 with short (20-40 nucleotide) DNA fragments corresponding to A boxes of the insulin promoter. Precisely how Pdx-1 binds to DNA in the complex milieu of chromatin, however, has never been studied. In this study, we explored how Pdx-1-DNA interactions might be influenced by chromatin accessibility at the insulin gene in beta-cells (betaTC3) vs. pancreatic ductal cells (mPAC). We demonstrate that Pdx-1 occupies the endogenous insulin promoter in betaTC3 cells but not in mPAC cells, a finding that is independent of the intracellular Pdx-1 protein concentration. Based on micrococcal nuclease protection assays, the difference in promoter binding between the two cell types appears to be secondary to chromatin accessibility at predicted Pdx-1 binding sites between bp -126 to -296 (relative to the transcriptional start site) of the insulin promoter. Binding studies using purified Pdx-1 and reconstituted chromatin in vitro suggest that the positioning of a nucleosome(s) within this crucial region of the promoter might account for differences in chromatin accessibility. Consistent with these observations, fluorescence colocalization studies show that Pdx-1 does not occupy regions of compacted, nucleosome-rich chromatin within the nucleus. Our findings suggest a model whereby insulin transcription in the beta-cell is at least partially facilitated by enhanced chromatin accessibility within a crucial regulatory region between bp -126 to -296, thereby permitting occupancy by transactivators such as Pdx-1.


Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL.
CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.


Water structure and chaotropicity: their uses, abuses and biological implications.
The concept of "water structure" has been invoked to explain all manner of aqueous phenomena. Here we look at the origins of this tendency to understand solute hydration in terms of structural changes in bulk water, and consider the validity of one particular example: the classification of small solutes as chaotropic or kosmotropic, and the putative relation of this terminology to notions of structure-making and structure-breaking in the solvent. We doubt whether complex phenomena such as Hofmeister and osmolyte effects on macromolecules can be understood simply on the basis of a change in solvent structure. Rather, we argue that chaotropicity, if understood in the original sense, arises from the activities that solutes exert on macromolecular systems, as well as from deviations of solvation water from bulk-like behaviour. If applied judiciously, chaotropicity remains a potent, biologically pertinent parameter useful for classifying and understanding solution phenomena in all types of living system.


MASSpy: Building, simulating, and visualizing dynamic biological models in Python using mass action kinetics.
Mathematical models of metabolic networks utilize simulation to study system-level mechanisms and functions. Various approaches have been used to model the steady state behavior of metabolic networks using genome-scale reconstructions, but formulating dynamic models from such reconstructions continues to be a key challenge. Here, we present the Mass Action Stoichiometric Simulation Python (MASSpy) package, an open-source computational framework for dynamic modeling of metabolism. MASSpy utilizes mass action kinetics and detailed chemical mechanisms to build dynamic models of complex biological processes. MASSpy adds dynamic modeling tools to the COnstraint-Based Reconstruction and Analysis Python (COBRApy) package to provide an unified framework for constraint-based and kinetic modeling of metabolic networks. MASSpy supports high-performance dynamic simulation through its implementation of libRoadRunner: the Systems Biology Markup Language (SBML) simulation engine. Three examples are provided to demonstrate how to use MASSpy: (1) a validation of the MASSpy modeling tool through dynamic simulation of detailed mechanisms of enzyme regulation; (2) a feature demonstration using a workflow for generating ensemble of kinetic models using Monte Carlo sampling to approximate missing numerical values of parameters and to quantify biological uncertainty, and (3) a case study in which MASSpy is utilized to overcome issues that arise when integrating experimental data with the computation of functional states of detailed biological mechanisms. MASSpy represents a powerful tool to address challenges that arise in dynamic modeling of metabolic networks, both at small and large scales.


[Optical properties of alpha-cyanoacrylate adhesives].
The growing increase in the production of medical endoscopes and their complicated design demand the use of materials and processes offering the whole complex of advantages. Assembly of rigid endoscopic systems presents great difficulties during cementing operations, especially when several adhesive joints should be obtained in a single optical element. Transparent, quick-setting alpha-cyanacrylate adhesives are of particular interest in view of their usage for cementing optical elements.


