The sentinel behaviour of Arabian babbler floaters.
The sentinel behaviour of 38 Arabian babbler adult floaters, who lived alone within a territory belonging to a foreign group, was studied and compared with their own sentinel behaviour in the past, when they were group members. All floaters acted as sentinels and uttered 'alarm calls'. This suggests that sentinel activity is due at least, in part, to selfish motives. Floaters sentinelled less than they did as group members, with the decrease in sentinel activity sharper for ex-dominants than for ex-subordinates. One possible explanation for these differences is that sentinel activity is aimed not only at detecting predators, but also at detecting foreign conspecifics. Within a group, the latter incentive is stronger for breeding dominants than for subordinates, whereas all floaters alike may be trying to detect the owners of the territory in which they were roaming but also to avoid being detected by them. Other possible explanations are that floaters have less time and energy for sentinel activity because they are weaker or because foraging is more difficult in a foreign territory. This may be especially so for dominants who used to enjoy privileged access to food in their group. No significant difference was found in the rate of sentinels' 'alarm calls' between floaters and group members, suggesting that their main purpose is predator-prey communication, of which warning groupmates may be a side benefit.


Photochemotherapy for psoriasis with orally administered methoxsalen.
Photochemotherapy denotes a therapeutic approach that is based on the interaction of light and a photoactive drug. This study describes the efficacy of photochemotherapy, using orally administered methoxsalen and long-wave ultraviolet light in 91 patients with severe, generalized psoriasis. Oral administration of methoxsalen was followed by exposure to a high-intensity long-wave ultraviolet light source, emitting a continuous spectrum between 320 and 390 nm (peak, 365 nm) and an energy of 5.6 to 7.5 mw/sq cm at 15 cm. There was complete clearing of 82 patients (90%), a 90% to 100% clearing in seven (8%), and a satisfactory improvement in two (2%). A paired comparison study in 54 patients showed photochemotherapy to be far more effective than ultraviolet light emitted by fluorescent bulbs or a xenon source. Eighty-five percent of the patients receiving outpatient maintenance treatment have remained in remission for periods up to 400 days.


Reducing the harms caused by cannabis use: the policy debate in Australia.
The debate about cannabis policy in Australia has revolved around the harms that cannabis causes to users and the community, on the one hand, and the harms that are caused by the prohibition of its use, on the other. This paper assesses evidence on: (1) the harms caused to users and the community by cannabis use (derived from the international scientific literature) and (2) the harms that arise from prohibition (as reflected in Australian research). The most probable harms caused by cannabis use include: an increased risk of motor vehicle accidents; respiratory disease; dependence; adverse effects on adolescent development; and the exacerbation of psychosis. The harms of the current prohibition on cannabis use policy are less tangible but probably include: the creation of a large blackmarket; disrespect for a widely broken law; harms to the reputation of the unlucky few cannabis users who are caught and prosecuted; lack of access to cannabis for medical uses; and an inefficient use of law enforcement resources. Cannabis policy unavoidably involves trade offs between competing values that should be made by the political process. Australian cannabis policy has converged on a solution which continues to prohibit cannabis but reduces the severity of penalties for cannabis use by either removing criminal penalties or diverting first time cannabis offenders into treatment and education.


Histochemical study of the activity of acid and alkaline phosphatases and lipase in the gastro-intestinal tract of Cirrhinus mrigala.
The sites of the activity of acid and alkaline phosphatases and lipase have been localized in the gastro-intestinal tract of the fresh water fish, Cirrhinus mrigala. All the three enzymes experimented have been recorded to be active in the mucosal epithelium of all the portions of the alimentary canal. Muscularis and serosa of all the parts of alimentary canal show negative sign for the presence of these enzymes. In the pancreas, both intra-hepatic and extrahepatic, strong activity of these enzymes is dicernible in the acinar cells. Hepatic cells also show intense reaction for these enzymes. In comparison to acid phosphatase, the activity of alkaline phosphatase is more pronounced in all the portions of the alimentary tract. The positive reaction for lipase in the blood and lymph vessels present in the tissues of the alimentary canal signifies the hydrolysis of fats during their transportation.


Biocompatible electric current attenuates HIV infectivity.
The number of individuals infected by the human immunodeficiency virus type-l (HIV) continues to increase on a worldwide basis.' A significant percentage, ifnot all, of these individuals will eventually develop the acquired immunodeficiency syndrome (AIDS).2 While horizontal transmission in the homosexual population may be contained or decreasing,' heterosexual transmission and infection through contaminated blood supplies continues to increase: Additionally, vertical transmission from infected females to their fetuses is also on the rise with a resultant increase in the number of children with AIDS.S New strategies, therefore, must be devised in order to limit more effectively the spread of this virus.


Iloprost, Prostaglandin E1, and Papaverine Relax Human Mesenteric Arteries With Similar Potency.
Nonocclusive mesenteric ischemia (NOMI) is accompanied by mesenteric artery spasms that are at least in part due to endothelin system activation. Acute treatment includes intra-arterial infusion of vasodilators such as iloprost, prostaglandin E1 (PGE1), and papaverine. Their effectiveness is not well characterized in human mesenteric arteries. We directly compared their potency to relax isolated human mesenteric arteries. To explore the potential of Rock inhibition to treat mesenteric artery spasms, we tested if endothelin-1 (ET-1)-induced mesenteric artery constrictions depend on rho kinase (Rock). Mesenteric artery segments were obtained from patients who underwent elective abdominal surgery. Vasodilator concentration-response curves were recorded from ET-1-preconstricted vessels by small vessel myography. Rock expression was investigated by Western blot and the potency of Rock inhibition to blunt ET-1-induced mesenteric artery constriction was tested. Iloprost, PGE1, and papaverine similarly reduced vascular tone to 20% to 30% of ET-1-induced wall tension. In human mesenteric arteries, logEC50 was significantly less for iloprost than for PGE1 or papaverine. Respective logEC50 values were -7.72 ± 0.08 mol/L, -6.58 ± 0.17 mol/L, and -6.73 ± 0.19 mol/L in 150 μm to 300 μm lumen diameter arteries. These vessels were also more sensitive to iloprost than 500 μm to 1,000 μm lumen diameter arteries (logEC50 -7.29 ± 0.07 mol/L). Rock1 and Rock2 were expressed in human mesenteric arteries but Rock inhibition did not significantly affect ET-1-induced vasoconstrictions. Iloprost, PGE1, and papaverine have a similar potency to relax mesenteric arteries. Our data suggest that iloprost but not Rock inhibition may be particularly useful to treat ET-1-induced spasms of distal mesenteric arteries.


Qualitative Comparative Analysis of Program and Participant Factors That Explain Success in a Micropolitan Pediatric Weight Management Intervention.
Background: Building Healthy Families (BHF) was developed through a community-academic partnership to provide a 12-week family-based obesity treatment program. Nine cohorts of BHF have been delivered in multiple micropolitan settings between 2009 and 2016, but participant outcomes have varied. This study sought to explore the variation in BHF outcomes to identify the necessary and sufficient conditions that are associated with larger 12-week reductions in BMI z-scores. Methods: A qualitative comparative analysis was used to determine potential causal conditions or combination of conditions associated with larger reductions in BMI z-score. Seventy-five participants with 12-week outcome data were rank ordered as the 10 most successful participants (largest reductions in BMI z-score; m ± std = -0.64 ± 0.18) and the 10 least successful participants (smallest reductions or an increase in BMI z-score; m ± std = 0.02 ± 0.04). The conditions selected for analysis were identified based on theory and the delivery team's experience with implementing BHF. Results: Necessary conditions (i.e., present in all highly successful participants, but also some less successful participants) included children with high attendance and self-regulation, at least one adult with high attendance and self-regulation, a mother who lost weight during the program and achieved clinically meaningful weight loss. Sufficient conditions (i.e., present in only the highly successful participants) included mothers with self-regulation scores >45% (range 46.7%-98.2%), and children with a combination of high attendance (72%-100%) and self-regulation scores ≥45% (45%-92.7%). Conclusion: Program implementers should continue to focus on encouraging high attendance and emphasize the necessity of enacting self-regulation strategies at both the child and parent level.


Movement disorders in spinocerebellar ataxias.
Autosomal dominant spinocerebellar ataxias (SCAs) can present with a large variety of noncerebellar symptoms, including movement disorders. In fact, movement disorders are frequent in many of the various SCA subtypes, and they can be the presenting, dominant, or even isolated disease feature. When combined with cerebellar ataxia, the occurrence of a specific movement disorder can provide a clue toward the underlying genotype. There are reasons to believe that for some coexisting movement disorders, the cerebellar pathology itself is the culprit, for example, in the case of cortical myoclonus and perhaps dystonia. However, movement disorders in SCAs are more likely related to extracerebellar pathology, and imaging and neuropathological data indeed show involvement of other parts of the motor system (substantia nigra, striatum, pallidum, motor cortex) in some SCA subtypes. When confronted with a patient with an isolated movement disorder, that is, without ataxia, there is currently no reason to routinely screen for SCA gene mutations, the only exceptions being SCA2 in autosomal dominant parkinsonism (particularly in Asian patients) and SCA17 in the case of a Huntington's disease-like presentation without an HTT mutation.


Time horizon dependent characterization factors for acidification in life-cycle assessment based on forest plant species occurrence in Europe.
This paper describes a new approach in life-cycle impact assessment to derive characterization factors for acidification in European forests. Time horizon dependent characterization factors for acidification were calculated, whereas before only steady-state factors were available. The characterization factors indicate the change in the potential occurrence of plant species due to a change in emission, and they consist of a fate and an effect factor. The fate factor combines the results of an atmospheric deposition model and a dynamic soil acidification model. The change in base saturation in soil due to an atmospheric emission change was derived for 20, 50, 100, and 500 year time horizons. The effect factor was based on a dose-response curve of the potential occurrence of plant species, derived from multiple regression equations per plant species. The results showed that characterization factors for acidification increase up to a factor of 13 from a 20 years to a 500 years time horizon. Characterization factors for ammonia are 4.0-4.3 times greater than those for nitrogen oxides (NO(x)), and characterization factors for sulfur dioxide are 1.4-2.0 times greater than those for NO(x). Aggregation of damage due to acidification with other impact categories on the European scale becomes feasible with the applied approach.


