A suicide gene therapy combining the improvement of cyclophosphamide tumor cytotoxicity and the development of an anti-tumor immune response.
Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8(+)T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.


Tilted Arch; Implementation of Additive Manufacturing and Bio-Welding of Mycelium-Based Composites.
Bio-based materials have found their way to the design and fabrication in the architectural context in recent years. Fungi-based materials, especially mycelium-based composites, are a group of these materials of growing interest among scholars due to their light weight, compostable and regenerative features. However, after about a decade of introducing this material to the architectural community, the proper ways of design and fabrication with this material are still under investigation. In this paper, we tried to integrate the material properties of mycelium-based composites with computational design and digital fabrication methods to offer a promising method of construction. Regarding different characteristics of the material, we found additive manufacturing parallel to bio-welding is an appropriate fabrication method. To show the feasibility of the proposed method, we manufactured a small-scale prototype, a tilted arch, made of extruded biomass bound with bio-welding. The project is described in the paper.


A third site of porton translocation in green plant photosynthetic electron transport.
Prereduction of the intersystem pool in isolated spinach chloroplasts leads to the appearance of a slow phase in the field-indicating 515-nm change induced by a flash. Measurements with the pH-indicator dye cresol red show that a proton uptake is associated with this slow 515-nm change. When water is the electron donor to photosystem II, electron transfer to ferricyanide is associated with the uptake of more than one proton per electron. Tetraphenylboron upon oxidation by system II releases a proton directly into the medium; yet, flash-induced electron transport from tetraphenylboron to ferricyanide is accompanied by a net uptake of protons from the medium. The above four results demonstrate the existence of two proton translocation sites in the chain between the two photoacts; the first two observations locate the new site at the oxidizing side of the plastoquinone pool.


High resolution live cell Raman imaging using subcellular organelle-targeting SERS-sensitive gold nanoparticles with highly narrow intra-nanogap.
We report a method to achieve high speed and high resolution live cell Raman images using small spherical gold nanoparticles with highly narrow intra-nanogap structures responding to NIR excitation (785 nm) and high-speed confocal Raman microscopy. The three different Raman-active molecules placed in the narrow intra-nanogap showed a strong and uniform Raman intensity in solution even under transient exposure time (10 ms) and low input power of incident laser (200 μW), which lead to obtain high-resolution single cell image within 30 s without inducing significant cell damage. The high resolution Raman image showed the distributions of gold nanoparticles for their targeted sites such as cytoplasm, mitochondria, or nucleus. The high speed Raman-based live cell imaging allowed us to monitor rapidly changing cell morphologies during cell death induced by the addition of highly toxic KCN solution to cells. These results strongly suggest that the use of SERS-active nanoparticle can greatly improve the current temporal resolution and image quality of Raman-based cell images enough to obtain the detailed cell dynamics and/or the responses of cells to potential drug molecules.


Critical incident reporting in emergency medicine: results of the prehospital reports.
Medical errors frequently contribute to morbidity and mortality. Prehospital emergency medicine is prone to incidents that can lead to immediate deadly consequences. Critical incident reporting can identify typical problems and be the basis for structured risk management in order to reduce and mitigate these incidents. We set up a free access internet website for German-speaking countries, with an anonymous reporting system for emergency medical services personnel. After a 7-year study period, an expert team analysed and classified the incidents into staff related, equipment related, organisation and tactics, or other. 845 reports were entered in the study period. Physicians reported 44% of incidents, paramedics 42%. Most patients were in a life-threatening or potentially life-threatening situation (82%), and only 53% of all incidents had no influence on the outcome of the patient. Staff-related problems were responsible for 56% of the incidents, when it came to harm, 78% of these incidents were staff related. Incident reporting in prehospital emergency medicine can identify system weaknesses. Most of the incidents were reported during care of patients in life-threatening conditions with a high impact on patient outcome. Staff-related problems contributed to the most frequent and most severe incidents.


Biochemical assessment of adequate levothyroxine replacement in primary hypothyroidism differs with different TSH assays: potential clinical implications.
Thyroid stimulating hormone (TSH) assays provided by Abbott Laboratories and Roche Diagnostics are used by approximately 75% of laboratories in the UK. We assessed the potential impact of Abbott and Roche TSH assay differences on the biochemical assessment of levothyroxine replacement in primary hypothyroidism. Samples from 100 consecutive primary care patients (83 women, median age 64 years, IQR 51-73 years) with primary hypothyroidism on adequate levothyroxine based on an Abbott Architect TSH in the reference range were analysed for TSH on Roche cobas within 24 hours. The Abbott and Roche TSH results were compared. Over 1 year, TSH results from patients in primary care from the laboratories with Abbott and Roche methods were compared. The median (IQR) Roche TSH (2.5 (1.3-3.6) mIU/L) was 30%±10% higher (p<0.001) than Abbott TSH (1.9 (1.1-2.6) mIU/L). Although all Abbott TSH results were in the Abbott specific reference range, 14 patients (14%) had Roche TSH results above the Roche specific reference range. In the 1 year gather, Roche TSH (1.9 (1.3-2.9) mIU/L, n=103 932) results were higher (p<0.001) than Abbott TSH (1.5 (1.0-2.2) mIU/L, n=1 10 544) results. The TSH results were above their assay-specific upper reference limit in 10.7% of Roche results and 4.2% of Abbott results. Biochemical assessment of levothyroxine replacement may be dependent on the type of TSH assay. Laboratorians and clinicians should be aware that the lack of harmonisation between TSH methods and their assay-specific reference ranges may potentially lead to different patient management decisions. We suggest lot verification in laboratories should include processes to identify cumulative drift in assay performance.


Theory of holographic optical trapping.
Optical traps use the forces exerted by structured beams of light to confine and manipulate microscopic objects in three dimensions. A popular implementation involves structuring the trap-forming beam with computer-generated holograms before focusing it into traps with a high-numerical-aperture optical train. Here, we present a fully vectorial theory for the forces and torques exerted by such systems.


Continuous intra-abdominal pressure monitoring.
Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) can develop within 12 hours of ICU admission in high-risk patients. Until recently the intermittent intra-abdominal pressure (IAP) measurement via the urinary catheter was the clinical standard. This is a relatively labour intensive technique and its intermittent nature could prevent timely recognition of significant changes in IAP. The historical continuous IAP (CIAP) measurements were poorly reproducible (gastric route) or invasive/impractical (direct measurement). The aim of this paper is to review the current evidence on CIAP monitoring. A broad Medline search of the English literature was performed using the terms of "intra abdominal pressure" and "continuous". This result was analysed based on the title and abstract. Only original clinical studies with continuous IAP measurement were considered in this review. New techniques of CIAP monitoring evaluated in large animal models are discussed as potential future directions. There is a growing evidence of measuring (monitoring) CIAP using several techniques (gastric, direct abdominal, inferior vena cava, and urinary bladder. The strongest evidence supports the direct abdominal, the gastric and the bladder route. From these three techniques the CIAP monitoring via the bladder has excellent agreement with the current standard of intermittent bladder pressure measurement. While the direct measurement could be very accurate it is an invasive method and feasible in patient who underwent laparotomy or laparoscopy. Until a better technique is available the CIAP monitoring via the bladder or stomach should be considered as the standard for continuous monitoring of the IAP. It is a less labour intensive, safe, less invasive and reliable method.


Measuring communicative participation using the FOCUS©: Focus on the Outcomes of Communication Under Six.
The FOCUS© is a new outcome tool for use by both parents and clinicians that measures changes in the communicative participation skills of preschool children. Changes in communicative participation skills as measured by the FOCUS were compared across three groups of children: those with speech impairments only (SI), those with language impairments only (LI) and those with both speech and language impairments (S/LI). Participating families (n = 112, 75 male children) were recruited through 13 Canadian organizations. Children ranged from 10 months to 6 years 0 months (mean = 2.11 years; SD = 1.18 years) and attended speech-language intervention. Parents completed the FOCUS at the start and end of treatment. There were 23 children in the SI group, 62 children in the LI group and 27 children in the S/LI group. The average amount of the children's therapy varied from 7 to 10 h. The FOCUS captures changes in communicative participation for children with a range of communication disorder types and severities. All three groups of children made clinically important improvements according to their FOCUS scores (MCID ≥ 16 points). The FOCUS captured improvements in intelligibility, independent communication, play and socialization. The FOCUS measured positive changes in communicative participation skills for all three groups of children after 7-10 h of speech-language therapy. An outcome measure that targets only specific speech and language skills would miss many of the important social function changes associated with speech-language treatment.


Enteropathogenic and enterohaemorrhagic Escherichia coli: even more subversive elements.
The human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) share a unique mechanism of colonization that results from the concerted action of effector proteins translocated into the host cell by a type III secretion system (T3SS). EPEC and EHEC not only induce characteristic attaching and effacing (A/E) lesions, but also subvert multiple host cell signalling pathways during infection. Our understanding of the mechanisms by which A/E pathogens hijack host cell signalling has advanced dramatically in recent months with the identification of novel activities for many effectors. In addition to further characterization of established effectors (Tir, EspH and Map), new effectors have emerged as important mediators of virulence through activities such as mimicry of Rho guanine nucleotide exchange factors (Map and EspM), inhibition of apoptosis (NleH and NleD), interference with inflammatory signalling pathways (NleB, NleC, NleE and NleH) and phagocytosis (EspF, EspH and EspJ). The findings have highlighted the multifunctional nature of the effectors and their ability to participate in redundant, synergistic or antagonistic relationships, acting in a co-ordinated spatial and temporal manner on different host organelles and cellular pathways during infection.