Comparative transcriptome analysis revealed the improved β-carotene production in Sporidiobolus pararoseus yellow mutant MuY9.
Carotenoids are ubiquitous constituents of living organisms. These structurally diverse pigments have received considerable attention due to their biotechnological applications and potential beneficial effects on human health. In this study, we characterized an over-producing β-carotene mutant of Sporidiobolus pararoseus, obtained by ultraviolet mutagenesis, named MuY9. We compared the transcriptome between the wild-type and MuY9. A total of 348 differential expressed genes (DEGs) were found, and only one DEG crtYB is involved in carotenoid biosynthesis. The overproduction of β-carotene in MuY9 should be attributed to the up-regulation of crtYB. Functional identification of crtYB was performed using heterologous complementation in Escherichia coli. Our findings indicate that the enzymatic conversions of geranylgeranyl pyrophosphate to phytoene, as well as lycopene to β-carotene, are catalyzed by this CrtYB. Furthermore, our insights into the crtYB gene should facilitate a more detailed understanding of the carotenogenic pathway in S. pararoseus, and advance the development of the genetic engineering for the bio-production of carotenoids.


Successful transduction of human multipotent, lymphoid (T, B, NK) and myeloid, and transplantable CD34+CD38low cord blood cells using a murine oncoretroviral vector.
Hematopoietic stem cells (HSC) are subject to great interest because of their medical importance and their biological properties. Therefore, the possibility of genetically modifying human HSC is a major concern in several inherited pathologies. In this study, we aimed to demonstrate that a murine oncoretroviral vector can transduce multipotential cord blood (CB) stem cells. Sorted CB CD34(+)CD38(low) cells were transduced with a Moloney-based MFG retroviral vector containing the coding sequence of the murine CD2 (mCD2). CD34(+)mCD2(+) cells were sorted by flow cytometry and cultured either in bulk or at one cell per well in culture conditions that allow differentiation along lymphoid (T, B, and NK) and myeloid (M) lineages. Phenotypic analysis of cells generated in culture showed that CD34(+)mCD2(+) cells could give rise to all lymphoid and myeloid progeny, indicating that the MFG/mCD2 vector had transduced progenitors of all tested lineages. Moreover, clonal cultures of 660 CD34(+)mCD2(+) cells showed that approximately 5% of these cells were able to generate both myeloid and lymphoid (B + NK) progenies; for 25% of them, this included the production of lymphoid T cells. We also demonstrate that transduced CD34(+)CD38(low) CB cells with lymphoid and myeloid potentials were capable of engraftment into the bone marrow (BM) of nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice during several months. These results show that MFG retroviral vectors can transduce multipotent (T, B, NK, M) human hematopoietic progenitors with in vivo repopulating activity.


Association of short-term use of nonsteroidal anti-inflammatory drugs with stroke in patients with hypertension.
Limited studies have investigated the risk of cerebrovascular events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects at high risk. We examined the short-term (defined as 30-day period) effect of selective and nonselective NSAIDs use on the risk of ischemic and hemorrhagic stroke in patients with hypertension. We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan. We identified 1653 hypertensive subjects with stroke (defined as International Classification of Diseases-Ninth Revision-CM-codes: 433.x, 434.x, and 436.x for ischemic stroke; 430 and 431 for hemorrhagic stroke) in 2010. We investigated the transient effect of NSAIDs use on stroke using conditional logistic regressions with the adjustment of potential confounders. The results suggested that NSAIDs use during the 30 days before stroke was associated with a 1.57-fold increased risk of ischemic stroke, but not of hemorrhagic stroke (adjusted odds ratio, 1.57; 95% confidence interval, 1.26-1.97 for ischemic stroke; and adjusted odds ratio, 1.38; 95% confidence interval, 0.79-2.40 for hemorrhagic stroke). When classifying NSAIDs into selective and nonselective groups, nonselective NSAIDs use significantly increased the risk of ischemic stroke (adjusted odds ratio, 1.55; 95% confidence interval, 1.24-1.94), but not of hemorrhagic stroke (adjusted odds ratio, 1.56; 95% confidence interval, 0.90-2.73). The results demonstrate an increased risk of stroke, specifically ischemic stroke among hypertensive subjects with NSAIDs use. It would be important to closely monitor the transient effect of initial NSAIDs treatment, particularly in patients with hypertension.