Prolonged Retrobulbar Local Anesthesia of the Cornea Does Not Cause Keratopathy in Mice.
Prolonged local anesthesia (PLA) of the cornea is currently assumed to cause neurotrophic keratitis and is strongly discouraged. We investigate whether PLA of the cornea per se causes neurotrophic keratitis. PLA of the cornea was induced in 12 female albino BALB/c mice by retrobulbar injection of a polymeric prodrug (PGS-TTX) where the site 1 sodium channel blocker tetrodotoxin (TTX) was slowly released from the polymer polyglycerol sebacate. The duration and depth of corneal anesthesia was monitored by the Cochet-Bonnet esthesiometer. Corneal injury from PLA was assessed by slit lamp examination with 2% sodium fluorescein dye, histology, corneal nerve density by immunohistochemistry with anti-β III tubulin antibody and confocal microscopy, and corneal neurotrophin levels (substance P and neurokinin A) by an enzyme-linked immunosorbent assay. PLA was also induced by topical amitriptyline (80 mM), used as a positive control for local anesthetic-induced corneal injury. Frequent ocular lubrication was provided. Retrobulbar PGS-TTX resulted in complete corneal anesthesia lasting 50.1 ± 3.6 hours and mean time to complete resolution of block of 55.1 ± 3.6 hours with no keratopathy provided lubrication was provided. Topical 80 mM amitriptyline induced complete corneal anesthesia for 24 hours and developed keratopathy. There was no difference in the histology, levels of corneal neurotrophins, and corneal nerve density between the retrobulbar PGS-TTX group and normal cornea. In the absence of topical toxicity or corneal exposure, PLA of the cornea per se does not cause keratitis. PLA of the cornea could be highly beneficial in acute and chronic painful corneal conditions.


Germinal centre-like versus undifferentiated stromal immunophenotypes in follicular lymphoma.
Follicular dendritic cells (FDCs) in reactive germinal centres (GCs) show modulated expression of antigens indicative of step-wise maturation from more undifferentiated stroma. The present study compared the expression of FDC markers CD21, CD23, CD35, and chemokine CXCL13 and the stromal markers low-affinity nerve growth factor receptor (LNGFR) and CNA.42 in 35 follicular lymphoma (FL) cases with reactive lymphoic tissue. CXCL13 was expressed by follicular stroma in all FLs but most cases showed either partial (11/35 cases, 31%) or complete (10/35 cases, 29%) absence of other FDC antigens, most commonly CD23, followed by CD21 and CD35, with variable patterns of LNGFR and CNA.42 immunostaining. Only a minority of FL cases (14/35, 40%) showed stroma that resembled mature FDCs (CD23+, CD21+, CD35+) and these tumours were always associated with numerous intrafollicular T-cells, similar to reactive GCs. In the 25 FL cases that had identifiable extrafollicular tumour cells, the immunophenotype of follicular stroma showed the same variability but the extrafollicular stroma showed an absence of FDC markers, with the exception of frequent strong LNGFR staining. Stromal phenotypic changes in FL were not correlated with mean follicle size, percentage of diffuse growth, tumour mitotic rate or the proliferation index as determined by PCNA immunostaining. Serial biopsy specimens analysed in a subset of 15 patients showed either a stable stromal phenotype (seven cases, 47%) or loss of FDC antigens in tumour-associated stroma over time (seven cases, 47%). The GC-like subset of FLs, having both abundant intrafollicular T-cells and fully differentiated CD23+ FDCs, comprises a minority of FL cases that likely have different growth requirements from FLs that lack these features. The pattern of FDC antigen loss in stroma of FL is a readily assessable biological feature that appears independent of architectural growth pattern and may serve as a useful surrogate marker of tumour progression.


The suppression of galactose metabolism in procylic form Trypanosoma brucei causes cessation of cell growth and alters procyclin glycoprotein structure and copy number.
Galactose metabolism is essential in bloodstream form Trypanosoma brucei and is initiated by the enzyme UDP-Glc 4'-epimerase. Here, we show that the parasite epimerase is a homodimer that can interconvert UDP-Glc and UDP-Gal but not UDP-GlcNAc and UDP-GalNAc. The epimerase was localized to the glycosomes by immunofluorescence microscopy and subcellular fractionation, suggesting a novel compartmentalization of galactose metabolism in this organism. The epimerase is encoded by the TbGALE gene and procyclic form T. brucei single-allele knockouts, and conditional (tetracycline-inducible) null mutants were constructed. Under non-permissive conditions, conditional null mutant cultures ceased growth after 8 days and resumed growth after 15 days. The resumption of growth coincided with constitutive re-expression epimerase mRNA. These data show that galactose metabolism is essential for cell growth in procyclic form T. brucei. The epimerase is required for glycoprotein galactosylation. The major procyclic form glycoproteins, the procyclins., were analyzed in TbGALE single-allele knockouts and in the conditional null mutant after removal of tetracycline. The procyclins contain glycosylphosphatidylinositol membrane anchors with large poly-N-acetyl-lactosamine side chains. The single allele knockouts exhibited 30% reduction in procyclin galactose content. This example of haploid insufficiency suggests that epimerase levels are close to limiting in this life cycle stage. Similar analyses of the conditional null mutant 9 days after the removal of tetracycline showed that the procyclins were virtually galactose-free and greatly reduced in size. The parasites compensated, ultimately unsuccessfully, by expressing 10-fold more procyclin. The implications of these data with respect to the relative roles of procyclin polypeptide and carbohydrate are discussed.


Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol.
Most studies of responses to transcriptional stimuli measure changes in cellular mRNA concentrations. By sequencing nascent RNA instead, it is possible to detect changes in transcription in minutes rather than hours and thereby distinguish primary from secondary responses to regulatory signals. Here, we describe the use of PRO-seq to characterize the immediate transcriptional response in human cells to celastrol, a compound derived from traditional Chinese medicine that has potent anti-inflammatory, tumor-inhibitory, and obesity-controlling effects. Celastrol is known to elicit a cellular stress response resembling the response to heat shock, but the transcriptional basis of this response remains unclear. Our analysis of PRO-seq data for K562 cells reveals dramatic transcriptional effects soon after celastrol treatment at a broad collection of both coding and noncoding transcription units. This transcriptional response occurred in two major waves, one within 10 min, and a second 40-60 min after treatment. Transcriptional activity was generally repressed by celastrol, but one distinct group of genes, enriched for roles in the heat shock response, displayed strong activation. Using a regression approach, we identified key transcription factors that appear to drive these transcriptional responses, including members of the E2F and RFX families. We also found sequence-based evidence that particular transcription factors drive the activation of enhancers. We observed increased polymerase pausing at both genes and enhancers, suggesting that pause release may be widely inhibited during the celastrol response. Our study demonstrates that a careful analysis of PRO-seq time-course data can disentangle key aspects of a complex transcriptional response, and it provides new insights into the activity of a powerful pharmacological agent.


The G9a Histone Methyltransferase Inhibitor BIX-01294 Modulates Gene Expression during Plasmodium falciparum Gametocyte Development and Transmission.
Transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is initiated by specialized sexual cells, the gametocytes. In the human, gametocytes are formed in response to stress signals and following uptake by a blood-feeding Anopheles mosquito initiate sexual reproduction. Gametocytes need to fine-tune their gene expression in order to develop inside the mosquito to continue life-cycle progression. Previously, we showed that post-translational histone acetylation controls gene expression during gametocyte development and transmission. However, the role of histone methylation remains poorly understood. We here use the histone G9a methyltransferase inhibitor BIX-01294 to investigate the role of histone methylation in regulating gene expression in gametocytes. In vitro assays demonstrated that BIX-01294 inhibits intraerythrocytic replication with a half maximal inhibitory concentration (IC50) of 13.0 nM. Furthermore, BIX-01294 significantly impairs gametocyte maturation and reduces the formation of gametes and zygotes. Comparative transcriptomics between BIX-01294-treated and untreated immature, mature and activated gametocytes demonstrated greater than 1.5-fold deregulation of approximately 359 genes. The majority of these genes are transcriptionally downregulated in the activated gametocytes and could be assigned to transcription, translation, and signaling, indicating a contribution of histone methylations in mediating gametogenesis. Our combined data show that inhibitors of histone methylation may serve as a multi-stage antimalarial.


Optimization of DNA Extraction from Field-Collected Mammalian Whole Blood on Filter Paper for Trypanosoma cruzi (Chagas Disease) Detection.
Blood filter paper strips are cost-effective materials used to store body fluid specimens under challenging field conditions, extending the reach of zoonotic pathogen surveillance and research. We describe an optimized procedure for the extraction of parasite DNA from whole blood (WB) stored on Type I Advantec Nobuto strips from both experimentally spiked and field-collected specimens from canine and skunks, respectively. When comparing two commercial kits for extraction, Qiagen's DNeasy Blood & Tissue Kit performed best for the detection of parasite DNA by PCR from Trypanosoma cruzi-spiked canine WB samples on Nobuto strips. To further optimize recovery of β-actin from field-collected skunk WB archived on Nobuto strips, we modified the extraction procedures for the Qiagen kit with a 90 °C incubation step and extended incubation post-addition of proteinase K, a method subsequently employed to identify a T. cruzi infection in one of the skunks. Using this optimized extraction method can efficaciously increase the accuracy and precision of future molecular epidemiologic investigations targeting neglected tropical diseases in field-collected WB specimens on filter strips.