Modulated expression of plasminogen activator system components in cultured cells from dissociated mouse dorsal root ganglia.
The development and regeneration of the peripheral nervous system (PNS) is highly dependent on the migration of Schwann cells and the extension of axons toward their distant targets. Plasminogen activators (PAs) are associated with the surface of several cell types of neural origin where they are believed to mediate localized degradation of extracellular matrix, thus facilitating cell motility. In this study, we characterize the expression of tissue-type (tPA) and urokinase (uPA) PAs, as well as the urokinase cell surface receptor (uPAR) during differentiation of cultured cells from mouse dorsal root ganglia. During the first day in culture, the mRNA levels of all three components increase from 75- to 163-fold, as shown using a quantitative PCR method. By 72 hr, the mRNA levels decrease and approach basal levels. This transient increase is in direct correlation with the differentiation of neurons and Schwann cells and the formation of a neuritic network in these regenerating cultures. Densitometric analysis of gel zymographs demonstrates that the elevation in mRNA levels is accompanied by similar increases in the activity levels of tPA and uPA. Interestingly, in situ hybridization studies of the cultures show that tPA mRNA is restricted to small sensory neurons, whereas uPA mRNA is localized predominantly in large sensory neurons. uPAR mRNA is expressed by both neuronal subpopulations and, to a lesser extent, by Schwann cells and fibroblasts. Taken together, these results further support a role for the PA system in facilitating axon extension and cell migration during development and regeneration of the PNS.


Responses and afferent pathways of superficial and deeper c(1)-c(2) spinal cells to intrapericardial algogenic chemicals in rats.
Electrical stimulation of vagal afferents or cardiopulmonary sympathetic afferent fibers excites C(1)--C(2) spinal neurons. The purposes of this study were to compare the responses of superficial (depth <0.35 mm) and deeper C(1)--C(2) spinal neurons to noxious chemical stimulation of cardiac afferents and determine the relative contribution of vagal and sympathetic afferent pathways for transmission of noxious cardiac afferent input to C(1)--C(2) neurons. Extracellular potentials of single C(1)--C(2) neurons were recorded in pentobarbital anesthetized and paralyzed male rats. A catheter was placed in the pericardial sac to administer a mixture of algogenic chemicals (0.2 ml) that contained adenosine (10(-3) M), bradykinin, histamine, serotonin, and prostaglandin E(2) (10(-5) M each). Intrapericardial chemicals changed the activity of 20/106 (19%) C(1)--C(2) spinal neurons in the superficial laminae, whereas 76/147 (52%) deeper neurons responded to cardiac noxious input (P < 0.01). Of 96 neurons responsive to cardiac inputs, 48 (50%) were excited (E), 41 (43%) were inhibited (I), and 7 were excited/inhibited (E-I) by intrapericardial chemicals. E or I neurons responsive to intrapericardial chemicals were subdivided into two groups: short-lasting (SL) and long-lasting (LL) response patterns. In superficial gray matter, excitatory responses to cardiac inputs were more likely to be LL-E than SL-E neurons. Mechanical stimulation of the somatic field from the head, neck, and shoulder areas excited 85 of 95 (89%) C(1)--C(2) spinal neurons that responded to intrapericardial chemicals; 31 neurons were classified as wide dynamic range, 49 were high threshold, 5 responded only to joint movement, and no neuron was classified as low threshold. For superficial neurons, 53% had small somatic fields and 21% had bilateral fields. In contrast, 31% of the deeper neurons had small somatic fields and 46% had bilateral fields. Ipsilateral cervical vagotomy interrupted cardiac noxious input to 8/30 (6 E, 2 I) neurons; sequential transection of the contralateral cervical vagus nerve (bilateral vagotomy) eliminated the responses to intrapericardial chemicals in 4/22 (3 E, 1 I) neurons. Spinal transection at C(6)--C(7) segments to interrupt effects of sympathetic afferent input abolished responses to cardiac input in 10/10 (7 E, 3 I) neurons that still responded after bilateral vagotomy. Results of this study support the concept that C(1)-C(2) superficial and deeper spinal neurons play a role in integrating cardiac noxious inputs that travel in both the cervical vagal and/or thoracic sympathetic afferent nerves.


The person in abortion.
The issue of what constitutes a person is examined in relation to whether or not the fetus or newborn has qualities of personhood. The discussion also dwells on birth and viability as determining factors in decisions concerning terminations. Such decisions are stated to be constrained by both biological and social factors, particularly in the way in which the fetus can possess personhood only through the 'absorption' of such from its mother; both mother and fetus together are 'the person'. This article also considers whether, on Piagetian grounds, one can make personhood comparisons between infants and adults and suggests that such comparisons are a mistake. A social critique of Piagetian principles shifts the emphasis from individualism towards consideration of school, family and environmental factors. Equally, it is not feasible to view the fetus as an entity that is separate from its mother's perceptions of its social as well as its physical status. Finally, because termination decisions occur against 'real life' (and highly charged) backgrounds, we must reject any notion that such decisions are only an intellectual exercise. It is assumed that nurses would implicitly understand this and some attempt is made to state why this is so.


3-hydroxybutyrate dehydrogenase in tissues from normal and ketonaemic sheep.
1. In liver, rumen epithelium and kidney cortex of the sheep, a dehydrogenase active against dl-3-hydroxybutyrate occurred in both the cytosol and particulate fractions of the tissues. In brain, heart, skeletal and smooth muscles, the enzyme occurred only in the particulate fraction. 2. Enzyme activity in the cytoplasmic fraction of liver and rumen epithelium was similar with either d(-)-3-hydroxybutyrate or dl-3-hydroxbutyrate, but was less with acetoacetate as the substrate. The cytosol fraction of kidney cortex showed very little activity with d(-)-3-hydroxybutyrate, confirming that most of the activity with dl-3-hydroxybutyrate was with the l(+) isomer in this tissue. 3. 3-Hydroxybutyrate dehydrogenase activities in the cytosol and particulate fractions of liver, rumen epithelium and kidney cortex and in the particulate fraction of brain tissue were not stimulated by phosphatidylcholine, unlike the enzyme in sheep muscle and in tissues of other species. 4. The activity of 3-hydroxybutyrate dehydrogenase was not increased significantly in any of the tissues of ketonaemic sheep. 5. Comparison of rates of 3-hydroxybutyrate production in vivo with the enzyme activity in ketogenic tissue suggested that in sheep the maximum rate of production might be limited by this activity.


The New Cutoff Value of the Hepatic Venous Pressure Gradient on Predicting Long-Term Survival in Cirrhotic Patients.
This study aimed to determine the prognostic role of the categorized hemodynamic stage (HS) based on the hepatic venous pressure gradient (HVPG) in patients with portal hypertension. Of 1,025 cirrhotic patients who underwent HVPG measurement, data on 572 non-critically-ill patients were collected retrospectively between 2008 and 2013. The following two HS categorizations were used: HS-1 (6-9, 10-12, 13-16, 17-20, and > 20 mmHg; designated as groups 1-5, respectively) and HS-2 (6-12, 13-20, and > 20 mmHg). Clinical characteristics, mortality rates, and prognostic predictors were analyzed according to the categorized HS. During the mean follow-up period of 25 months, 86 (15.0%) patients died. The numbers of deaths in HS-1 groups were 7 (6.3%), 7 (6.9%), 30 (18.0%), 20 (15.6%), and 22 (34.4%), respectively (P < 0.001). However, the traditional HVPG cutoffs of 10 and 16 mmHg did not improve the discrimination of mortality. In contrast, the mortality rates did differ significantly between the three HS-2 groups (P < 0.05). In the multivariate analysis, all models revealed that HS-2 was a common prognostic factor in predicting mortality. The mortality rates increased significantly according to HS-2 in patients with hypoalbuminemia (HVPG, 13-20 mmHg; hazard ratio [HR], 2.54 and HVPG > 20 mmHg; HR, 5.45) and intermediate model for end-stage liver disease (MELD) score (HVPG, 13-20 mmHg; HR, 3.86 and HVPG > 20 mmHg; HR, 8.77; P < 0.05). Categorizing HVPG values according to HS-2 is a useful prognostic modality in patients with portal hypertension and can play an independent role in predicting the prognosis in patients with hypoalbuminemia and an intermediate MELD score.


Fluoride release and secondary caries inhibition by adhesive systems on root dentine.
This study tested the fluoride-release rate and the root caries inhibitory effect of dental adhesives. In phase 1, the fluoride released from samples (n = 5) of the adhesives A (Optibond Solo), B (One-up Bond F), C (Prime & Bond NT), D (Tenure Quick), and also of the controls [+] (glass-ionomer cement) and [-] (non-fluoride releasing adhesive), was quantified on a daily basis during a pH-cycling, caries-simulating phenomenon. In phase 2, restorations were made in bovine root dentine slabs (n = 16) with the same adhesives associated with a non-fluoridated composite. Control [+] restorations were made entirely with glass-ionomer cement. Specimens were thermocycled and submitted to the pH-cycling regimen. Demineralization areas and the presence of the wall lesion (WL) and the inhibition zone (IZ) were determined by polarizing light microscopy in dentine adjacent to the restoration. The highest concentration of fluoride was released by the control [+]; adhesives A, B and C, also released fluoride. No detectable amount of fluoride was released by D or [-]. Smaller areas of demineralization were found with control [+], whereas the demineralization areas of adhesives A-D and [-] did not differ from each other. No WL was detected, and higher percentages of IZ were recorded to [+] and to adhesive A. Although some dental adhesives were able to release fluoride, they could not inhibit secondary caries development as well as the glass-ionomer cement.