Dietary adherence in Hispanic patients receiving hemodialysis.
The study objective was to identify the factors that influence dietary adherence in Hispanic patients receiving maintenance hemodialysis and to determine the differences in dietary adherence between Hispanic and non-Hispanic patients. We performed a cross-sectional study using a descriptive-comparative design. The study took place at hemodialysis centers at Winthrop-University Hospital, New York. The participants were adult patients of Hispanic descent receiving maintenance hemodialysis three times per week for 3 months or more and an equal number of age- and sex-matched non-Hispanic patients. Information was obtained by a questionnaire about knowledge of the diet, preferred language for education, consumption of potassium- (K(+)) and phosphorus- (PO(4)) containing foods, and adherence attitudes and behaviors. Serum albumin (SAlb), K(+), and PO(4) for the past 3 months were obtained from medical records and evaluated to assess dietary adherence. The main outcome measure was a mean SAlb of 3.2g/dL or greater, K(+) of 5.5 mEq/L or less, and PO(4) of 5.5 mg/dL or less. A total of 17 Hispanic and 17 comparison patients were included. Both groups were adherent to the diet because their mean levels of SAlb, K(+), and PO(4) were within acceptable limits. Dietary adherence was observed in 76% of the Hispanic patients for SAlb, 88% for K(+), and 65% for PO(4), whereas the rate of adherence was 59%, 88%, and 76%, respectively, for the comparison group. Both groups were adherent to the restrictions of the renal diet. More patients from both groups were adherent to K(+) than to PO(4) restrictions. Among the factors that probably influenced dietary adherence to the renal diet in this dialysis facility are knowledge of the renal diet, language, food frequency consumption, socioeconomic status, family support, and attitudes toward the renal diet. Patient education provided in Spanish with family involvement is an important element for promoting adherence among Hispanic patients receiving dialysis.


Neuroprotective effects of erythropoietin in acute ischemic stroke.
Ischemic brain strokes consisttwo-thirdsof strokesand their complications bear a lot of disability for patient and society. In this study, we seek for effect of Erythropoietin on ischemic brain stroke's outcomes according to National Institutes of Health Stroke Scale (NIHSS) changes. This study is a RCT (randomized clinical trial). All patients with focal neurologic deficit with primary suspicion of brain stroke undergone neuroimaging evaluations. After confirmation of new ischemic brain stroke, the patients with inclusion criteria'srandomized into two groups of cases and controls. NIHSS was defined for each patient and all patients received a routine treatment protocol. Erythropoietin 16,000 IU as a bolus intravenous dose was given to case patients as soon as neuroimaging study confirmed new ischemic stroke and continued as 8000 IU each 12 h up to total dose of 56,000 IU during 3 days. Patients re-evaluated at days 14 and 28 and NIHSS was assessed by another neurologist blinded to patient's group. Finally, NIHSS changes of both groups compared with each other's. Evaluations revealed that in days14 and 28 during follow-up, Erythropoietin was effective in NIHSS (P= 0.0001). This effect was of value in level of consciousness Commands (P= 0.024), facial palsy (P= 0.003), motor arm (P= 0.0001), motor leg (P= 0.0001), sensory (P= 0.009), and best language (P= 0.023). Administration of high-dose erythropoietin in first 24 h can be effective on reduction of ischemic stroke complication. A larger scale clinical trial is warranted.