Quantitative epigenetics through epigenomic perturbation of isogenic lines.
Interindividual differences in chromatin states at a locus (epialleles) can result in gene expression changes that are sometimes transmitted across generations. In this way, they can contribute to heritable phenotypic variation in natural and experimental populations independent of DNA sequence. Recent molecular evidence shows that epialleles often display high levels of transgenerational instability. This property gives rise to a dynamic dimension in phenotypic inheritance. To be able to incorporate these non-Mendelian features into quantitative genetic models, it is necessary to study the induction and the transgenerational behavior of epialleles in controlled settings. Here we outline a general experimental approach for achieving this using crosses of epigenomically perturbed isogenic lines in mammalian and plant species. We develop a theoretical description of such crosses and model the relationship between epiallelic instability, recombination, parent-of-origin effects, as well as transgressive segregation and their joint impact on phenotypic variation across generations. In the limiting case of fully stable epialleles our approach reduces to the classical theory of experimental line crosses and thus illustrates a fundamental continuity between genetic and epigenetic inheritance. We consider data from a panel of Arabidopsis epigenetic recombinant inbred lines and explore estimates of the number of quantitative trait loci for plant height that resulted from a manipulation of DNA methylation levels in one of the two isogenic founder strains.


Effects of a two-week, hospitalized phase II cardiac rehabilitation program on physical capacity, lipid profiles and psychological variables in patients with acute myocardial infarction.
A new 2-week hospitalized phase II cardiac rehabilitation program has been designed and the present study sought to clarify whether the physical and psychological status of patients with acute myocardial infarction (AMI) improved after participation in the program. Fifty-one patients with AMI were enrolled in the rehabilitation program, which consisted of exercise training, education and counselling, and another 34 patients with AMI who did not participate in the program served as the control group. The physical and psychological status of the patients was evaluated before, at 1-month after the program, and at 6- and 12-months follow-ups. The physical status was assessed by exercise tolerance and serum lipid profiles and the psychological status was assessed by the Spielberger State-Trait anxiety inventory questionnaire (STAI) and self-rating questionnaire for depression. Quality of life (QOL) was assessed using established and validated QOL scales. After participation in the program, the exercise tolerance, serum lipid profiles and STAI anxiety score of the patients were improved significantly and at the 6-month follow-up these parameters remained improved and regular physical activity was maintained. The QOL score also improved significantly. Even at the 12-month follow-up, lipid profiles remained improved and regular physical activity was maintained. The 2-week hospitalized phase II cardiac rehabilitation program improved the management of cardiac risk factors and psychological status in patients with myocardial infarction (MI). It provides beneficial effects on the patient's physical and psychological activities in the recovery phase and may also contribute to the secondary prevention of MI.


Safety and tolerability of a rapidly escalating dose-loading regimen for risperidone.
Risperidone is an "atypical" antipsychotic with strong binding affinity for dopamine-2 and serotonin-2 receptors. Risperidone is often used to treat hospitalized patients who have acute psychotic decompensation, and the therapeutic target dose commonly used is 2 to 6 mg/day. The most common clinical practice is to titrate the dose of risperidone to the target therapeutic dose over several days. This study investigated the safety and tolerability of a rapid oral-loading regimen for risperidone developed to achieve therapeutic doses of this antipsychotic within 24 hours. Rapid-loaded risperidone was initiated with 1 mg. Subsequent doses were increased by 1 mg every 6 to 8 hours up to 3 mg. Dose increases were contingent on tolerance of last administered dose. Of a sample of 11 consecutive inpatients admitted to an acute psychiatric facility who were treated with this protocol, 7 tolerated the most rapid titration, achieving a standing dose of 3 mg b.i.d. in 16 hours. Three required a slightly slower titration and achieved this target dose in 24 hours. One patient could not tolerate the 3-mg dose but tolerated a standing regimen of 2 mg t.i.d. No patient experienced serious extrapyramidal side effects, sedation, or any other adverse event during the rapid titration, and in no case did risperidone have to be discontinued. These results suggest that aggressive dosing of risperidone is well tolerated in most psychiatric inpatients.


A Comparison Between Hyaluronic Acid Filler and Dermofat Grafts With or Without Tie-Over Dressing for Lip Augmentation.
There are many different autologous grafts used for lip augmentation, such as fat, fascia, or dermofat grafts (DFG). However, filling with synthetic materials such as hyaluronic acid (HA) fillers is the most preferred method. The authors aimed to compare DFG with HA fillers regarding cost, permanence, complication rate, gained volume, and satisfaction rate. The authors investigated the effect of tie-over dressings on the viability of DFG. Patients who received hyaluronic acid fillers were referred to as Group H. Patients who received grafts without tie-over and with tie-over dressings formed Groups D1 and D2, respectively. The lip index (LI) was used for volume comparisons. The viable area of the grafts was measured using ultrasound imaging. At postoperative month 6, the only significant difference was found between Group D1 and Group D2 (p < .05). At the postoperative first year, Groups D1 and D2 had a statistically higher LI value compared with Group H. Group D2 had a higher viable area than Group D2 (p < .05). Group H and Group D2 showed higher satisfaction scores than Group D1 (p < .05). Dermofat grafts with or without tie-over dressings can be considered a reliable and inexpensive choice for patients who seek a more permanent procedure. Tie-over dressings increase the predictability of DFG and reduce the need for overcorrection.


Overcoming ACLS dogma: how quickly should we change?
The ECC Guidelines 2000 considered interesting new evidence about a pre-defibrillation period of prescribed CPR to increase the probability that the postshock rhythm would be perfusing rather than asystole. If victims of out-of-hospital cardiac arrest have not received bystander CPR before the arrival of the defibrillator, a period of preshock CPR could enhance the value of the shocks. At the end of the year 2000 there was insufficient evidence to recommend any other approach than shock as soon as possible and perform CPR at all other times.


Highly luminescent water-dispersed silicon quantum dots for fluorometric determination of oxytetracycline in milk samples.
A fluorescent probe based on silicon quantum dots (SiQDs) was developed for the selective and sensitive detection of oxytetracycline (OTC) via the inner filter effect (IFE). The water-soluble fluorescent SiQD was synthesized based on the reaction of 3-Aminopropyltriethoxysilane (APTES) and sodium citrate as precursors by the one-pot hydrothermal process. The strong fluorescence emission of quantum dots (QDs) was obtained at 440 nm when excited at 350 nm and OTC had a broad absorption band between 200 and 400 nm. The excitation spectrum of SiQDs was completely overlapped with the absorption spectrum of OTC. The light at an excitation wavelength of QDs absorbed by OTC caused a decrease in fluorescence intensity with an increase in the concentration of OTC. Under optimal conditions, the linear concentration range was 0.92-9.2 µg mL1 with a detection limit (LOD; S/N = 3) of 0.19 µg mL -1 . The proposed method was applied to the determination of OTC in milk samples and satisfactory recoveries (98.8-100.5%) with low RSD % values (0.93-2.31%) were achieved. This simple, selective, sensitive, rapid, and cheap method can be used as a promising tool for OTC analysis in food safety.


[Telemedicine collaboration between the Rikshospitalet and the Ulleval hospital].
During the last two years the Intervention Centre at the Nation Hospital of Norway and Ullevål Hospital have pursued a research programme in telemedicine aimed at exploring the potential of inter-hospital collaboration. Both hospitals established a communication network between operating rooms and lecture halls. Sound and video from minimally invasive surgical and radiology procedures were transmitted on a wide bandwidth ATM network (34 Mbits/s) to gain experience with the use of telemedicine for educational purposes and the treatment of patients. Evaluations of technical off-line and clinical line transmissions have given us helpful information about the potential of telemedicine and what it will take to utilise this potential. With the MPEG2 standard, a wide bandwidth network yields sufficient sound and image quality for educational and clinical collaboration. However, multimedia communication requires changes in the organisation to secure quality of service in relation to technical management and telemedical production. Inter-hospital collaboration on telemedicine may be a resource in clinical practice, facilitating professional enhancements, particularly in surgery, radiology and internal medicine. Changes in the organisation are needed, but they are feasible.


Chemokine secretion of human cells in response to Toxoplasma gondii infection.
The ubiquitous protozoan parasite Toxoplasma gondii is a major cause of morbidity and mortality in neonates and immunocompromised hosts. Both acute invasion and reactivation of latent infection result in an inflammatory reaction with lymphocytes, macrophages, and neutrophils. The mechanisms responsible for triggering the local host response to toxoplasmosis are not fully understood. Infection of monolayers of human HeLa epithelial cells and fibroblasts with T. gondii resulted in a marked increase in the expression of interleukin-8 (IL-8)-specific mRNA and secretion of the proinflammatory and chemoattractant cytokines interleukin-8 (IL-8), GROalpha, and MCP-1. Host cell invasion and lysis were required for this response, as tachyzoite lysates alone had no effect on IL-8 secretion. IL-8 release was dependent on the release of soluble host cell factors: IL-1alpha in HeLa cells and an additional mediator in fibroblasts. HT-29 epithelial cells, which lack IL-1alpha or another IL-8-inducing activity, did not release IL-8 after infection, although they were efficiently infected with T. gondii and increased IL-8 secretion in response to added IL-1alpha. These data suggest that proinflammatory chemokine secretion is an important host cell response to toxoplasmosis and that the release of IL-1alpha and other mediators from lysed host cells is critical for this chemokine response.