Transvaginal cholecystectomy learning curve.
There are few surgeons in the United States, within private practice and academic centers, currently performing transvaginal cholecystectomies (TVC). The lack of exposure to TVC during residency or fellowship training, coupled with a poorly defined learning curve, further limits interested surgeons who want to apply this technique to their practice. This study describes the learning curve encountered during the introduction of TVC to our academic facility. This study is an analysis of consecutive TVCs performed between August 14, 2009 and August 3, 2012 at an academic center. The TVC patients were divided into sequential quartiles (n = 15/16). The learning curve outcome was measured as the operative time of TVC patients and compared to the operative time of female laparoscopic cholecystectomy (LC) patients performed during the same time period. Sixty-one patients underwent a TVC with a mean age of 38 ± 12 years and mean BMI was 29 ± 6 kg/m(2). Sixty-seven female patients who underwent a LC with average age 41 ± 15 years and average BMI 33 ± 12 kg/m(2). The average operative time of LC patients and TVC patients was 48 ± 20 and 60 ± 17 min, respectively. Significant improvement in TVC operative times was seen between the first (n = 15 TVCs) and second quartiles (p = 0.04) and stayed relatively constant for third quartile, during which there was no statistically significant difference between the mean LC operative time for the second and third TVC quartiles The learning curve of a fellowship-trained surgeon introducing TVC to their surgical repertoire, as measured by improved operative times, can be achieved with approximately 15 cases.


Clinical profile of acute lower respiratory tract infections in children aged 2-60 months: An observational study.
Assessment of risk factors and clinical profile for acute lower respiratory tract infections (ALRIs) with severe and very severe pneumonia in children <5 years age is obligatory. To study the clinical profile, risk factors, and clinical outcomes associated with ALRIs in children aged 2-60 months. In total, 130 children of either gender, diagnosed with ALRIs, admitted in a tertiary care hospital were enrolled. Demographic data and clinical history was collected. Clinical profile data such as respiratory and heart rate, oxygen supplementation, ventilator use, and lab investigation such as erythrocyte sedimentation rate, hemoglobin, total leucocyte count, differential leucocytes count, and blood culture were analyzed and noted. The study findings demonstrated male gender predominance for ALRIs with 1.3:1 male to female ratio. Around 16% of them had pneumonia, 61% had severe pneumonia, and 23% had very severe pneumonia. The birth weight of child, maternal and paternal literacy, socioeconomic status, overcrowding at home, immunization status of children, type of kitchen and fuel used for cooking, malnutrition, anemia, and need for oxygen supplementation were found to be associated with the occurrence of ALRIs (P < 0.05). Most of the presented symptoms were cough (100%), breathlessness (96.92%), and fever (92.31%). Bronchiolitis (63%), bronchopneumonia (27%), and lobar pneumonia (25%) were the major clinical outcomes. The study identified various sociodemographic, environmental, and nutritional risk factors for ALRIs along with the clinical profile, which can be managed by effective peripheral health personnel's training and persuasive community health education.


A Novel Interaction of Ecdysoneless (ECD) Protein with R2TP Complex Component RUVBL1 Is Required for the Functional Role of ECD in Cell Cycle Progression.
Ecdysoneless (ECD) is an evolutionarily conserved protein whose germ line deletion is embryonic lethal. Deletion of Ecd in cells causes cell cycle arrest, which is rescued by exogenous ECD, demonstrating a requirement of ECD for normal mammalian cell cycle progression. However, the exact mechanism by which ECD regulates cell cycle is unknown. Here, we demonstrate that ECD protein levels and subcellular localization are invariant during cell cycle progression, suggesting a potential role of posttranslational modifications or protein-protein interactions. Since phosphorylated ECD was recently shown to interact with the PIH1D1 adaptor component of the R2TP cochaperone complex, we examined the requirement of ECD phosphorylation in cell cycle progression. Notably, phosphorylation-deficient ECD mutants that failed to bind to PIH1D1 in vitro fully retained the ability to interact with the R2TP complex and yet exhibited a reduced ability to rescue Ecd-deficient cells from cell cycle arrest. Biochemical analyses demonstrated an additional phosphorylation-independent interaction of ECD with the RUVBL1 component of the R2TP complex, and this interaction is essential for ECD's cell cycle progression function. These studies demonstrate that interaction of ECD with RUVBL1, and its CK2-mediated phosphorylation, independent of its interaction with PIH1D1, are important for its cell cycle regulatory function.


Adaptation of a microimmunofluorescence test to the study of human Rickettsia tsutsugamuskh antibody.
A microimmunofluorescence (micro-IFA) test has been adapted to the study of naturally occurring antibody to Rickettsia tsutsugamushi in humans. The micro-IFA test was comparable to the present immlnofluorescent assay in sensitivity and reproducibility, but offered distinct advantages in the quantity of reagents necessary. Also the micro-IFA could be used to simultaneously titer a serum to as many as nine strains of the organism resulting in a great saving of time.


[Comparative dynamics of elimination of potential chromosome damage in mouse bone marrow cells after low and moderate doses of radiation].
Possible dynamics of the incidence, repair, and realization of potential chromosome aberrations (PAs) was examined by indirect methods based on cytogenetic analysis of radiation effects. PAs were characterized as chemical modifications of DNA responsible for the incidence of structural aberrations of chromosomes. We interpreted our data as providing evidence that two types of radiation-induced PAs, differing in repair rates, could occur in the exposed cells: quick- (short-term) and slow (long-term) repairing PAs. We showed that the PA spectrum gradually changed with an increase in radiation dose within the interval from 24 to 150 cGy. This process was paralleled by changes in the cell response and chromosome resistance to radiation. Short-term PAs were induced mainly by low radiation doses ranging from 24 to 75 cGy. Their incidence was associated with activation of the corresponding repair process. Further increase in radiation dose resulted in changes in the PA spectrum, and doses of 150 cGy induced predominantly long-term PAs with concomitant activation of the appropriate repair process. Induction of repair occurred in the dose intervals limited by lower and upper threshold doses, Dl and Du. In our experiments, short-term PAs were repaired when Dl < 24 cGy and 126 cGy < Du < < 150 cGy. Long-term PAs were repaired when 75 cGy < Dl < 99 cGy and Du > 150 cGy.


Pressure ulcers in veterans with spinal cord injury: a retrospective study.
Pressure ulcers are a major complication of spinal cord injury (SCI) and have a significant effect on general health and quality of life. The objectives of this retrospective chart review were to determine prevalence, duration, and severity of pressure ulcers in veterans with SCI and to identify predictors of (1) outcome in terms of healing without surgery, not healing, or referral for surgery; (2) number of visits veterans made to the SCI outpatient clinic or received from home care services for pressure ulcer treatment; and (3) number of hospital admissions and days hospitalized for pressure ulcer treatment. From a sampling frame of 553 veterans on the Houston Veterans Affairs Medical Center SCI roster, 215 (39%) were reported to have visited the clinic or received home care for pressure ulcers (ICD-9 code 707.0 = decubitus, any site) during the 3 years studied (1997, 1998, and 1999). From this sample, 102 veterans met the inclusion criteria for further analyses, 56% of whom had paraplegia. The duration of ulcers varied greatly from 1 week to the entire 3-year time-frame. Overall, Stage IV pressure ulcers were the most prevalent as the worst ulcer documented. Number and severity of ulcers predicted outcome and healthcare utilization. This study illustrates the magnitude of the pressure ulcer problem among veterans with SCI living in the community. Reducing the prevalence of pressure ulcers among veterans with SCI will have a significant impact on the Department of Veterans Affairs' financial and social resources. Innovative approaches are needed to reduce pressure ulcer risk in veterans with SCI.


Evaluation of appropriateness of patient transfers for hand and microsurgery to a level I trauma center.
The transfer of patients for hand and microsurgical emergencies to level I trauma centers is a common practice. Many of these transfers do not actually require a hand specialist and could be taken care of at most regional hospitals. In this study, we will evaluate the appropriateness of patient transfers for hand trauma and determine if there is a correlation between inappropriate transfers and undesirable factors, such as insurance status and off-hour's presentation. A retrospective chart review was performed in all patients transferred to a level I trauma center for hand and microsurgical trauma over a 22-month period. Collected data included indication for transfer, mode of transfer, time and day of the week, patient demographics, insurance status, and whether the transferring facilities had surgical coverage available. A synopsis, including treatment details, of each transfer was created, and a survey was sent to a review committee who rated the appropriateness of the transfers. Statistical analysis was performed to determine whether appropriateness of transfers was influenced by nonmedical variables. Over a 22-month period, a total of 95 hand or microsurgical patients were transferred to a single tertiary referral center. Of these, 66 % of the transfers were considered inappropriate by the surveyed physicians. Inappropriate transfers were statistically more likely to be under insured or transferred during nonbusiness hours. A large percentage of patients are being transferred to tertiary care centers for reasons other than medical necessity, generating a large burden on already strained medical resources.


Fracture of the mandibular body and ramus during horizontal osteotomy for augmentation genioplasty.
A fracture of the body and ramus of the mandible occurred during a horizontal esteotomy for augmentation genioplasty. Care must be exercised when using osteotomes to free the posteroinferior border during this procedure.