RNA editing makes mistakes in plant mitochondria: editing loses sense in transcripts of a rps19 pseudogene and in creating stop codons in coxI and rps3 mRNAs of Oenothera.
An intact gene for the ribosomal protein S19 (rps19) is absent from Oenothera mitochondria. The conserved rps19 reading frame found in the mitochondrial genome is interrupted by a termination codon. This rps19 pseudogene is cotranscribed with the downstream rps3 gene and is edited on both sides of the translational stop. Editing, however, changes the amino acid sequence at positions that were well conserved before editing. Other strange editings create translational stops in open reading frames coding for functional proteins. In coxI and rps3 mRNAs CGA codons are edited to UGA stop codons only five and three codons, respectively, downstream to the initiation codon. These aberrant editings in essential open reading frames and in the rps19 pseudogene appear to have been shifted to these positions from other editing sites. These observations suggest a requirement for a continuous evolutionary constraint on the editing specificities in plant mitochondria.


Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme.
Pathological findings in 20 cases of glioblastoma multiforme were correlated with clinical histories and computerized tomographic (CT) scans. This was done to define the neoplasm in three stages: before treatment, during remission, and during recurrence. The untreated lesions were markedly cellular neoplasms composed predominantly of small anaplastic cells. The radiographic central region of low density was necrosis, the enhancing rim was a cellular zone of viable neoplasm, and the perilesional low-density area was edema with infiltrating tumor. In these 20 cases, all of the identifiable neoplasms lay within the zone of peritumoral edema or contrast enhancement, although small anaplastic cells may have been present in more distant regions. The lesions in remission were remarkable for their minimal mass effect, discrete nature, extensive necrosis, and content of large bizarre glia. The large cells were confined to the original tumor bed and were consistent with neoplastic cells inactivated and immobilized by radio- and chemotherapy. These lesions were accurately localized by CT scanning. The recurrent lesions were heterogeneous, but most were formed of widely disseminated small anaplastic cells. The highly cellular regions of such lesions could be localized by CT scanning, but CT could not detect less cellular foci in the cerebrum, cerebellum, or brain stem. In one patient, the contrast-enhancing lesions of "recurrence," were foci of radionecrosis, underscoring the difficulty in distinguishing this entity from recurrent neoplasm.


Air Quality Effects on Human Health and Approaches for Its Assessment through Microfluidic Chips.
Air quality depends on the various gases and particles present in it. Both natural phenomena and human activities affect the cleanliness of air. In the last decade, many countries experienced an unprecedented industrial growth, resulting in changing air quality values, and correspondingly, affecting our life quality. Air quality can be accessed by employing microchips that qualitatively and quantitatively determine the present gases and dust particles. The so-called particular matter 2.5 (PM2.5) values are of high importance, as such small particles can penetrate the human lung barrier and enter the blood system. There are cancer cases related to many air pollutants, and especially to PM2.5, contributing to exploding costs within the healthcare system. We focus on various current and potential future air pollutants, and propose solutions on how to protect our health against such dangerous substances. Recent developments in the Organ-on-Chip (OoC) technology can be used to study air pollution as well. OoC allows determination of pollutant toxicity and speeds up the development of novel pharmaceutical drugs.


Genomic and transcriptomic analysis of Laccaria bicolor CAZome reveals insights into polysaccharides remodelling during symbiosis establishment.
Ectomycorrhizal fungi, living in soil forests, are required microorganisms to sustain tree growth and productivity. The establishment of mutualistic interaction with roots to form ectomycorrhiza (ECM) is not well known at the molecular level. In particular, how fungal and plant cell walls are rearranged to establish a fully functional ectomycorrhiza is poorly understood. Nevertheless, it is likely that Carbohydrate Active enZymes (CAZyme) produced by the fungus participate in this process. Genome-wide transcriptome profiling during ECM development was used to examine how the CAZome of Laccaria bicolor is regulated during symbiosis establishment. CAZymes active on fungal cell wall were upregulated during ECM development in particular after 4weeks of contact when the hyphae are surrounding the root cells and start to colonize the apoplast. We demonstrated that one expansin-like protein, whose expression is specific to symbiotic tissues, localizes within fungal cell wall. Whereas L. bicolor genome contained a constricted repertoire of CAZymes active on cellulose and hemicellulose, these CAZymes were expressed during the first steps of root cells colonization. L. bicolor retained the ability to use homogalacturonan, a pectin-derived substrate, as carbon source. CAZymes likely involved in pectin hydrolysis were mainly expressed at the stage of a fully mature ECM. All together, our data suggest an active remodelling of fungal cell wall with a possible involvement of expansin during ECM development. By contrast, a soft remodelling of the plant cell wall likely occurs through the loosening of the cellulose microfibrils by AA9 or GH12 CAZymes and middle lamella smooth remodelling through pectin (homogalacturonan) hydrolysis likely by GH28, GH12 CAZymes.