Measurement equivalence of the short-form Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-16).
The aim of this study was to assess measurement equivalence in the 16-item short-form Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-16) across age, sex, and time in a sample of children with newly diagnosed epilepsy. Data came from 373 children participating in the Health-related Quality of Life in Children with Epilepsy Study (HERQULES), a multicenter prospective cohort study. Measurement equivalence was assessed using multigroup confirmatory factor analysis methods. Comparison groups were stratified by age (4-7 years vs. 8-12 years), sex (male vs. female), and time (at diagnosis vs. 24 months postdiagnosis). The QOLCE-16 demonstrated measurement equivalence at the level of strict invariance for each comparison group tested - age: χ2 (3, 274) = 429.6, p < 0.001; comparative fit index (CFI) = 0.985; root mean square error of approximation (RMSEA) = 0.056 (0.046, 0.066); sex: χ2 (3, 271) = 430.5, p < 0.001; CFI = 0.984; RMSEA = 0.057 (0.047, 0.067); and time: χ2 (3, 269) = 566.4, p < 0.001; CFI = 0.985; RMSEA = 0.059 (0.052, 0.066). The findings provide support for the robust psychometric profile of the QOLCE-16 as a reliable and valid measure of health-related quality of life for children with epilepsy. Demonstrating good properties and a multidimensional structure, the QOLCE-16 is an appropriate short measure for both clinicians and researchers wanting to obtain health-related quality of life information on children with epilepsy.


Suppression of secondary hyperparathyroidism in children with chronic renal failure by high dose phosphate binders: calcium carbonate versus aluminium hydroxide.
Secondary hyperparathyroidism was suppressed over a period of one year in 12 children with chronic renal failure by using a regimen of mild dietary phosphate restriction and high dose phosphate binders. The patients were randomised to receive either aluminium hydroxide or calcium carbonate by mouth for six months and then crossed over to the other medication. Vitamin D (dihydrotachysterol) dosage was unchanged. Serum parathyroid hormone concentrations were reduced to within the normal range, urinary cyclic adenosine monophosphate values fell, plasma phosphate concentrations decreased, and the theoretical renal phosphate threshold increased significantly. Transiliac bone biopsy findings improved in four patients with adequate suppression of parathyroid hormone concentrations, deteriorated in two patients who were not compliant, and did not change in five patients in whom initial bone disease was mild. Growth velocity improved significantly. There was no difference in the clinical response, biochemical changes, or incidence of complications during treatment with the two agents. In view of the risk of aluminium toxicity the use of high dose calcium carbonate with dietary phosphate restriction and vitamin D supplementation is recommended in the control of secondary hyperparathyroidism in children with chronic renal failure.


Interrogating differences in expression of targeted gene sets to predict breast cancer outcome.
Genomics provides opportunities to develop precise tests for diagnostics, therapy selection and monitoring. From analyses of our studies and those of published results, 32 candidate genes were identified, whose expression appears related to clinical outcome of breast cancer. Expression of these genes was validated by qPCR and correlated with clinical follow-up to identify a gene subset for development of a prognostic test. RNA was isolated from 225 frozen invasive ductal carcinomas,and qRT-PCR was performed. Univariate hazard ratios and 95% confidence intervals for breast cancer mortality and recurrence were calculated for each of the 32 candidate genes. A multivariable gene expression model for predicting each outcome was determined using the LASSO, with 1000 splits of the data into training and testing sets to determine predictive accuracy based on the C-index. Models with gene expression data were compared to models with standard clinical covariates and models with both gene expression and clinical covariates. Univariate analyses revealed over-expression of RABEP1, PGR, NAT1, PTP4A2, SLC39A6, ESR1, EVL, TBC1D9, FUT8, and SCUBE2 were all associated with reduced time to disease-related mortality (HR between 0.8 and 0.91, adjusted p < 0.05), while RABEP1, PGR, SLC39A6, and FUT8 were also associated with reduced recurrence times. Multivariable analyses using the LASSO revealed PGR, ESR1, NAT1, GABRP, TBC1D9, SLC39A6, and LRBA to be the most important predictors for both disease mortality and recurrence. Median C-indexes on test data sets for the gene expression, clinical, and combined models were 0.65, 0.63, and 0.65 for disease mortality and 0.64, 0.63, and 0.66 for disease recurrence, respectively. Molecular signatures consisting of five genes (PGR, GABRP, TBC1D9, SLC39A6 and LRBA) for disease mortality and of six genes (PGR, ESR1, GABRP, TBC1D9, SLC39A6 and LRBA) for disease recurrence were identified. These signatures were as effective as standard clinical parameters in predicting recurrence/mortality, and when combined, offered some improvement relative to clinical information alone for disease recurrence (median difference in C-values of 0.03, 95% CI of -0.08 to 0.13). Collectively, results suggest that these genes form the basis for a clinical laboratory test to predict clinical outcome of breast cancer.


Use of amplified fragment length polymorphism markers to assess genetic diversity of Lolium species from Portugal.
We evaluated the use of amplified fragment length polymorphism (AFLP) markers to distinguish genotypes, populations and species of Lolium. Accessions of two species Lolium perenne and Lolium multiflorum and their hybrid Lolium x hybridum, collected by the Institute of Grass and Environmental Research in 1995 from locations across Portugal, were used. The genetic variation within and between populations from the extremes of latitude and altitude was determined and assessed. Three primer pair combinations generated 765 polymorphic bands. Principal coordinate analysis of similarities between 127 plants showed high dimensionality in the data. Axes 1-3 were associated primarily with species differences, axes 4-14 with population differences within species and axis 15 onwards with within population differences. UPGMA analysis confirmed the groupings. The three populations of L. perenne formed a discrete cluster widely separated from all other populations. There were two distinct groups of L. x hybridum, of which one was similar to and overlapped with L. multiflorum and the second formed a distinct cluster. Analyses of individual bands showed that every inter- and intraspecific contrast involved a different sets of bands, again confirming the high dimensionality of the data. No single band was strictly diagnostic of any population or species. Nevertheless, the UPGMA analysis showed little or no overlap between populations. Thus, despite the high ratio of within-to-between population genetic variance, the full AFLP banding pattern of each genotype is a relatively reliable fingerprint diagnostic of its parent population. The high dimensionality implies that many different factors contribute to the differences observed. This adds to the potential value of the methodology, since it implies that there is a reasonably high likelihood of finding bands relevant to a given environmental gradient or other factor influencing the distribution of genetic diversity.


Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension.
Autoregulation of cerebral blood flow (CBF) was studied by the arteriovenous oxygen difference method in 13 patients with untreated or ineffectively treated severe hypertension, nine patients with effectively treated, formerly severe hypertension, and ten normotensive controls. Resting mean blood pressure in these three groups was 145 +/- 17 (1 SD) mm Hg, 116 +/- 18 mm Hg, and 98 +/- 10 mm Hg, respectively. Blood pressure was decreased by trimethaphan infusion combined with head-up tilt. The lower limit of CBF autoregulation in the three groups was 113 +/- 17 mm Hg, 96 +/- 17 mm Hg, and 73 +/- 9 mm Hg, and the lowest tolerated blood pressure where mild symptoms of brain hypoperfusion were encountered was 65 +/- 10 mm Hg, 53 +/- 18 mm Hg, and 43 +/- 8 mm Hg. These pressures were all significantly higher (P less than 0.01) in the group of untreated or ineffectively treated hypertensive patients than in the normotensive group demonstrating a shift of CBF autoregulation in the former. The observations in effectively treated hypertensive patients strongly suggested a readaptation of CBF autoregulation toward normal in some cases. In four hypertensive patients studied twice it was found that 8-12 months of antihypertensive treatment on average did not influence the lower limit of CBF autoregulation.


Synthesis of the core structure of acutumine.
[reaction: see text] The tricyclic core of the bioactive natural product acutumine has been synthesized. Key steps include an oxidative phenolic coupling to form a masked o-benzoquinone, an anionic oxy-Cope rearrangement to construct an all-carbon quaternary center, and a Michael-type cyclization to form an amine-bearing quaternary carbon. The target compound exists in solution as an enol, in contrast to related compounds that are ketones. A model explaining these observations is presented.


Exploring Bacterial Carboxylate Reductases for the Reduction of Bifunctional Carboxylic Acids.
Carboxylic acid reductases (CARs) selectively reduce carboxylic acids to aldehydes using ATP and NADPH as cofactors under mild conditions. Although CARs attracts significant interest, only a few enzymes have been characterized to date, whereas the vast majority of CARs have yet to be examined. Herein the authors report that 12 bacterial CARs reduces a broad range of bifunctional carboxylic acids containing oxo-, hydroxy-, amino-, or second carboxyl groups with several enzymes showing activity toward 4-hydroxybutanoic (4-HB) and adipic acids. These CARs exhibits significant reductase activity against substrates whose second functional group is separated from the carboxylate by at least three carbons with both carboxylate groups being reduced in dicarboxylic acids. Purified CARs supplemented with cofactor regenerating systems (for ATP and NADPH), an inorganic pyrophosphatase, and an aldo-keto reductase catalyzes a high conversion (50-76%) of 4-HB to 1,4-butanediol (1,4-BDO) and adipic acid to 1,6-hexanediol (1,6-HDO). Likewise, Escherichia coli strains expressing eight different CARs efficiently reduces 4-HB to 1,4-BDO with 50-95% conversion, whereas adipic acid is reduced to a mixture of 6-hydroxyhexanoic acid (6-HHA) and 1,6-HDO. Thus, our results illustrate the broad biochemical diversity of bacterial CARs and their compatibility with other enzymes for applications in biocatalysis.