Covalent binding of BP-metabolites to DNA of cultured human hair follicle keratinocytes.
Primary cultures of human hair follicle keratinocytes were established by using a basement membrane-like growth substrate, the bovine eye lens capsule. A method was adapted for the isolation of 3H-benzo(a)pyrene (BP)-modified DNA from the cellular outgrowth of only one hair follicle (approximately 2 X 10(5) cells). In a routine procedure hair follicle keratinocytes were incubated with 0.5 microM 3H-BP for 24 h. The purified DNA was subjected to enzymic hydrolysis and the adducts were analyzed by Sephadex LH-20 column chromatography followed by HPLC. Only one major adduct, which represented 60-80% of the total radioactivity which can be confined to modified nucleosides in the LH-20 chromatograph, could be identified. This adduct co-chromatographed with the marker adducts resulting from the trans-addition of the N-2-amino group of guanine to the 10-position of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Co-incubation with 7,8-benzoflavone (0.3 microM), an inhibitor of cytochrome P-448, and with 1,1,1-trichloropropene-2,3-oxide (0.2 microM), an inhibitor of epoxide hydrolase, resulted in a marked inhibitory effect (15% of the control binding) and a large increase (300% of the control value) in BP-DNA binding respectively. Induction of aryl hydrocarbon hydroxylase activity in the cultures with 5,6-benzoflavone (10 microM) or benz(a)anthracene (10 microM) caused a decrease (75 and 46% of the control value respectively) in BP-DNA binding.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetically engineered mice demonstrate that adenosine deaminase is essential for early postimplantation development.
Adenosine deaminase (ADA) is an essential enzyme of purine metabolism that is enriched at the maternal-fetal interface of mice throughout postimplantation development. During early postimplantation stages Ada is highly expressed in both maternally derived decidual cells and zygotically derived trophoblast cells. For the current study we utilized genetically modified mice to delineate the relative contribution and importance of decidual and trophoblast ADA at the maternal-fetal interface. In females genetically engineered to lack decidual ADA a striking pattern of expression was revealed in giant trophoblast cells that surround the early postimplantation embryo. Embryos within gestation sites lacking both decidual and trophoblast ADA died during the early postimplantation period, whereas expression in trophoblast cells alone was sufficient for survival through this period. Severe disturbances in purine metabolism were observed in gestation sites lacking decidual ADA, including the accumulation of the potentially toxic ADA substrates adenosine and 2'-deoxyadenosine. These experiments provide genetic evidence that Ada expression at the maternal-fetal interface is essential for early postimplantation development in mice.


Novel mechanism of blood pressure regulation by forkhead box class O1-mediated transcriptional control of hepatic angiotensinogen.
The renin-angiotensin system is a major determinant of blood pressure regulation. It consists of a cascade of enzymatic reactions involving 3 components: angiotensinogen, renin, and angiotensin-converting enzyme, which generate angiotensin II as a biologically active product. Angiotensinogen is largely produced in the liver, acting as a major determinant of the circulating renin-angiotensin system, which exerts acute hemodynamic effects on blood pressure regulation. How the expression of angiotensinogen is regulated is not completely understood. Here, we hypothesize that angiotensinogen is regulated by forkhead transcription factor forkhead box class O1 (Foxo1), an insulin-suppressed transcription factor, and thereby controls blood pressure in mice. We generated liver-specific Foxo1 knockout mice, which exhibited a reduction in plasma angiotensinogen and angiotensin II levels and a significant decrease in blood pressure. Using hepatocyte cultures, we demonstrated that overexpression of Foxo1 increased angiotensinogen expression, whereas hepatocytes lacking Foxo1 demonstrated a reduction of angiotensinogen gene expression and partially impaired insulin inhibition on angiotensinogen gene expression. Furthermore, mouse angiotensinogen prompter analysis demonstrated that the angiotensinogen promoter region contains a functional Foxo1-binding site, which is responsible for both Foxo1 stimulation and insulin suppression on the promoter activity. Together, these data demonstrate that Foxo1 regulates hepatic angiotensinogen gene expression and controls plasma angiotensinogen and angiotensin II levels, modulating blood pressure control in mice.


Cervical spine motion during flexible bronchoscopy compared with the Lo-Pro GlideScope.
The most appropriate device for tracheal intubation in patients with potential cervical spine injury remains controversial. We hypothesized that the Lo-Pro GlideScope (LP-G) videolaryngoscope would not cause significantly greater cervical spine movement than fibreoptic bronchoscopy even in the non-immobilized spine. Twenty-eight healthy adults requiring intubation for radiographic procedures were randomized to either the LP-G or the flexible bronchoscope (FB) devices. Continuous fluoroscopy was used to assess cervical spine movement during tracheal intubation. The point of maximum movement was compared with baseline for change in angulation between Occiput (Occ)-C1, Occ-C2, Occ-C4, Occ-C5, C1-2, C2-4, and C4-5. Measurements were made by two independent observers. The change in angulation was also measured for tongue pull and jaw thrust, manoeuvres for enlarging the pharyngeal space, before FB intubation. LP-G resulted in greater cervical extension compared with FB for every angle calculated, statistically significant between Occ-C1 (P<0.05), Occ-C2 (P<0.05), and Occ-C4 (P<0.01). Tongue pull resulted in significantly less cervical spine motion than FB intubation at Occ-C1, Occ-C2, Occ-C4, and Occ-C5 (P<0.05). When jaw thrust was added to tongue pull, there was a tendency for greater movement than FB intubation at Occ-C1, Occ-C2, and Occ-C3. This was statistically significant at Occ-C1 and Occ-C3 (P<0.05) for one of the two observers. During intubation under general anaesthesia, LP-G resulted in greater cervical movement than FB when no cervical immobilization was used in adults without cervical disease. Airway manoeuvres performed before FB, especially jaw thrust, also resulted in cervical spine movement.


Ion mobility spectrometry combined with multivariate statistical analysis: revealing the effects of a drug candidate for Alzheimer's disease on Aβ1-40 peptide early assembly.
Inhibition of the initial stages of amyloid-β peptide self-assembly is a key approach in drug development for Alzheimer's disease, in which soluble and highly neurotoxic low molecular weight oligomers are produced and aggregate in the brain over time. Here we report a high-throughput method based on ion mobility mass spectrometry and multivariate statistical analysis to rapidly select statistically significant early-stage species of amyloid-β1-40 whose formation is inhibited by a candidate theranostic agent. Using this method, we have confirmed the inhibition of a Zn-porphyrin-peptide conjugate in the early self-assembly of Aβ40 peptide. The MS/MS fragmentation patterns of the species detected in the samples containing the Zn-porphyrin-peptide conjugate suggested a porphyrin-catalyzed oxidation at Met-35(O) of Aβ40. We introduce ion mobility MS combined with multivariate statistics as a systematic approach to perform data analytics in drug discovery/amyloid research that aims at the evaluation of the inhibitory effect on the Aβ early assembly in vitro models at very low concentration levels of Aβ peptides.


Large inversion in Escherichia coli K-12 1485IN between inversely oriented IS3 elements near lac and cdd.
A companion study has shown that the inversion carried by strain 1485IN has one terminus between lac and proC and the other between his and cdd of the normal strain. Starting with this mapping data, we have done molecular work demonstrating that the inversion occurred by recombination between inversely oriented two IS3 elements, one present near lac and the other near the cdd locus; i.e., the inversion is IN(is3B-is3E). Evidence supporting this conclusion includes: (i) Normal and inversion strains share two short regions with identical restriction maps. One of these regions is near lac and the other near cdd. (ii) IS3 homology was detected in each of the terminus regions of both the normal and inversion strains. (iii) The sequence on one side of the original IS3 element near lac has been exchanged with the sequence on one side of the IS3 near cdd. Whether the inversion has occurred by one event of homologous recombination between the two IS3 elements or has been caused by involvement of IS3 elements on an F factor is discussed. Another rearrangement, probably related to inversion and deletion, was detected between the IS3 and cdd of the inversion strain.


Efficacy of prophylactic negative pressure wound therapy after open ventral hernia repair: a systematic review meta-analysis.
The susceptibility to surgical site occurrence (SSO) is high following ventral hernia repair (VHR) surgery. SSO severely increases the physical and mental burden on patients. The main purpose of this review was to analyze the efficacy of negative pressure wound therapy (NPWT) after open VHR(OVHR) and explore benefits to patients. The Cochrane Library, PubMed, and Embase databases were searched from the date of establishment to 15 October 2022. All randomized controlled trials and retrospective cohort studies comparing NPWT with standard dressings after OVHR were included. The Revman 5.4 software recommended by Cochrane and the STATA16 software were used in this meta-analysis. Fifteen studies (involving 1666 patients) were identified and included in the meta-analysis, with 821 patients receiving NPWT. Overall, the incidence rate of SSO in the NPWT group was lower compared to the control group (odds ratio [OR] = 0.44; 95% confidence interval [CI] = 0.21-0.93; I2 = 86%; P = 0.03). The occurrence rate of surgical site infection (SSI; OR = 0.51; 95% CI = 0.38-0.68, P < 0.001), wound dehiscence (OR = 0.64; 95% CI = 0. 43-0.96; P = 0.03), and hernia recurrence (OR = 0.51; 95% CI = 0.28-0.91, P = 0.02) was also lowered. There was no significant difference in seroma (OR = 0.76; 95% CI = 0.54-1.06; P = 0.11), hematoma (OR = 0.53; 95% CI = 0.25-1.11; P = 0.09), or skin necrosis (OR = 0.83; 95% CI = 0.47-1.46; P = 0.52). NPWT can effectively decrease the occurrence of SSO, SSI wound dehiscence and hernia recurrence and should be considered following OVHR.


Congenital malformations among children of women working with video display terminals.
In a case-base study among 214,108 commercial and clerical employees in Denmark the potential effect of the use of video display terminals on the risk of congenital malformations in pregnancy was investigated. The study base was identified by means of register linkage of the Medical Birth Register and the National Register of In-Patients. In the source population 24,352 pregnancy outcomes were registered, 661 of which with congenital malformations entered the case group, and a base sample of 2252 pregnancies was drawn. Data concerning the use of video display terminals, job stress, ergonomic factors, exposure to organic solvents, and life-style factors were obtained from postal questionnaires. The results of this study did not support the hypothesis that the use of video display terminals during pregnancy is associated with an increased risk of congenital malformations.


[Structural organization and mechanisms of mobility of the gene cassette coding for resistance to antibiotics and bacterial virulence factors].
The review is focussed on two types of gene cassettes which are significant in bacterial variability. The first type are cassettes with antibiotic resistance genes; these are the smallest mobile genetic elements including a gene (most commonly an antibiotic resistance gene) and a short sequence acting as a recombination site. Sometimes these cassettes contain genes not responsible for antibiotic resistance but their functions are not yet known. The second type contains large clusters of genes coding for bacterial virulence factors. They were termed "pathogenicity islands" due to their difference in the percentage of G-C pairs in comparison with bacterial chromosomes, in which they are contained. The structural organization and mechanisms of mobility of various types of gene cassettes are discussed.