Pancreatic Torsion Resulting in Acute Pancreatic Necrosis in a Young Dog.
We report a case of 7 mo old French bulldog who was referred to North Carolina State University Small Animal Emergency and Triage Services because of acute abdomen, regurgitation, lethargy, and fever. The patient had a history of pulmonic stenosis, which was corrected by balloon valvuloplasty 3 wk before presenting for the current complaint. The patient had nonspecific changes noted on blood work at his referring veterinarian. An abdominal ultrasound examination showed pathological changes that were supportive of a left-limb pancreatic torsion that was confirmed postmortem.


Distal Hereditary Motor Neuronopathy of the Jerash Type.
A novel form of autosomal recessive distal hereditary motor neuronopathy (distal HMN) is reported. The presence of pyramidal signs within the early stages of the disease with persistence of knee hyperreflexia form distinctive clinical features. We have mapped the HMN-J gene to chromosome 9p21.1-p12, within an estimated interval of 1.2-Mb.


Widespread white matter aberration is associated with the severity of apathy in amnestic Mild Cognitive Impairment: Tract-based spatial statistics analysis.
Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer's Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p < .05, TFCE-corrected) after controlling for age, gender and GDS non-apathy. A trend association was observed in the right posterior corona radiata and corticospinal tract/internal capsule, and bilateral forceps minor (p < .065, TFCE-corrected). In conclusion, in aMCI, severity of apathy is associated with aberrant white matter integrity in widely distributed pathways, within and between hemispheres.


[Studies on the thyrotropin receptor and adenylate cyclase activity in various thyroid diseases: I. The properties of TSH receptor and adenylate cyclase in Graves' thyroid and retro-orbital adipose tissues (author's transl)].
Most current etiologic concepts of Graves' disease postulate that this is an autoimmune disorder. A humoral factor, such as thyroid stimulating immunoglobulin, may be the mediator. On the other hand, it has also been suggested that abnormalities in the thyroid gland itself might be responsible for hyperfunction of the gland in Graves' disease. The true etiology of Graves' disease is still unknown. Similarly, the pathogenesis of the ophthalmic changes of Graves' disease is obscure, but immune mechanisms figure prominently in current hypotheses of the pathogenesis. It has been suggested that human adipose cell membranes have TSH receptors and that antibodies reacting with the receptors may stimulate fat cells. In this study, we have evaluated TSH receptor and adenylate cyclase of Graves' thyroid glands. Furthermore, we have investigated those of retro-orbital and the other adipose tissues in the guinea pig and in man. Human thyroid tissues were obtained at surgery and immediately minced homogenized with a loose-fitting Dounce homogenizer. A part of 10,000 g pellet of the homogenate was used for adenylate cyclase assay. The rest of the pellet was further purified by a discontinuous sucrose gradient ultracentrifugation, and the plasma membrane fraction was used for the receptor assay. The 125I-TSH binding to the fraction was measured, and the affinity constant (Ka) and capacity (Ro) were obtained from Scatchard plots using Rosenthal's method of analysis. Normal thyroid tissue contained high affinity (Ka = 2.4 x 10(10) M-1; Ro = 0.9 pmole/mg protein) and low affinity (Ka = 1.9 x 10(8) M-1; Ro = 386 pmole/mg protein) receptors. The two orders of TSH receptor were also found in Graves' thyroid tissue. The affinity constant and capacity of high affinity receptors were identical with those of normal thyroids, but the affinity constant of low affinity receptors was lower in Graves' thyroid (P less than 0.05). The basal adenylate cyclase activity in normal thyroid tissues was 0.35 nmole/10 min/mg protein. The activity rose to 280% of basal with 166 mU/ml of TSH and 680% of basal with 10 mM of NaF. These values obtained in Graves' disease were not significantly different from the values of normal thyroids. It is concluded that thyroid hyperfunction in Graves' disease is probably not the result of an intrinsic abnormality of the TSH receptor-adenylate cyclase system. Human retro-orbital adipose tissue was obtained at surgery from patients of Graves' exophthalmos or malignant neoplasm of accessory sinus. Guinea pigs tissue was obtained from 250g male animals. We were unable to demonstrate high affinity TSH receptor in human retro-orbital fat, perirenal fat or guinea pig retro-orbital fat. In contrast, guinea pig epididymal fat membranes showed TSH receptor characteristics similar to guinea pig thyroid membranes. In human adipose tissue, TSH did not stimulate the adenylate cyclase activity, although NaF definitely stimulated the enzyme...