Phone-Based Text Therapy for Youth Mental Health: Rapid Review.
Mental illness has become a prevalent issue impacting adolescents worldwide. Many barriers, including stigma and poor health literacy, prevent this population group from accessing reliable mental health care services. Synchronous text-therapy counseling is an underused therapeutic approach in combating adolescent mental illness. Phone-based text therapy is uniquely placed to offer personalized counseling to adolescents through a familiar and engaging treatment modality. This rapid review aims to understand the clinical effectiveness, usability, and accessibility of phone-based text therapy for youth mental health. Cochrane CENTRAL, Embase, PubMed, and PsycINFO were used to search for suitable literature. Five groups of keywords were used: those related to (1) "therapy," (2) "text," (3) "phone," (4) "youth," and (5) "mental health." Eligibility criteria were formed through the PICO (Population, Intervention, Control, and Outcome) framework. Studies were included if a synchronous phone-based text therapy intervention was used in an adolescent population, with an age range of 12-24 years. Only literature available in full-text, English, and a peer-reviewed journal was considered. Furthermore, a date limit of 5 years was set to reflect the recent development of digital interventions for mental health. Pertinent information from each study was tabulated, and a narrative synthesis was used to assess, describe, and organize the included studies comprehensively and concisely. Of the 771 studies dual screened, 7 studies were included in this rapid review. Most of the exclusions occurred due to the use of the wrong intervention, such as asynchronous messaging. The selected studies had a low risk of bias and were suitable for the review. All interventional trials demonstrated reductions in mental health symptoms, primarily depression and anxiety. Most studies displayed high usability among participants, while data were unclear regarding accessibility. This review reveals the high potential of phone-based text therapy as an intervention for adolescents experiencing mental illness. We hope that this review promotes further refinement of text-based phone therapies and encourages future research on this subject matter.


Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.
Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.


Linkage of biopsy, cancer, and population records aimed at the estimation of family risks in neoplasia: a pilot study.
The aim was to link individual demographic and medical records into sibships to obtain the sibling distribution of biopsies and cancers, and thereby calculate heritability and recurrence risks in families, thus aiding early diagnosis and prevention of cancers. The 157,823 individual records of the inhabitants of the town of Ferrara in Italy were automatically linked into 106,821 sibships. A 10% sample (10,842 sibships) was then extracted from the distribution of sibships and tabulated, for linkage to medical records. The biopsy records at the Institute of Pathological Anatomy of the University of Ferrara were manually linked to cancer records and then to sibships. It was possible to construct the distribution of 2062 biopsies and of 829 cancers in sibships. From the distribution of biopsies and tumours in sibships, it was possible to estimate the incidence of tumours in the population (0.052) and in siblings of affected (0.083), and to apply to such distributions current methods for the estimate of heritability (h2 = 0.246) and of recurrence risks of tumours in sibships, age independent. The study shows that the procedure resulting in the estimation of incidences and recurrence risks for tumours could be completely automated, and extended to whole populations and homogeneous subgroups in post industrial cultures.


Epinephrine inhibits endotoxin-induced IL-1 beta production: roles of tumor necrosis factor-alpha and IL-10.
Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1 beta production, the following experiments were performed: 1) blood obtained from subjects at 4-21 h after the start of a continuous infusion of epinephrine (30 ng.kg-1.min-1) produced less IL-1 beta after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1 beta production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1 beta production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.


Anatomical features and clinical correlations in Caucasian patients with definite arrhythmogenic right ventricular dysplasia/cardiomyopathy.
Arrhythmogenic right ventrticular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by fibrofatty replacement and a high risk of ventricular arrhythmias (VA) and sudden cardiac death (SCD). The aim of the present investigation is to examine the pathological profile and the clinical correlations in a group of ARVD/C patients. We conducted a multicenter study evaluating 47 patients (31 men; mean age 37±14 years) with definite ARVD/C. Diagnosis was established according to the actual clinicomorphologic criteria at autopsy or clinically. We divided the study population in 2 different groups. First group included 28 alive patients and the second 19 patients dead suddenly. Age at presentation was different in the two groups (P=0.0015). We observed an important association regarding the risk of sudden death and the history of physical exercise (P=0.0017). Moreover patients with negative outcome (i.e., SCD, cardiac transplantation, congestive heart failure) had a significantly association with biventricular form of ARVD/C (P=0.0034) and age presentation (P=0.003). Left ventricular (LV) involvement was frequently observed in the two groups (17% and 32% respectively). Post-mortem examination revealed frequent inflammatory infiltrates (26%) indicating active myocarditis, which probably justify the fatal arrhythmic events occurred in these patients. Frequent LV involvement justifies the recent adoption of the broad term Arrhythmogenic Cardiomyopathy. Early age presentation, sport activity and the biventricular form of ARVD/C represent important predictors of adverse outcome that can be useful to early identify patients at high risk.


Prepared to Act: Lessons Learned by the Special Pathogens Research Network, Based on Collaborations with the NIAID-Led Adaptive COVID-19 Treatment Trial.
The need for well-controlled clinical trials is fundamental to advancing medicine. Care should be taken to maintain high standards in trial design and conduct even during emergency medical events such as an infectious disease outbreak. In 2020, SARS-CoV-2 emerged and rapidly impacted populations around the globe. The need for effective therapeutics was immediately evident, prompting the National Institutes of Health to initiate the Adaptive COVID-19 Treatment Trial. The Special Pathogens Research Network, made up of 10 Regional Emerging Special Pathogens Treatment Centers, was approached to participate in this trial and readily joined the trial on short notice. By trial closure, the Special Pathogens Research Network sites, making up 19% of all study sites, enrolled 26% of the total participants. The initial resources available and experience in running clinical trials at each treatment center varied from minimal experience and few staff to extensive experience and a large staff. Based on experiences during the first phase of this trial, the Special Pathogens Research Network members provided feedback regarding operational lessons learned and recommendations for conducting future studies during a pandemic. Communication, collaboration, information technology, regulatory processes, and access to resources were identified as important topics to address. Key stakeholders including institutions, institutional review boards, and study personnel must maintain routine communication to efficiently and effectively activate when future research needs arise. Regular and standardized training for new personnel will aid in transitions and project continuity, especially in a rapidly evolving environment. Trainings should include local just-in-time training for new staff and sponsor-designed modules to refresh current staff knowledge. We offer recommendations that can be used by institutions and sponsors to determine goals and needs when preparing to set up this type of trial for critical, short-notice needs.


Novel antioxidants protect mitochondria from the effects of oligomeric amyloid beta and contribute to the maintenance of epigenome function.
Alzheimer's disease is associated with metabolic deficits and reduced mitochondrial function, with the latter due to the effects of oligomeric amyloid beta peptide (AβO) on the respiratory chain. Recent evidence has demonstrated reduction of epigenetic markers, such as DNA methylation, in Alzheimer's disease. Here we demonstrate a link between metabolic and epigenetic deficits via reduction of mitochondrial function which alters the expression of mediators of epigenetic modifications. AβO-induced loss of mitochondrial function in differentiated neuronal cells was reversed using two novel antioxidants (1 and 2); both have been shown to mitigate the effects of reactive oxygen species (ROS), and compound 1 also restores adenosine triphosphate (ATP) levels. While both compounds were effective in reducing ROS, restoration of ATP levels was associated with a more robust response to AβO treatment. Our in vitro system recapitulates key aspects of data from Alzheimer's brain samples, the expression of epigenetic genes in which are also shown to be normalized by the novel analogues.


Application of High-Intensity Ultrasound to Improve Food Processing Efficiency: A Review.
The use of non-thermal processing technologies has grown in response to an ever-increasing demand for high-quality, convenient meals with natural taste and flavour that are free of chemical additions and preservatives. Food processing plays a crucial role in addressing food security issues by reducing loss and controlling spoilage. Among the several non-thermal processing methods, ultrasound technology has shown to be very beneficial. Ultrasound processing, whether used alone or in combination with other methods, improves food quality significantly and is thus considered beneficial. Cutting, freezing, drying, homogenization, foaming and defoaming, filtration, emulsification, and extraction are just a few of the applications for ultrasound in the food business. Ultrasounds can be used to destroy germs and inactivate enzymes without affecting the quality of the food. As a result, ultrasonography is being hailed as a game-changing processing technique for reducing organoleptic and nutritional waste. This review intends to investigate the underlying principles of ultrasonic generation and to improve understanding of their applications in food processing to make ultrasonic generation a safe, viable, and innovative food processing technology, as well as investigate the technology's benefits and downsides. The breadth of ultrasound's application in the industry has also been examined. This will also help researchers and the food sector develop more efficient strategies for frequency-controlled power ultrasound in food processing applications.


Tubulization techniques in brachial plexus surgery in an animal model for long-nerve defects (40 mm): a pilot study.
The critical length of 30 mm beyond which nerve regeneration was not possible limited up to now the use of tubulization. In this pilot study, a novel animal model is introduced using tubulization techniques for long-nerve defects (40 mm) in brachial plexus surgery. Twelve Sprague-Dawley rats were divided into 3 groups. A poly-DL-lactide-epsilon-caprolactone tube (group 1), a collagen tube (group 2), and a nerve graft (group 3) were, respectively, used to bridge a 40-mm gap between the right C7 root and the left musculocutaneous nerve. Animals were euthanized on day 30. Evaluation consisted of behavioral assessment, needle electromyography studies, biceps muscle weight measurements, qualitative, and quantitative morphometry. Only group 3 demonstrated axon regeneration and reinnervation potentials. There was statistical significant difference for biceps weight left/right ratio (P = 0.010) but not for behavioral results (P = 0.10) between group 3 and groups 1 and 2. This study introduced a novel rat model for the studying of nerve regeneration along long-nerve gaps (4 cm). Although using an autologous nerve graft regeneration achieved, the use of synthetic conduits failed to show regeneration. This may be attributed to gap length; duration of follow-up; and to no administration of a neurotrophic factor.


[Radionuclide and macro-microangiographic study of pulmonary ventilation and blood flow in chronic nonspecific lung diseases].
A study was made of ventilation and perfusion in 105 patients with chronic pulmonary nonspecific diseases using radiopneumography with 133Xe. A simultaneous macro-microangiographic study was made of the pulmonary artery on specimens taken after lobectomy in 35 patients with bronchiectasia in the lower lobe. The control group was composed of 35 specimens of the healthy lungs taken from unembalmed cadavers of people who died of diseases unrelated to the involvement of the respiratory system as well as from 30 healthy people after radiopneumography. Asymmetry of the distribution of ventilation and perfusion is typical of patients with bronchiectasia. It manifests itself in a significant decrease in the VLC and the blood flow in the affected zone. A simultaneous compensatory rise of perfusion was recorded. In a macro-microangiographic study a rough deformity of the vascular trunks at the level of the segmental and subsegmental vessels was marked in these patients; angles of the outgoing of vessels of the main trunk decreased significantly, the number of vessels with a winding course increased. Simultaneous anatomostructural radionuclide studies make it possible to understand more deeply the essence of a pathological process.


Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II.
Cardiac ATP-sensitive potassium (K(ATP)) channels are key sensors and effectors of the metabolic status of cardiomyocytes. Alteration in their expression impacts their effectiveness in maintaining cellular energy homeostasis and resistance to injury. We sought to determine how activation of calcium/calmodulin-dependent protein kinase II (CaMKII), a central regulator of calcium signaling, translates into reduced membrane expression and current capacity of cardiac K(ATP) channels. We used real-time monitoring of K(ATP) channel current density, immunohistochemistry, and biotinylation studies in isolated hearts and cardiomyocytes from wild-type and transgenic mice as well as HEK cells expressing wild-type and mutant K(ATP) channel subunits to track the dynamics of K(ATP) channel surface expression. Results showed that activation of CaMKII triggered dynamin-dependent internalization of K(ATP) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)YSKF(333) endocytosis motif of the K(ATP) channel Kir6.2 pore-forming subunit. A molecular model of the μ2 subunit of the endocytosis adaptor protein, AP2, complexed with Kir6.2 predicted that μ2 docks by interaction with (330)YSKF(333) and Thr-180 on one and Thr-224 on the adjacent Kir6.2 subunit. Phosphorylation of Thr-180 and Thr-224 would favor interactions with the corresponding arginine- and lysine-rich loops on μ2. We concluded that calcium-dependent activation of CaMKII results in phosphorylation of Kir6.2, which promotes endocytosis of cardiac K(ATP) channel subunits. This mechanism couples the surface expression of cardiac K(ATP) channels with calcium signaling and reveals new targets to improve cardiac energy efficiency and stress resistance.


[Risk indices of reagin allergy. I. The rhesus phenotype and specific IgE production].
The authors have studied the frequency of the rhesus phenotype elements CC, Cc or cc, in relationship with the different specific IgE antibodies determined by Radio immunoassay (Phadebas IgE Rast). They found a regular distribution of these phenotype elements, whatever the different IgE among all subjects with family respiratory allergic diseases. On the other hand, among all subjects who have no family atopic history, rhesus cc phenotype is significantly more frequent. This situation is observed in both sexes equally. To understand, the causal mechanicism, serum IgA and IgM were compared. A good correlation was found only with CC rhesus allergic patients. It is suggested that these patients are carrying a non yet identified immune response gene, whereas cc rhesus subjects could be suffering from an important transmucosal penetration of the environmental antigens.


Preseptal transconjunctival approach in orbital floor fracture repairs to prevent postoperative lower eyelid malposition.
Lower eyelid malposition can be a complication following orbital floor fracture surgeries. We present our incidence of lower eyelid malposition from a large case series of orbital floor fracture repairs using the 'swinging eyelid' approach and 'hang back' technique. A retrospective review of all orbital fracture surgeries at our institution from November 2011 to March 2021 was performed. Primary outcomes included the incidence of lower eyelid malposition by category, the average time to presentation after primary surgery, and reoperation rates among cases with lower eyelid complications. A total of 438 cases that involved repair of the fractured orbital floor were identified. Six patients (1.37 %) developed lower eyelid malposition following primary orbital floor repair. Two patients (0.46 %) developed reverse ptosis of the lower eyelid. Two patients (0.46 %) returned with lower lid cicatricial ectropion. One patient (0.23 %) had postoperative lower eyelid retraction. One patient (0.23 %) had postoperative lower eyelid cicatricial entropion. No cases of lower lid flattening, lower eyelid fat flattening, or eyelid notch was noted. All patients with lower eyelid malposition underwent additional surgeries except one patient with reverse ptosis (83.3 %). The average time to the presentation of postoperative complications from the surgery date was 292.8 days (range = 49 days to 3.5 years). Lower eyelid malposition after orbital floor repair is a known complication that can be decreased by employing the 'swinging eyelid' with a preseptal approach and closure by the 'hang back' technique.


Effect of in vivo injection of cholera and pertussis toxin on glucose transport in rat skeletal muscle.
Cholera toxin (CTX) and pertussis toxin (PTX) were examined for their ability to inhibit glucose transport in perfused skeletal muscle. Twenty-five hours after an intravenous injection of CTX, basal transport was decreased approximately 30%, and insulin- and contraction-stimulated transport was reduced at least 86 and 49%, respectively, in both the soleus and red and white gastrocnemius muscles. In contrast, PTX treatment was much less efficient. Impairment of glucose transport appeared to develop 10-15 h after CTX administration, which coincided with development of hyperglycemia despite hyperinsulinimia, increased plasma free fatty acid levels, increased adenosine 3',5'-cyclic monophosphate (cAMP) concentrations in muscle, but no difference in plasma catecholamines. Twenty-five hours after CTX treatment, GLUT-4 protein in both soleus and red gastrocnemius muscles was decreased, whereas no change in GLUT-1 protein content was found. In contrast, GLUT-4 mRNA was unchanged, but transcripts for GLUT-1 were increased > or = 150% in all three muscles from CTX-treated rats. The findings suggest that CTX via increased cAMP impairs basal as well as insulin- and contraction-stimulated muscle glucose transport, at least in part from a decrease in intramuscular GLUT-4 protein.


[Carinal resection of bronchogenic carcinoma].
Carinal resection was performed in 10 cases of bronchogenic carcinoma during 12 year-period. The mean age of patients was 58 years, with a range of 42 to 68 years. There were 7 male and 3 female. The tumor was located on the right side in 7 cases, on the left side in 1 case on the carina in 2 cases. The histological examination showed squamous cell carcinoma in 5 cases, adenocarcinoma in 4 cases and adenoid cystic carcinoma in 1 case. The staging revealed T3N2 M0 Stage IIIA in 2 cases, T4N0M0 Stage IIIB in 1 case, T4N1M0 Stage IIIB in 1 case, T4N2M0 Stage IIIB in 5 cases and T4N3M0 Stage IIIB in 1 case. The surgical methods were as follows; sleeve pneumonectomy in 5 cases, wedge carinal resection with pulmonary resection in 3 cases (right sleeve upper lobectomy in 2 cases and right pneumonectomy in 1 case), carinal resection in 2 cases. The site of bronchial anastomosis was overlapped by thymus in 6 cases. The 30-day mortality rate in tracheo-carinal resection was 10% (one patient). Eight patients died and remaining 2 patients are still alive without any evidence of recurrence. 5-year survival rate was 36%. These outcomes were almost equal to those of surgical case in the same stage.


Safety assessment of the substance silver nanoparticles for use in food contact materials.
The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the additive silver nanoparticles intended to be used in plastics. All the silver particles are in the size range of 1-100 nm, with about 15 nm mean diameter and 99% by number of particles below 20 nm. The additive is intended to be used as a surface biocide at up to 0.025% w/w in non-polar plastics for contact with a wide variety of foods, times, temperatures and food contact surface/mass of food ratios. The particulate form is maintained when the additive is incorporated into plastics, albeit with some aggregation/agglomeration observed. The data and information on theoretical considerations, on specific migration and abrasion tests show that, under the intended and tested conditions of uses, the silver nanoparticles stay embedded in the polymer, do not migrate and resist release by abrasion, thus, do not give rise to exposure via food and to toxicological concern. There is migration of silver in soluble ionic form up to 6 μg/kg food from the surface of the additive particles. This is below the group restriction of 50 μg silver/kg food proposed by the AFC Panel in 2004 and would lead to a maximum exposure from FCM that would be below the acceptable daily intake (ADI) of 0.9 μg silver ions/kg body weight (bw) per day established by ECHA. Therefore, the Panel concluded that the substance does not raise safety concern for the consumer if used as an additive at up to 0.025% w/w in polymers, such as polyolefins, polyesters and styrenics, that do not swell in contact with aqueous foods and food simulants. The Panel noted, however, that exposure to silver from other sources of dietary exposure may exceed the ADI set by ECHA.


Acute kidney injury after percutaneous nephrolithotomy for stones in solitary kidneys.
The aim of this study was to report the incidence, severity, outcome and risk factors of acute kidney injury (AKI) following percutaneous nephrolithotomy (PNL) in solitary kidneys. The study included consecutive adult patients who underwent PNL for treatment of calculi in a solitary kidney between May 2012 and July 2015. Patients with congenital renal anomalies or with stages 4 and 5 chronic kidney disease (CKD) were excluded. Serum creatinine levels were measured the day before PNL, daily after PNL for 2-5 days and after 3 months. AKI was depicted according to changes in early postoperative serum creatinine levels and its severity was determined based on the Acute Kidney Injury Network (AKIN) classification. The outcome of AKI was evaluated after 3 months by changes in the stage of CKD. Univariate and multivariate statistical analyses were conducted to determine risk factors for developing AKI. The study included 100 patients (62 males) with a mean ± SD age of 50 ± 11.7 years. Complications were reported for 27 patients. AKI developed in 25 patients; at the 3 month follow-up, 23 of them (92%) had completely recovered from AKI and two (8%) had developed stage 4 CKD. Independent risk factors for developing AKI were multiple PNL tracts and postoperative ureteric obstruction (relative risks were 14 and 22, respectively). The incidence of AKI was 25% after PNL for a solitary kidney. The likelihood of renal function recovery was 92%. Multiple PNL tracts and postoperative ureteric obstruction were risk factors for developing AKI.