[Secular trends of caries prevalence among 6 and 12 year-old youths in the Netherlands].
In order to gain insight into the development of caries prevalence and caries experience among Dutch youth, a meta-analysis was carried out on epidemiological caries data collected in 5 and 6 and 11 and 12 year-olds between 1980 and 2009. From the present analysis it appears that after the mid-1980's a halt occurred in the decline of caries experience in the primary dentition among 5 and 6 year-olds. At the same time, the percentage of children with a caries-free primary dentition who were covered by public health insurance or participated in institutions for youth dental care decreased. Among 11 to 12 year-olds there is no indication that the prevalence of caries in the permanent dentition has changed. Considering the high percentage of 12 year-olds with a caries-free permanent dentition, an additional improvement in oral health for this age-group will be difficult to achieve. The average restorative index of the primary dentition in 5-6 year-old children covered by public health insurance and children in The Hague appears not to have changed dramatically in the last 15 years.


Stereoscopic visualization and haptic technology used to create a virtual environment for remote surgery - biomed 2011.
The objective of this research is to study the effectiveness of using a stereoscopic visualization system for performing remote surgery. The use of stereoscopic vision has become common with the advent of the da Vinci® system (Intuitive, Sunnyvale CA). This system creates a virtual environment that consists of a 3-D display for visual feedback and haptic tactile feedback, together providing an intuitive environment for remote surgical applications. This study will use simple in vivo robotic surgical devices and compare the performance of surgeons using the stereoscopic interfacing system to the performance of surgeons using one dimensional monitors. The stereoscopic viewing system consists of two cameras, two monitors, and four mirrors. The cameras are mounted to a multi-functional miniature in vivo robot; and mimic the depth perception of the actual human eyes. This is done by placing the cameras at a calculated angle and distance apart. Live video streams from the left and right cameras are displayed on the left and right monitors, respectively. A system of angled mirrors allows the left and right eyes to see the video stream from the left and right monitor, respectively, creating the illusion of depth. The haptic interface consists of two PHANTOM Omni® (SensAble, Woburn Ma) controllers. These controllers measure the position and orientation of a pen-like end effector with three degrees of freedom. As the surgeon uses this interface, they see a 3-D image and feel force feedback for collision and workspace limits. The stereoscopic viewing system has been used in several surgical training tests and shows a potential improvement in depth perception and 3-D vision. The haptic system accurately gives force feedback that aids in surgery. Both have been used in non-survival animal surgeries, and have successfully been used in suturing and gallbladder removal. Bench top experiments using the interfacing system have also been conducted. A group of participants completed two different surgical training tasks using both a two dimensional visual system and the stereoscopic visual system. Results suggest that the stereoscopic visual system decreased the amount of time taken to complete the tasks. All participants also reported that the stereoscopic system was easier to utilize than the two dimensional system. Haptic controllers combined with stereoscopic vision provides for a more intuitive virtual environment. This system provides the surgeon with 3-D vision, depth perception, and the ability to receive feedback through forces applied in the haptic controller while performing surgery. These capabilities potentially enable the performance of more complex surgeries with a higher level of precision.


Deposition and depletion of five anticoccidials in eggs.
Anticoccidials are compounds that are widely used as feed additives to prevent and treat coccidiosis. They are licensed for use in a prescribed concentration and during a certain time interval for broilers and pullets but not for laying hens. It was shown in the past that carry-over at the feeding mill is found to be the main reason for the presence of residues in eggs. An animal experiment was set up to investigate the effect of carry-over at the feeding mill on the presence of residues of anticoccidials in eggs. For the compounds diclazuril, robenidine, halofuginone and nicarbazin in combination with narasin, two concentration levels were tested: the maximum allowed concentration for broilers (100%) and a concentration corresponding to 5% carry-over during feed preparation. Also dimetridazole was included in the experiment but only at one concentration level. Eggs were sampled during treatment (14 days) and for a period of 30 days after withdrawal of the anticoccidial-containing feed. Residues were determined, and deposition and depletion curves were generated. Analyses were performed by ELISA and LC-MS/MS. For all compounds, substantial residues could be found in the 5% groups, which points out the risk of carry-over at the feeding mill. The distribution of the residues between egg yolk and white was determined by analyzing both fractions.


New Australovenator hind limb elements pertaining to the holotype reveal the most complete Neovenatorid leg.
We report new skeletal elements pertaining to the same individual which represents the holotype of Australovenator wintonensis, from the 'Matilda Site' in the Winton Formation (Upper Cretaceous) of western Queensland. The discovery of these new elements means that the hind limb of Australovenator is now the most completely understood hind limb among Neovenatoridae. The new hind limb elements include: the left fibula; left metatarsal IV; left pedal phalanges I-2, II-1, III-4, IV-2, IV-3; and right pedal phalanges, II-2 and III-1. The detailed descriptions are supported with three dimensional figures. These coupled with the completeness of the hind limb will increase the utility of Australovenator in comparisons with less complete neovenatorid genera. These specimens and the previously described hind limb elements of Australovenator are compared with other theropods classified as neovenatorids (including Neovenator, Chilantaisaurus, Fukuiraptor, Orkoraptor and Megaraptor). Hind limb length proportion comparisons indicate that the smaller neovenatorids Australovenator and Fukuiraptor possess more elongate and gracile hind limb elements than the larger Neovenator and Chilantaisaurus. Greater stride lengths to body size exist in both Fukuiraptor and Australovenator with the femur discovered to be proportionally shorter the rest of the hind limb length. Additionally Australovenator is identified as possessing the most elongate metatarsus. The metatarsus morphology varies with body size. The larger neoventorids possess a metatarsus with greater width but shorter length compared to smaller forms.


Ultrasound-guided 'two-in-one' femoral and obturator nerve block in the dog: an anatomical study.
To evaluate the dye extent and distribution at the lumbar plexus (LP) of three volumes of local anaesthetic-methylene-blue solution administered close to the femoral nerve (FN) by the use of a ventral ultrasound (US)-guided suprainguinal approach (SIA). Prospective experimental trial. Twenty mongrel canine cadavers weighing 17.7 ± 3.8 kg (mean ± SD). The left and right LP of two cadavers were dissected to identify the FN, obturator nerve (ON) and lateral femoral cutaneous nerve (LFCN). The extent and distribution of dye at the LP of each of three volumes of injectate of 0.2, 0.4 and 0.6 mL kg(-1) administered close to the FN by a ventral US-guided SIA then were studied in a further 18 dog cadavers (n = 6 per group). Staining of ≥2 cm along the target nerves was indicative of sufficient spread to produce a nerve block. The ventral US-guided SIA allowed the observation of the FN within the iliopsoas muscle (IPM) in a total of 17 cadavers. The assessment of the dye extent and distribution revealed a similar pattern regardless of the injected volume. From the injection site, the spreading of injectate occurred in cranial, lateral and caudal directions. The FN and ON were effectively stained in all the cases. The LFCN was not effectively stained in any case. A volume of 0.2 mL kg(-1) administered close to the FN by a ventral US-guided SIA produced a sufficient distribution of the injectate within the IPM to produce effective staining of the FN and ON. This US-guided technique may be an appropriate alternative to previously reported techniques based on electrolocation to block the FN and ON in the dog.


Exploring and rationalising effective n-doping of large area CVD-graphene by NH3.
Despite the large number of papers on the NH3 doping of graphene, the achievement of stable n-doped large area CVD (chemical vapor deposition) graphene, which is intrinsically p-doped, is still challenging. A control of the NH3 chemisorption and of the N-bond configuration is still needed. The feasibility of a room temperature high pressure NH3 treatment of CVD graphene to achieve n-type doping is shown here. We use and correlate data for (a) sheet resistance, R(sh), and the Hall coefficient, R(H), in van der Pauw configuration, acquired in real time during the NH3 doping of CVD-graphene on a glass substrate, (b) optical measurements of the effect of doping on the graphene Van Hove singularity point at 4.6 eV in the dielectric function spectra by spectroscopic ellipsometry, and of (c) N-bond configuration by XPS to better understand and, finally, control the NH3 doping of graphene. The discussion is focused on the thermal and time stability of the n-doping after air exposure. A chemical rationale is provided for the NH3 n-doping based on the interaction of (i) NH3 with intrinsic oxygen functionalities and defects of CVD graphene and of (ii) C-NH2 doping centers with acceptor species present in the air.


Diabetes home monitoring by telephone data entry.
The use of microcomputers to help physicians manage diabetic patients who perform home glucose monitoring is presented. Patients enter blood glucose information directly into an office database from their homes, using the push-button telephone with voice synthesizer prompts. The computer-enhanced organization of this information as well as future possibilities is discussed.


Support ellagic acid therapy in patients with hormone refractory prostate cancer (HRPC) on standard chemotherapy using vinorelbine and estramustine phosphate.
Recent phase III studies in hormone refractory prostate cancer (HRPC) showed an improvement in terms of overall survival (OS), objective response (OR) and biochemical response (BR); however, chemotherapy is usually accompanied by negative side effects that determines poor quality of life (QoL) and only marginally improves individual clinical response (ICR) in terms of pain relief and performance status. Ellagic acid is a polyphenol that is found in many species of flowering plants. It is an antioxidant that determines apoptosis, down regulation of IGF-II, activates p21 (waf1/Cip1), mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells. The aim of this study was to assess the effects of ellagic acid support therapy on toxicity, OR, ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine. Patients with HRPC were randomly distributed in two study groups: a control group (group A) who underwent chemotherapy with vinorelbine and estramustine phosphate, and an experimental group (group B) where chemotherapy regimen was associated with ellagic acid. The mean number of chemotherapy cycles/patient was 4 (range 3-8 cycles) and 6.5 (range 5-11) in group A and B patients, respectively. A reduction in systemic toxicity, statistically significant for neutropenia, associated with better results in term of OR rate, ICR, and BR were observed in group B compared with group A. On the contrary no significant difference in OS and PFS was detected between groups. our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity, in particular neutropenia, in HRCP patients; however, further studies are required to confirm our results.