The inhibitory effect of tobacco smoke compound on ciliary activity.
The embryo chicken trachea was used as an in vitro model to study the ciliotoxicity of the volatile part of the particulate phase of cigarette smoke condensate (CSC). We also report on the ciliotoxicity of 11 phenols belonging to the semi-volatile fraction. The particulate phase of CSC was divided into a semi-volatile (SV) and a non-volatile (NV) fraction. The toxicity of CSC, SV and NV was approximately the same, giving ciliostasis within 21-28 minutes at a concentration of 1 mg/ml. The SV-fraction, constituting 12 percent of the particulate phase, was further divided into 4 subfractions: acids, phenols, bases and neutrals. The neutral fraction was significantly (p less than 0.001) more toxic than any of the other fractions, giving ciliostasis after 17 minutes at a concentration of 1 mg/ml. Least toxic was the basic fraction, mainly consisting of nicotine. At a concentration of 3 mg/ml, the mean value for ciliostasis was 64 minutes. From the investigation of phenols it was found that alkylated phenols were more ciliotoxic than phenol. The toxicity was enhanced with increasing chain-length of the substituent, i.e. with increasing lipophilicity.


BioAfrica's HIV-1 proteomics resource: combining protein data with bioinformatics tools.
Most Internet online resources for investigating HIV biology contain either bioinformatics tools, protein information or sequence data. The objective of this study was to develop a comprehensive online proteomics resource that integrates bioinformatics with the latest information on HIV-1 protein structure, gene expression, post-transcriptional/post-translational modification, functional activity, and protein-macromolecule interactions. The BioAfrica HIV-1 Proteomics Resource http://bioafrica.mrc.ac.za/proteomics/index.html is a website that contains detailed information about the HIV-1 proteome and protease cleavage sites, as well as data-mining tools that can be used to manipulate and query protein sequence data, a BLAST tool for initiating structural analyses of HIV-1 proteins, and a proteomics tools directory. The Proteome section contains extensive data on each of 19 HIV-1 proteins, including their functional properties, a sample analysis of HIV-1HXB2, structural models and links to other online resources. The HIV-1 Protease Cleavage Sites section provides information on the position, subtype variation and genetic evolution of Gag, Gag-Pol and Nef cleavage sites. The HIV-1 Protein Data-mining Tool includes a set of 27 group M (subtypes A through K) reference sequences that can be used to assess the influence of genetic variation on immunological and functional domains of the protein. The BLAST Structure Tool identifies proteins with similar, experimentally determined topologies, and the Tools Directory provides a categorized list of websites and relevant software programs. This combined database and software repository is designed to facilitate the capture, retrieval and analysis of HIV-1 protein data, and to convert it into clinically useful information relating to the pathogenesis, transmission and therapeutic response of different HIV-1 variants. The HIV-1 Proteomics Resource is readily accessible through the BioAfrica website at: http://bioafrica.mrc.ac.za/proteomics/index.html.