[Respiratory symptoms and functions in tea workers].
Respiratory symptoms and function tests were studied in tea workers and in a control group. The prevalance of acute and chronic respiratory symptoms were not different in two groups except for an acute burning sensation of eye-nose-throat and a chronic cough. Also the comparison of the respiratory function tests between tea workers (both smokers and nonsmokers) and the controls were not different at preshift and postshift 30th minute and 8th hour. When preshift and postshift results were compared in tea workers (both in smokers and nonsmokers); statistically significant reductions of FEV1, FEV1/FVC, FEF25-75 and FEF25 were seen at the postshift values. However statistically significant reductions were not observed in controls. Thus we conclude acute tea dust exposure may cause bronchial obstruction particularly in small airways.


A perspective on the enabling technologies of explainable AI-based industrial packetized energy management.
This paper reviews the key information and communication technologies that are necessary to build an effective industrial energy management system considering the intermittence of renewable sources like wind and solar †. In particular, we first introduce the concept of software-defined energy networks in the context of industrial cyber-physical systems aiming at the optimal energy resource allocation in terms of its environmental impact. The task is formulated as a dynamic scheduling problem where supply and demand must match at minute-level timescale, also considering energy storage units. The use of (explainable and trustworthy) artificial intelligence (AI), (informative) networked data, demand-side management, machine-type (wireless) communications, and energy-aware scheduling in industrial plants are explored in detail. The paper also provides a framework for understanding the complexities of managing renewable energy sources in industrial plants while maintaining efficiency and environmental sustainability.


Ensuring right to organic food in public health system.
Introduction: Human health directly depends on safety and quality of food. In turn, quality and safety of food directly depend on its production conditions and methods. There are two main food production methods: traditional and organic. Organic food production is considered safer and more beneficial for human health. Aim: to determine whether the organic food production method affects human health. Materials and methods: international acts, data of international organizations and conclusions of scientists have been examined and used in the study. The article also summarizes information from scientific journals and monographs from a medical and legal point of view with scientific methods. This article is based on dialectical, comparative, analytic, synthetic and comprehensive research methods. The problems of effects of food production methods and conditions on human health have been analyzed within the framework of the system approach. Conclusions: Food production methods and conditions ultimately affect the state and level of human health. The organic method of production activity has a positive effect on human health.


Gender Differences in Relations of Smoking Status, Depression, and Suicidality in Korea: Findings from the Korea National Health and Nutrition Examination Survey 2008-2012.
As mental health problems may play an important role in initiating and maintaining cigarette smoking in females and there are an increasing number of female smokers, we evaluated the relationship between smoking status and mental health problems including depression and suicide ideation in women in Korea. We analyzed the 5-year cumulative data (19 years of age or older, n=32,184) from the Korean National Health and Nutrition Examination Survey (KNHANES) conducted from 2008 to 2012. Logistic regression analyses were used to evaluate associations between cigarette smoking status and mental health parameters while controlling for potentially confounding variables. Among current smokers, females showed higher lifetime prevalence in having a depressive episode, a doctor-diagnosed major depression, a current diagnosis of depression, or receiving treatment for depression in comparison with males. In addition, females were more likely to report on having a depressive episode, suicidal ideation and attempts, and psychiatric counselling within the previous year, as compared to males. Female former smokers showed intermediate characteristics in parameters of mental health status within the previous year, ranking between lifetime non-smokers and the current smokers. Identifying the factors related to mental health status among current smokers can increase opportunities for an early intervention and help reduce the prevalence of smoking and increase smoking cessation rates particularly in females. Developing adaptive coping strategies other than smoking in female youth is potentially important in reducing the initiation of smoking.


Clusterin is a potential lymphotoxin beta receptor target that is upregulated and accumulates in germinal centers of mouse spleen during immune response.
Clusterin is a multifunctional protein that participates in tissue remodeling, apoptosis, lipid transport, complement-mediated cell lysis and serves as an extracellular chaperone. The role of clusterin in cancer and neurodegeneration has been extensively studied, however little is known about its functions in the immune system. Using expression profiling we found that clusterin mRNA is considerably down-regulated in mouse spleen stroma upon knock-out of lymphotoxin β receptor which plays pivotal role in secondary lymphoid organ development, maintenance and function. Using immunohistochemistry and western blot we studied clusterin protein level and distribution in mouse spleen and mesenteric lymph nodes in steady state and upon immunization with sheep red blood cells. We showed that clusterin protein, represented mainly by the secreted heterodimeric form, is present in all stromal compartments of secondary lymphoid organs except for marginal reticular cells. Clusterin protein level rose after immunization and accumulated in light zones of germinal centers in spleen--the effect that was not observed in lymph nodes. Regulation of clusterin expression by the lymphotoxin beta signaling pathway and its protein dynamics during immune response suggest a specific role of this enigmatic protein in the immune system that needs further study.


Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant.
Myxofibrosarcoma is one of the most common sarcomas in the extremities of elderly patients. We analysed the clinicopathologic features in a series of 75 patients. All patients were adults (range, 22-91 years; median, 66 years) with an approximately equal incidence in men and women. Thirty-five tumors arose in the lower and 25 in the upper extremities, nine on the trunk, two each in the retroperitoneum and the head and neck region, and one each in the pelvis and penis. Forty-eight cases (69.5%) were located in dermal or subcutaneous tissues. Distinctive histologic features included the following: a commonly nodular growth pattern; a myxoid matrix containing elongated, curvilinear capillaries; and fusiform, round or stellate tumor cells with indistinct cell margins, slightly eosinophilic cytoplasm, and hyperchromatic atypical nuclei. These lesions varied from a hypocellular, mainly myxoid, and purely spindle-cell appearance (low-grade neoplasms) to high-grade, pleomorphic (malignant fibrous histiocytoma-like) lesions with multinucleated giant cells, high mitotic activity, and areas of necrosis. Immunohistochemistry in 44 cases revealed only vimentin and occasional actin positivity. Ultrastructurally, tumor cells had a fibroblastic phenotype. DNA flow cytometry and proliferation analysis showed an association between aneuploidy and histologic grade. An average follow-up of 45 months (range, 5-300 months) in 60 cases has revealed local recurrence in 33 cases (54%). Thirteen patients developed metastases, and 13 tumor-related deaths occurred. A short interval to first local recurrence was associated with poor clinical outcome. The rate of local recurrence was independent of histologic grade, but only intermediate and high-grade neoplasms metastasized. The depth of the primary lesion did not influence the incidence of local recurrence. However, in deep-seated neoplasms, the incidence of metastases was higher and the percentage of tumor-related deaths was twice as high as in superficially located lesions, reflecting the fact that deep-seated lesions tended to be higher-grade, larger tumors. Myxofibrosarcoma tends to become progressively higher grade in recurrences, as demonstrated in five cases in our series. The poorly recognized low-grade myxofibrosarcoma is emphasized, as proper diagnosis and treatment and scrupulous follow-up are mandatory to avoid local recurrence and gradual tumor progression to a higher-grade neoplasm that may then metastasize.


Cranial Autonomic Symptoms of Migraine in Japan: Prospective Study of 373 Migraine Patients at a Tertiary Headache Center.
To clarify the detailed clinical characteristics of cranial autonomic symptoms (CAS) of Japanese patients with migraine and to get insight into the pathophysiological implications. Recent studies reported that CAS in migraine is causing diagnostic confusion with cluster headache or sinus headache; however, most reports have concerned Caucasians, and Asian data are scarce. The regional differences in the clinical characteristics of primary headaches between Caucasians and Asians have also been revealed recently. This was a cross-sectional study. We investigated 373 patients with migraine in a tertiary headache center with face-to-face interviews. According to our findings, 158/373 (42.4%) patients with migraine had CAS and were characterized by more frequent cutaneous allodynia than those without CAS, suggesting the contribution of central sensitization; however, there were no statistically significant differences in pulsating pain or motion sensitivity as signs of peripheral sensitization. In contrast to the previous study, osmophobia was found to be significantly related to CAS. CAS in patients with migraine is common not only in Caucasians but also in Asians. Central sensitization seems to contribute more than peripheral sensitization to CAS manifestation, and osmophobia might be noteworthy among Asian patients with migraine. To avoid a misdiagnosis, we emphasize the need for comments on CAS in the international classification of headache disorders migraine criteria.


Functional dissociation of behavioral effects from acetylcholine and glutamate released from cholinergic striatal interneurons.
In the striatum, cholinergic interneurons (CINs) have the ability to release both acetylcholine and glutamate, due to the expression of the vesicular acetylcholine transporter (VAChT) and the vesicular glutamate transporter 3 (VGLUT3). However, the relationship these neurotransmitters have in the regulation of behavior is not fully understood. Here we used reward-based touchscreen tests in mice to assess the individual and combined contributions of acetylcholine/glutamate co-transmission in behavior. We found that reduced levels of the VAChT from CINs negatively impacted dopamine signalling in response to reward, and disrupted complex responses in a sequential chain of events. In contrast, diminished VGLUT3 levels had somewhat opposite effects. When mutant mice were treated with haloperidol in a cue-based task, the drug did not affect the performance of VAChT mutant mice, whereas VGLUT3 mutant mice were highly sensitive to haloperidol. In mice where both vesicular transporters were deleted from CINs, we observed altered reward-evoked dopaminergic signalling and behavioral deficits that resemble, but were worse, than those in mice with specific loss of VAChT alone. These results demonstrate that the ability to secrete two different neurotransmitters allows CINs to exert complex modulation of a wide range of behaviors.