Lymphocytic thrombophilic arteritis: a newly described medium-sized vessel arteritis of the skin.
We encountered a distinct arteriolar histopathologic finding of lymphocytic vasculitis associated with a hyalinized fibrin ring in vessel lumina. Identical histologic findings have previously been described as macular arteritis. We describe 5 women (mean age, 25 years; age range, 20-34 years) with persistent, slowly progressive, patchy and reticular hyperpigmentation associated with livedo racemosa affecting predominantly the lower limbs. In the biopsy samples, infiltration of muscular vessel wall by inflammatory cells, affecting small arteries of the dermosubcutaneous junction or superficial subcutis, was present. Of the infiltrate, 90% or more consisted of mononuclear cells, mainly lymphocytes with an admixture of histiocytes. Neutrophils and eosinophils were absent or scant. Inflammation was confined to the vicinity of the vessel and the immediate surrounding panniculus. A concentric fibrin ring involving the entire periphery of the lumina of affected vessels was present in all the patients. Laboratory investigation results revealed that 4 patients had antiphospholipid antibodies in their serum. One of these patients had a heterozygous mutation of the factor V Leiden gene. Conclusion We term this arteritis lymphocytic thrombophilic arteritis to reflect the histologic features that combine lymphocytic vascular inflammation with changes representing a thrombophilic endovasculitis.


Cryptochrome-dependent magnetic field effect on seizure response in Drosophila larvae.
The mechanisms that facilitate animal magnetoreception have both fascinated and confounded scientists for decades, and its precise biophysical origin remains unclear. Among the proposed primary magnetic sensors is the flavoprotein, cryptochrome, which is thought to provide geomagnetic information via a quantum effect in a light-initiated radical pair reaction. Despite recent advances in the radical pair model of magnetoreception from theoretical, molecular and animal behaviour studies, very little is known of a possible signal transduction mechanism. We report a substantial effect of magnetic field exposure on seizure response in Drosophila larvae. The effect is dependent on cryptochrome, the presence and wavelength of light and is blocked by prior ingestion of typical antiepileptic drugs. These data are consistent with a magnetically-sensitive, photochemical radical pair reaction in cryptochrome that alters levels of neuronal excitation, and represent a vital step forward in our understanding of the signal transduction mechanism involved in animal magnetoreception.


Aligned 1-D nanorods of a π-gelator exhibit molecular orientation and excitation energy transport different from entangled fiber networks.
Linear π-gelators self-assemble into entangled fibers in which the molecules are arranged perpendicular to the fiber long axis. However, orientation of gelator molecules in a direction parallel to the long axes of the one-dimensional (1-D) structures remains challenging. Herein we demonstrate that, at the air-water interface, an oligo(p-phenylenevinylene)-derived π-gelator forms aligned nanorods of 340 ± 120 nm length and 34 ± 5 nm width, in which the gelator molecules are reoriented parallel to the long axis of the rods. The orientation change of the molecules results in distinct excited-state properties upon local photoexcitation, as evidenced by near-field scanning optical microscopy. A detailed understanding of the mechanism by which excitation energy migrates through these 1-D molecular assemblies might help in the design of supramolecular structures with improved charge-transport properties.


Structural Connectomes of COVID-Survivors Show Disruption in Global Integration and Small-Worldness.
Even after recovery from the COVID-19 infection, there have been a multitude of cases reporting post-COVID neurological symptoms including memory loss, brain fog, and attention deficit. Many studies have observed localized microstructural damages in the white matter regions of COVID survivors, indicating potential damage to the axonal pathways in the brain. Therefore, in this study, we have investigated the global impact of localized damage to white matter tracts using graph theoretical analysis of the structural connectome of 45 COVID-recovered subjects and 30 Healthy Controls (HCs). We have implemented Diffusion Tensor Imaging based reconstruction followed by deterministic tractography to extract structural connections among different regions of the brain. Interpreting this structural connectivity as weighted undirected graphs, we have used graph theoretical measures like global efficiency, characteristic path length (CPL), clustering coefficient (CC), modularity, Fiedler value, and assortativity coefficient to quantify the global integration, segregation, and robustness of the brain networks. We statistically compare the cohorts based on these graph measures by employing permutation testing for 100,000 permutations. Post multiple comparisons error correction, we find that the COVID-recovered cohort shows a reduction in global efficiency and CC while they exhibit higher modularity and CPL. This disruption of the balance between global integration and segregation indicates the loss of small-world property in COVID survivors' connectomes which has been linked with other disorders such as cognitive impairment and Alzheimer's. Overall, our study sheds light on the alterations in structural connectivity and its role in post-COVID symptoms.


A comparison of sex offenders against female and male minors.
Male sex offenders against minors were grouped according to age and sex of victims, and according to whether they had offended against one or more than one minor. Cases of incest or courtship disorder were not included in the study. Among offenders against female children, the number of one-case offenders was substantially larger than that of multicase offenders. The opposite was true of offenders against male children, and there was no significant difference between one-case and multicase offenders against female or male early adolescents. If these counts reflect corresponding prevalences within sex offenders against minors in a Western cultural setting, some inferences can be made from these comparisons.


Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database.
Subjects with autosomal dominant polycystic kidney disease (ADPKD) who were taking tolvaptan experienced aminotransferase elevations more frequently than those on placebo in the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) clinical trial. An independent, blinded, expert Hepatic Adjudication Committee re-examined data from TEMPO 3:4 and its open-label extension TEMPO 4:4, as well as from long-term (>14 months) non-ADPKD tolvaptan trials, using the 5-point Drug-Induced Liver Injury Network classification. In TEMPO 3:4, 1445 subjects were randomized 2:1 (tolvaptan vs. placebo) and 1441 had post-baseline assessments of hepatic injury. Sixteen patients on tolvaptan and one on placebo had significant aminotransferase elevations judged to be at least probably related to study drug. No association with dose or systemic exposure was found. Two of 957 subjects taking tolvaptan (0.2 %) and zero of 484 taking placebo met the definition of a Hy's Law case. One additional Hy's Law case was identified in a TEMPO 4:4 subject who had received placebo in the lead study. The onset of a hepatocellular injury occurred between 3 and 18 months after starting tolvaptan, with gradual resolution over the subsequent 1-4 months. None of the events were associated with liver failure or chronic liver injury/dysfunction. No imbalance in hepatic events was observed between tolvaptan and placebo in lower-dose clinical trials of patients with hyponatremia, heart failure, or cirrhosis. Although hepatocellular injury following long-term tolvaptan treatment in ADPKD subjects was infrequent and reversible, the potential for serious irreversible injury exists. Regular monitoring of transaminase levels is warranted in this patient population.


Characteristic patterns of dendritic remodeling in early-stage glaucoma: evidence from genetically identified retinal ganglion cell types.
Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and the second leading cause of blindness worldwide. The type and timing of cellular changes leading to RGC loss in glaucoma remain incompletely understood, including whether specific RGC subtypes are preferentially impacted at early stages of this disease. Here we applied the microbead occlusion model of glaucoma to different transgenic mouse lines, each expressing green fluorescent protein in 1-2 specific RGC subtypes. Targeted filling, reconstruction, and subsequent comparison of the genetically identified RGCs in control and bead-injected eyes revealed that some subtypes undergo significant dendritic rearrangements as early as 7 d following induction of elevated intraocular pressure (IOP). By comparing specific On-type, On-Off-type and Off-type RGCs, we found that RGCs that target the majority of their dendritic arbors to the scleral half or "Off" sublamina of the inner plexiform layer (IPL) undergo the greatest changes, whereas RGCs with the majority of their dendrites in the On sublamina did not alter their structure at this time point. Moreover, M1 intrinsically photosensitive RGCs, which functionally are On RGCs but structurally stratify their dendrites in the Off sublamina of the IPL, also underwent significant changes in dendritic structure 1 week after elevated IOP. Thus, our findings reveal that certain RGC subtypes manifest significant changes in dendritic structure after very brief exposure to elevated IOP. The observation that RGCs stratifying most of their dendrites in the Off sublamina are first to alter their structure may inform the development of new strategies to detect, monitor, and treat glaucoma in humans.


Study of school fatigue on a group of teenagers studying at "dimitrie cantemir" highschool, iaşi.
Purpose. Fatigue is a physiological phenomenon which is permanently present at students because of the scholar demands. Excessive demands can cause pathological fatigue phenomenon, which should be avoided. Subjects and method. The study included a group of 203 students from Dimitrie Cantemir Highschool in Iaşi. The teenagers were questioned about the presence of the fatigue phenomenon. Results. Fatigue is rarely present at 62.6% of the questioned students. During the week, this phenomenon appears especially at the beginning (22.2%) or in the middle of the week (34.5%). In a few cases it appears at the end of the week, as it should. Night sleep is only of 6-7 hours (37.4%) or 7-8 hours (36.9%), which is not enough.The insufficient number of sleeping hours can be paid by day sleep, but most of the responses are "rarely" (50.7%). Active rest is represented by sport or other activities of choice. Sport is the only less attractive option - in most cases children allocate only 15-30 minutes a day for it (33.5%). They stay in front of the TV between 0.5 and 1 hour (42.9%) and of the computer between 2-3 hours (44.3%) daily. Conclusions. Children's daily schedule isn't balanced, so the risk of excessive fatigue really exists.


Sylvatic maintenance of Borrelia burgdorferi (Spirochaetales) in Northern California: untangling the web of transmission.
Lyme borreliosis is associated with several genospecies of Borrelia burgdorferi sensu lato (s.l.) (Spirochaetales), but human disease has been associated only with Borrelia burgdorferi sensu stricto (s.s.) Johnson, Schmid, Hyde, Steigerwalt & Brenner in the western United States. Restriction fragment length polymorphism (RFLP) analysis of rrf-rrl amplicons from 124 tick and mammalian isolates from various habitats yielded 13 RFLP patterns. Of these patterns, six were patterns previously associated either with Borrelia bissettii Postic, Marti Ras, Lane, Hendson & Baranton or Borrelia burgdorferi s.s., and the remaining seven patterns belonged to diverse and previously uncharacterized Borrelia spp. Uncharacterized Borrelia spp. were cultured most frequently from Ixodes spinipalpis Hadwen & Nuttall and California kangaroo rats, Dipodomys californicus Merriam, inhabiting grasslands, and B. bissettii from I. spinipalpis and dusky-footed woodrats, Neotoma fuscipes Baird, associated with oak woodlands or chaparral. B. burgdorferi s.s. typically was isolated from host-seeking Ixodes pacificus Cooley & Kohls collected in dense oak woodlands, woodland-grass, or redwood forests. Although some isolates of B. burgdorferi s.s. were cultured from woodrats, there was no clear association of this human pathogen with any vertebrate host. These findings, along with recent evidence indicating that the western gray squirrel, Sciurus griseus Ord, may be an important reservoir of B. burgdorferi s.s. in Californian oak woodlands, suggest that our earlier hypothesis implicating an enzootic cycle involving woodrats and I. spinipalpis is insufficient to account for observed patterns of infection in nature.


Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.
Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer.


Education and acute coronary syndromes: results from the CARDIO2000 epidemiological study.
As a measure of socioeconomic status, low educational level is positively associated with the risk of developing adverse health events. The aim of this study was to investigate the relationship between the level of education and the risk of developing non- fatal acute coronary syndromes. During 2000 and 2001, 1619 randomly selected subjects from several regions of Greece were entered into a case-control study. Of these, 750 were patients with their first acute coronary heart syndrome event, and 869 were hospitalized controls with no cardiovascular disease in their medical history. Trends in cardiovascular risk factors were then examined across patient and control educational level by years of schooling. In both patients and controls, education status was related to economic and occupation status, smoking habits, physical inactivity, alcohol consumption and non-compliance to treatment. After adjusting for these and other conventional risk factors, as well as for the effects of age and sex, we found that coronary risk increases by 82% (odds ratio (OR) = 1.82, P <0.05) for individuals with a lower level of education, and by 65% (OR = 1.65, P <0.05) for individuals with an average education, compared to those with an academic education. Although the least-educated subjects adopted a more adverse lifestyle than the more-educated subjects, the inverse association between education and coronary risk was independent from such factors. The inverse association may be due to psychosocial differences, and prospective cohort studies are needed to confirm or refute these results.


Reactions towards organizational change: a systematic literature review.
Regardless of the prevalence and value of change initiatives in contemporary organizations, these often face resistance by employees. This resistance is the outcome of change recipients' cognitive and behavioral reactions towards change. To better understand the causes and effects of reactions to change, a holistic view of prior research is needed. Accordingly, we provide a systematic literature review on this topic. We categorize extant research into four major and several subcategories: micro and macro reactions. We analyze the essential characteristics of the emerging field of change reactions along research issues and challenges, benefits of (even negative) reactions, managerial implications, and propose future research opportunities.


[A new site-specific endonuclease from Bacillus species ST5].
A site-specific endonuclease R.BspST5I has been isolated in a functionally pure state from the thermophilic strain of Bacillus species ST5. The enzyme recognizes sequence 5'-GCATC-3' on the DNA and splits it at a distance of five nucleotides from the 3'-end of the recognition site as well as at distances of nine or ten nucleotides at the complementary filament depending on the hydrolyzed sequence of the DNA. The enzyme is a isomer of endonuclease SfaNI from Streptococcus faecalis ND547.


Molecular Imaging: a Novel Tool To Visualize Pathogenesis of Infections In Situ.
Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans. PET enables dynamic assessment of infectious processes within the same subject with high temporal and spatial resolution and obviates the need for invasive tissue sampling, which is difficult in patients and generally limited to a single time point, even in animal models. This review presents current state-of-the-art concepts on the application of molecular imaging for infectious diseases and details how PET imaging can facilitate novel insights into infectious processes, ongoing development of pathogen-specific imaging, and simultaneous in situ measurements of intralesional antimicrobial pharmacokinetics in multiple compartments, including privileged sites. Finally, the potential clinical applications of this promising technology are also discussed.


An open trial of transdermal nicotine replacement therapy for smoking cessation among alcohol- and drug-dependent inpatients.
An open trial of transdermal nicotine replacement for smoking cessation was conducted. Over a 7-month period, all patients admitted to the inpatient alcohol and drug treatment unit of the Seattle Veterans Affairs Medical Center, (n = 207) were offered the opportunity to participate in an open trial of transdermal nicotine replacement for smoking cessation. Forty-nine (23.7%) elected to attempt cessation with transdermal nicotine during their inpatient treatment episodes. These subjects received no psychosocial treatments directed specifically at smoking cessation. They smoked a mean of 28.5 (SD = 16.4) cigarettes per day and obtained a mean score of 8.3 (SD = 1.9) on the Fagerstrom Test for Nicotine Dependence. Subjects remained on transdermal nicotine an average of 18.8 (SD = 8.2) days with desire to resume smoking the major reason for discontinuation. Seven subjects (14.3%) self-reported tobacco abstinence at 21 days, and 5 (10.2%) self-reported abstinence as outpatients at 6 weeks. These results show that a substantial proportion of alcohol- and drug-dependent patients entering inpatient treatment are willing to attempt alcohol and illicit drug cessation and tobacco cessation simultaneously and that transdermal nicotine holds promise as a treatment modality in this population.


A subtraction technique in conventional angiography.
A subtraction technique is described for conventional angiography by which a superimposed vessel can be removed, allowing exact visualization of the area in question. The method is easy, requires only standard subtraction apparatus, and obviates the need for additional contrast material injections.


Clinical implications of prostatic capsular abutment or bulging on multiparametric magnetic resonance imaging.
The presence of capsular abutment or bulging can raise concern when planning surgery. In this study we aimed to test the clinical implications of capsular abutment or bulging on preoperative multiparametric magnetic resonance imaging (mpMRI). We analyzed the data of 291 patients who underwent radical prostatectomy (RP) for a cT1-2N0 prostate cancer in a single surgeon series. All patients underwent preoperative staging with mpMRI. PIRADS v2 was used for characterizing lesions. The role of capsular abutment or bulging was tested in a multivariable logistic regression adjusting for prostate-specific antigen and highest ipsilateral biopsy Gleason grade. The presence of focal versus extensive extracapsular extension (ECE) was investigated. Overall, ECE on final pathology was documented in 35 (12%) cases and ECE was focal in 32 (91%) patients. Overall, mpMRI demonstrated capsule bulging or abutment in 12 (24%) cases. After adjusting for confounders, capsule bulging or abutment on mpMRI emerged as predictor for ECE (OR=6.70; 95% CI: 2.97-15.12, P<0.001). The sensitivity and specificity of capsule abutment or bulging in predicting ECE were 43% and 95%, respectively. Sensitivity and specificity were 36% and 48% respectively to predict focal ECE. The PIRADS v2 scoring system has a grey zone concerning ECE as defined by capsule abutment or bulging. We found an increased risk of ECE and specifically focal ECE when capsule bulging or abutment on mpMRI are documented.


Cystic fibrosis-related diabetes onset can be predicted using biomarkers measured at birth.
Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.


FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis.
The survival of long-lived plasma cells, which produce most serum immunoglobulin, is central to humoral immunity. We found here that the inhibitory Fc receptor FcgammaRIIb was expressed on plasma cells and controlled their persistence in the bone marrow. Crosslinking FcgammaRIIb induced apoptosis of plasma cells, which we propose contributes to the control of their homeostasis and suggests a method for therapeutic deletion. Plasma cells from mice prone to systemic lupus erythematosus did not express FcgammaRIIb and were protected from apoptosis. Human plasmablasts expressed FcgammaRIIb and were killed by crosslinking, as were FcgammaRIIb-expressing myeloma cells. Our results suggest that FcgammaRIIb controls bone marrow plasma cell persistence and that defects in it may contribute to autoantibody production.


Horizon scanning for translational genomic research beyond bench to bedside.
The dizzying pace of genomic discoveries is leading to an increasing number of clinical applications. In this report, we provide a method for horizon scanning and 1 year data on translational research beyond bench to bedside to assess the validity, utility, implementation, and outcomes of such applications. We compiled cross-sectional results of ongoing horizon scanning of translational genomic research, conducted between 16 May 2012 and 15 May 2013, based on a weekly, systematic query of PubMed. A set of 505 beyond bench to bedside articles were collected and classified, including 312 original research articles; 123 systematic and other reviews; 38 clinical guidelines, policies, and recommendations; and 32 articles describing tools, decision support, and educational materials. Most articles (62%) addressed a specific genomic test or other health application; almost half of these (n = 180) were related to cancer. We estimate that these publications account for 0.5% of reported human genomics and genetics research during the same time. These data provide baseline information to track the evolving knowledge base and gaps in genomic medicine. Continuous horizon scanning of the translational genomics literature is crucial for an evidence-based translation of genomics discoveries into improved health care and disease prevention.