Testicular protective effects of ellagic acid on monosodium glutamate-induced testicular structural alterations in male rats.
Ellagic acid (EA) has significant protective and antioxidant effects on several tissues. Monosodium glutamate (MG) is known as a flavor promoter that reversibly influences the male reproductive system. This study aims to assess the ameliorative effect of EA on oxidative stress and testicular damage induced by MG. In total, 48 male rats were included in this study and separated into six groups: control, EA (20 mg/kg), MG (low dose) (17.5 mg/kg), MG (high dose) (60 mg/kg), MG (low dose) combined with EA, and MG (high dose) combined with EA. Testicular antioxidant biomarkers [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRx), catalase (CAT), myeloperoxidase (MPO), and xanthine oxidase (XO)] were examined. Testes were examined and scored for histological variation as an indicator of testicular damage following administration of MG alone or in combination with EA. Serum testosterone, inhibin B, 8-hydroxydeoxyguanosine (as a marker of DNA damage), and transmission electron microscope sections of the testis were evaluated, and a comet assay was performed. Results showed that administration of EA combined with MG significantly elevated the levels of enzymatic antioxidants and decreased lipid peroxidation compared with MG treatment alone. EA elevated testosterone hormone levels and thus enhanced male reproductive capacity. It is clear from the data that EA inhibits histological and ultrastructure testicular damage and improves the redox state in male rats.


Update: Interim Guidance for the Diagnosis, Evaluation, and Management of Infants with Possible Congenital Zika Virus Infection - United States, October 2017.
CDC has updated its interim guidance for U.S. health care providers caring for infants with possible congenital Zika virus infection (1) in response to recently published updated guidance for health care providers caring for pregnant women with possible Zika virus exposure (2), unknown sensitivity and specificity of currently available diagnostic tests for congenital Zika virus infection, and recognition of additional clinical findings associated with congenital Zika virus infection. All infants born to mothers with possible Zika virus exposure* during pregnancy should receive a standard evaluation at birth and at each subsequent well-child visit including a comprehensive physical examination, age-appropriate vision screening and developmental monitoring and screening using validated tools (3-5), and newborn hearing screen at birth, preferably using auditory brainstem response (ABR) methodology (6). Specific guidance for laboratory testing and clinical evaluation are provided for three clinical scenarios in the setting of possible maternal Zika virus exposure: 1) infants with clinical findings consistent with congenital Zika syndrome regardless of maternal testing results, 2) infants without clinical findings consistent with congenital Zika syndrome who were born to mothers with laboratory evidence of possible Zika virus infection,† and 3) infants without clinical findings consistent with congenital Zika syndrome who were born to mothers without laboratory evidence of possible Zika virus infection. Infants in the first two scenarios should receive further testing and evaluation for Zika virus, whereas for the third group, further testing and clinical evaluation for Zika virus are not recommended. Health care providers should remain alert for abnormal findings (e.g., postnatal-onset microcephaly and eye abnormalities without microcephaly) in infants with possible congenital Zika virus exposure without apparent abnormalities at birth.


A rough sets approach to patient classification in medical records.
This study used the original model of rough sets for data analysis of objective clinical findings from pneumonia patients. Rough sets data analysis was used to draw data dependencies, data reductions, approximate set classifications, and rule inductions from records in a clinical database. This study utilized Pawlak's rough classification algorithm [1] to examine the relationship between a constellation of findings and the ICD-9-CM classification scheme used for disease coding in order to generate a reduct. The reduct is a logical construct of the most information-preserving findings from a decision table. The Iliad expert system, which is based on Bayes Theorem, was used to validate the results we obtained using rough sets analysis to discriminate between the different types of pneumonia in the patient population. From a set of 25 objective clinical findings, chosen because they had a positive or negative predictive value for probability of death for pneumonia patients, the rough sets analysis constructed a logical classifier of six attributes that was as discriminatory as the statistical classifier in Iliad which utilized 11 of those 25 attributes. The rough sets methods are capable of identifying a minimal set of attribute values that are associated with a disease label. These methods could be applied to develop more consistent labeling methods, and, potentially flag activities which do not contribute to diagnostic labeling or health results.


Vestibulo-ocular responses to vertical translation in normal human subjects.
Prior studies of the human translational vestibulo-ocular reflex (tVOR) report that eye rotations amount to less than 60% of those required to keep the eyes pointed at a stationary visual target, unlike the angular VOR (aVOR) which is optimized to maintain stable gaze. Our first goal was to determine if the performance of the tVOR improves when head translations are combined with head rotations in ambient lighting. A second goal was to measure tVOR during vertical head translations (bob), which has not received systematic study. We measured tVOR alone and in combination with the aVOR in 20 normal human subjects, aged 25-72 years, as they sat on a moving platform that bobbed at 2.0 Hz while rotating horizontally (yaw) at 1.0 Hz. When subjects viewed a visual target at 2 m, median "compensation gain" (eye rotational velocity/required eye rotational velocity to maintain foveal target fixation) was 0.52 during pure bob and 0.59 during combined bob-yaw; during viewing of a near target at approximately 17 cm, compensation gain was 0.58 for pure bob and 0.60 for combined bob-yaw. Mean phase lag of eye-in-head velocity for the tVOR was approximately 19 degrees with respect to the ideal compensatory response, irrespective of whether translation was accompanied by rotation. Thus, the tVOR changed only slightly during translation-rotation versus pure translation, and our subjects' ocular rotations remained at about 60% of those required to point the eyes at the target. Comparison of response during binocular or monocular viewing, and ambient or reduced illumination, indicated that relative image motion between the target and background was an important determinant of tVOR behavior. We postulate that tVOR evolved not to stabilize the image of the target on the fovea, but rather to minimize retinal image motion between objects lying in different planes, in order to optimize motion parallax information.


Ties in proximity and clustering compounds.
Hierarchical clustering algorithms such as Wards or complete-link are commonly used in compound selection and diversity analysis. Many such applications utilize binary representations of chemical structures, such as MACCS keys or Daylight fingerprints, and dissimilarity measures, such as the Euclidean or the Soergel measure. However, hierarchical clustering algorithms can generate ambiguous results owing to what is known in the cluster analysis literature as the ties in proximity problem, i.e., compounds or clusters of compounds that are equidistant from a compound or cluster in a given collection. Ambiguous ties can occur when clustering only a few hundred compounds, and the larger the number of compounds to be clustered, the greater the chance for significant ambiguity. Namely, as the number of "ties in proximity" increases relative to the total number of proximities, the possibility of ambiguity also increases. To ensure that there are no ambiguous ties, we show by a probabilistic argument that the number of compounds needs to be less than 2(n 1/4), where n is the total number of proximities, and the measure used to generate the proximities creates a uniform distribution without statistically preferred values. The common measures do not produce uniformly distributed proximities, but rather statistically preferred values that tend to increase the number of ties in proximity. Hence, the number of possible proximities and the distribution of statistically preferred values of a similarity measure, given a bit vector representation of a specific length, are directly related to the number of ties in proximities for a given data set. We explore the ties in proximity problem, using a number of chemical collections with varying degrees of diversity, given several common similarity measures and clustering algorithms. Our results are consistent with our probabilistic argument and show that this problem is significant for relatively small compound sets.


Existing FDA pathways have potential to ensure early access to, and appropriate use of, specialty drugs.
Specialty drugs are notable among prescription drugs in that they offer the possibility of substantial clinical improvement, come with important risks of adverse events and mortality, can be complex to manufacture or administer, and are usually extremely costly. The Food and Drug Administration (FDA) plays a critical role in ensuring that patients who could benefit from specialty drugs have access to them in a timely fashion. In this article we review the different strategies that the FDA can use to approve and influence the post-approval prescribing of specialty drugs. When specialty drugs show promise in early clinical trials, the FDA can expedite the drugs' availability to patients through expanded access programs and expedited approval pathways that speed regulatory authorization. After approval, to ensure that specialty drugs are directed to the patients who are most likely to benefit from them, the FDA can limit the scope of the drugs' indications, encourage the development of companion diagnostic tests to indicate which patients should receive the drugs, or require that manufacturers subject them to Risk Evaluation and Mitigation Strategies to ensure that their use is appropriately limited to a restricted population that is aware of the drugs' risks and benefits. Implementing these existing regulatory approaches can promote timely patient access to specialty drugs while preventing expensive and potentially inappropriate overuse.


A putative "chemokine switch" that regulates systemic acute inflammation in humans.
Systemic inflammation is complex and likely drives clinical outcomes in critical illness such as that which ensues following severe injury. We obtained time course data on multiple inflammatory mediators in the blood of blunt trauma patients. Using dynamic network analyses, we inferred a novel control architecture for systemic inflammation: a three-way switch comprising the chemokines MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10. To test this hypothesis, we created a logical model comprising this putative architecture. This model predicted key qualitative features of systemic inflammation in patient sub-groups, as well as the different patterns of hospital discharge of moderately vs. severely injured patients. Thus, a rational transition from data to data-driven models to mechanistic models suggests a novel, chemokine-based mechanism for control of acute inflammation in humans and points to the potential utility of this workflow in defining novel features in other complex diseases.


Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway.
Osteoporosis is a systemic metabolic bone disorder for which inflammatory cytokines play an important role. To develop new osteoporosis treatments, strategies for improving the microenvironment for osteoblast and osteoclast balance are needed. Tumor necrosis factor-α (TNF-α) plays an important role in the initiation and development of osteoporosis. Atsttrin is an engineered protein derived from the growth factor, progranulin (PGRN). The present study investigates whether Atsttrin affects osteoclast formation and osteoblast formation. Here we show Atsttrin inhibits TNF-α-induced osteoclastogenesis and inflammation. Further mechanistic investigation indicates Atsttrin inhibits TNF-α-induced osteoclastogenesis through the TNFR1 signaling pathway. Moreover, Atsttrin rescues TNF-α-mediated inhibition of osteoblastogenesis via the TNFR1 pathway. Importantly, the present study indicates that while Atsttrin cannot directly induce osteoblastogenesis, it can significantly enhance osteoblastogenesis through TNFR2-Akt-Erk1/2 signaling. These results suggest that Atsttrin treatment could potentially be a strategy for maintaining proper bone homeostasis by regulating the osteoclast/osteoblast balance. Additionally, these results provide new insights for other bone metabolism-related diseases.