Tangeretin, a citrus pentamethoxyflavone, exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinoma.
Breast cancer is the most commonly diagnosed cancer among women worldwide, which is characterized by unregulated cell growth and metastasis. Many bioactive compounds of plant origin such as tangeretin have been shown to possess potent antioxidant and anticancerous properties. In the present study we have investigated the chemotherapeutic effect of tangeretin against 7,12-dimethylbenz(α)anthracene (DMBA)-induced rat mammary carcinogenesis and studied its underlying mechanism of action. Breast cancer was induced by "air pouch technique" with a single dose of 25mg/kg of DMBA. Tangeretin (50 mg/kg) was administered orally for four weeks. Remarkably, tangeretin treatment controlled the growth of cancer cells which was clearly evidenced by morphological and histological analysis. Also, serum levels of estradiol, progesterone and prolactin; lipid bound sialic acid and total sialic acid and the tissue levels of nitric oxide and protein carbonyls of cancer induced animals were decreased upon tangeretin treatment. Staining of breast tissues for nucleolar organizer regions, mast cells, glycoproteins, lipids and collagen showed that tangeretin treatment to breast cancer induced rats significantly reduced tumorigenesis. Oral tangeretin treatment also effectively reduced the tumor cell proliferation markers such as PCNA, COX-2 and Ki-67. Further, tangeretin treatment arrested the cancer cell division at the G1/S phase via p53/p21 up-regulation and inhibited metastasis by suppressing matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor. Taken together, the data provides new evidence on the mechanism of action of tangeretin in breast cancer and hence extends the hypothesis supporting its potential use in chemotherapy.


Role of cytotoxic T lymphocytes in murine cytomegalovirus infection.
Cell-mediated immunity is important in host control of CMV infection. A chromium release microcytoxicity assay was used to evaluate the role of cytotoxic T lymphocytes (CTL) in murine CMV infection. Within a few days after intranasal inoculation virus was detected in cultures of buffy-coat, spleens, anterior cervical lymph nodes and salivary glands. CTL were first detected on day 5 post-infection in spleen and peripheral blood, and on day 6 in anterior cervical nodes. The course of the CTL response approximated to that of virus titres during the acute phase of infection in the spleen and blood. The findings indicate that CTL are distributed to infected tissues and appear to be important during the acute, viraemic phase of infection.


Acute aortic stenosis in the conscious dog: effects of inotropic state on heart rate.
Effects of acute distension of the left ventricle on heart rate were studied in conscious, instrumented dogs. In intact dogs, increasing left ventricular (LV) systolic pressure by a maximum of 77.6 +/- 3.6 mmHg from a control of 123.1 +/- 3.6 and LV end-diastolic pressure by a maximum of 24.1 +/- 2.0 mmHg from a control of 8.5 +/- 1.3 did not result in any consistent change in heart rate. Reduction of arterial pressure with sodium nitroprusside caused an increase in heart rate to 143.9 +/- 13.8 beats/min. With baroreceptors unloaded, increasing LV pressure by a similar degree as in the control group now resulted in consistent and significant bradycardia. Removal of arterial baroreceptors in a final group of dogs abolished the baroreflex. Increasing LV pressure by aortic stenosis now resulted in a stimulus-dependent decrease in heart rate that was significantly greater than that in the nitroprusside group. Both administration of atropine and bilateral cervical vagotomy abolished bradycardia. The second part of this study was concerned with effects of increases in LV inotropic state on heart rate change evoked by aortic stenosis. Each group was infused with intracoronary epinephrine. Infusion of epinephrine (12.5-50.0 ng . kg-1 . min-1) significantly increased LV dP/dt without any significant change in heart rate or mean arterial blood pressure. Aortic stenosis during epinephrine infusion did not result in any significant difference in heart rate responses in any group studied. It is concluded that LV distension can cause a reduction in heart rate that is opposed by the presence of arterial baroreceptors and that increases in LV myocardial contractility do not have any effect on the magnitude of this response.


Fundamental sensitivity limit imposed by dark 1/f noise in the low optical signal detection regime.
The impact of dark 1/f noise on fundamental signal sensitivity in direct low optical signal detection is an understudied issue. In this theoretical manuscript, we study the limitations of an idealized detector with a combination of white noise and 1/f noise, operating in detector dark noise limited mode. In contrast to white noise limited detection schemes, for which there is no fundamental minimum signal sensitivity limit, we find that the 1/f noise characteristics, including the noise exponent factor and the relative amplitudes of white and 1/f noise, set a fundamental limit on the minimum signal that such a detector can detect.


Effect of imipramine and prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on activity of proline-specific peptidases in the brain of rats with experimental anxious-depressive syndrome.
Activities of prolyl endopeptidase and dipeptidyl peptidase IV in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus were measured in rats with the experimental anxious-depressive syndrome induced by treatment with a dipeptidyl peptidase IV inhibitor during the early postnatal period (days 5-18). Prolyl endopeptidase activity was elevated in the frontal cortex, hypothalamus, and nucleus accumbens. Increased activity of dipeptidyl peptidase IV was observed in the hypothalamus and striatum. Norepinephrine/serotonin reuptake inhibitor, imipramine, and noncompetitive prolyl endopeptidase inhibitor, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, were shown to abolish depression-like behavior of animals in the forced swimming test. These compounds had a normalizing effect on activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats.


Clinically meaningful responses to sequential gemcitabine-based chemotherapy regimens in a patient with metastatic pancreatic cancer.
Pancreatic cancer exhibits profound chemoresistance resulting either from pre-existing (intrinsic) mechanisms, or from anticancer drug treatment itself (acquired chemoresistance). We present the case of a patient with pancreatic adenocarcinoma metastatic to the liver who experienced clinical, radiographic and tumor marker response to three lines of gemcitabine-based chemotherapy. The regimens included: 8 cycles of gemcitabine and oxaliplatin (GEMOX), 8 cycles of gemcitabine, docetaxel and capecitabine (GTX) and more than 3 cycles of gemcitabine and nab-paclitaxel, with an exceptional response 2 years from the initiation of chemotherapy for metastatic pancreatic cancer.


Fetal echocardiography: the prenatal diagnosis of a ventricular septal defect in a 14-week fetus with pulmonary artery hypoplasia.
As the result of auscultation of fetal bradycardia in a class C diabetic, real-time and M-mode echocardiography were performed at 14 weeks of gestation. M-mode evaluation revealed fetal bradycardia (70 beats per minute) with atrial and ventricular systole occurring simultaneously, suggesting a nodal rhythm. Real-time examination demonstrated a ventricular septal defect, pericardial effusion, ventricular wall hypertrophy, and a dilated aortic root. Also present were fetal ascites and situs inversus of the stomach. A repeat ultrasound examination revealed fetal death at 16 weeks of gestation. Autopsy confirmed the above structural abnormalities, and also demonstrated bilobed lungs, pulmonary artery and valve hypoplasia, midline small intestine, and asplenia.


Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity.
Mixtures of different Cannabis sativa phytocannabinoids are more active biologically than single phytocannabinoids. However, cannabis terpenoids as potential instigators of phytocannabinoid activity have not yet been explored in detail. Terpenoid groups were statistically co-related to certain cannabis strains rich in Δ9-tetrahydrocannabinolic acid (THCA) or cannabidiolic acid (CBDA), and their ability to enhance the activity of decarboxylase phytocannabinoids (i.e., THC or CBD) was determined. Analytical HPLC and GC/MS were used to identify and quantify the secondary metabolites in 17 strains of C. sativa, and correlations between cannabinoids and terpenoids in each strain were determined. Column separation was used to separate and collect the compounds, and cell viability assay was used to assess biological activity. We found that in "high THC" or "high CBD" strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence. The correlation in a particular strain between THCA or CBDA and a certain set of terpenoids, and the partial specificity in interaction may have influenced the cultivation of cannabis and may have implications for therapeutic treatments.


Understanding the role of nurse practitioners in Canada.
The practice of medicine and nursing continues to evolve as a result of changes in knowledge, technology and health care needs. New areas of specialization have developed and, in particular, the roles and duties of registered nurses have been expanded. This expansion has enabled nurses with advanced education and skills to function as independent and interdependent clinicians who practise in partnership with physicians and other health care professionals.


Revisiting the fetal loss rate after second-trimester genetic amniocentesis: a single center's 16-year experience.
To estimate an institution's specific fetal loss rate after a second-trimester genetic amniocentesis. This is a retrospective cohort study using our prenatal diagnosis database for all pregnant women presenting for care between 1990 and 2006. We compared the fetal loss rate in women who underwent amniocentesis between 15 and 22 weeks of gestation with those women who did not have any invasive procedure and had a live fetus documented on ultrasound examination between 15 and 22 weeks. Only singleton gestations were included. Logistic regression analysis was used to adjust for potential confounders between the groups. Among 58,436 women meeting the inclusion criteria, complete outcome data were available for 51,557 (88%), 11,746 (91%) in the amniocentesis group and 39,811 (87%) in the group that did not have amniocentesis. The fetal loss (miscarriages and intrauterine fetal death) rate in the amniocentesis group was 0.4% compared with 0.26% in those without amniocentesis (relative risk 1.6, 95% confidence interval [CI] 1.1-2.2). Fetal loss less than 24 weeks (including induction for ruptured membranes and oligohydramnios) occurred in 0.97% of the amniocentesis group and 0.84% of the group with no procedure (P=.33). The fetal loss rate less than 24 weeks attributable to amniocentesis was 0.13% (95% CI -0.07 to 0.20%) or 1 in 769. The only subgroup that had a significantly higher amniocentesis attributable fetal loss rate was women with a normal serum screen (0.17%, P=.03). The institutional fetal loss rate attributable to amniocentesis is 0.13%, or 1 in 769 at Washington University School of Medicine. The total fetal loss rate was not significantly different from that observed in patients who had no procedure.