Comparison of performance parameters of photothermal procedures in homogeneous and heterogeneous systems.
The main types of analytical procedures used in thermal-lens spectroscopy and microscopy, which are based on photometric reactions in (i) aqueous solutions, (ii) organo-aqueous mixtures, (iii) polymer-containing (nonionic surfactants or polyethylene glycol) aqueous solutions, (iv) water-organic extraction systems, and (v) two-phase aqueous extraction systems, were compared from the viewpoint of both reproducibility and sensitivity. This comparison was made by examples of the determination of cobalt and iron for batch conditions, flow determination, and detection in HPLC, flow-injection analysis (FIA), and µFIA. It was revealed that for all five types, the real analytical efficiency (a decrease in the limit of detection (LOD) as compared to spectrophotometry) is primarily determined by the reaction conditions, provided that excitation of the thermal lens is the same. Aqueous solutions provide more efficient optimization of reaction conditions than do those in organo-aqueous solutions and solvent-extraction water-organic mixtures. The best results are achieved when shifting to polymer-containing aqueous solutions and two-phase aqueous extraction systems, which decreases in the LODs by a factor of 20 - 100%.


On the mechanisms of the antitumor effects of interferon.
The effect of interferon in animals infected with some oncogenic viruses can be attributed to inhibition of viral replication or inhibition of the early events following viral infection. In those experimental systems in which continued administration of interferon proved effective after inoculation of oncogenic viruses, the effect may be due in part to an antiviral effect and in part to a direct action of interferon on the multiplication of precursor cells or tumor cells themselves. In animals bearing autochthonous tumors or grafted with transplantable tumors, the effects appear to be due in part to a a direct inhibition of the multiplication of the tumor cell (or an effect on the behavior of these tumor cells) and in part to an effect on the host - the nature of which remains to be defined. We must learn more of the interaction of interferon with host cells and understand how so many apparently different effects are triggered by this "polypractic substance" (6) before we can clarify the mechanism by which interferon can confer protection on animals infested with viruses, protozoa, or tumor cells.


A complicated incomplete syndactylism.
Surgical desyndactylism is reviewed. A case report of an incomplete, complicated syndactylism and its surgical treatment is presented. The operative method consists of a commissure created by a dorsal V-flap with removal of abnormal bone and closure without grafting.


[Scientific production in international journals by Acta Médica Portuguesa authors].
Local and national scientific journals have been widely criticized by some authors. Additionally, they are quite rarely indexed at international databases, which results in a reduced visibility of their articles. To analyze international scientific productions of authors publishing in Acta Medica Portuguesa during 2008. A database with all the authors publishing in Acta Medica Portuguesa in 2008 was built. In July 2009, production of all those authors from the previous five years (2003-2007) was retrieved from Science Citation Index. Journals where they published, Impact Factors of those journals, articles' references, and times cited were analyzed. The 78 articles published by Acta Medica Portuguesa in 2008 were produced by 259 different authors. Ninety four (36.3%) of those authors wrote 420 articles from 2003 to 2007 indexed at Science Citation Index. These articles were published in 249 different journals, with an average Impact Factor of 2.973 (SD = 2.92). Journal with highest Impact Factor was The Lancet (IF2008 = 28.409) with two papers published. Eighty seven of those authors received some citation to their articles, with a total amount of 5001 cites. Out of the 14035 references on those 420 articles, only 10 cited any article published in Acta Médica Portuguesa. Authors publishing in Acta Médica Portuguesa produce a good amount of international publications in journals with an acceptable Impact Factor and they receive quite a good number of citations. Conversely, these authors when publishing in international journals have an extremely low citation of articles published in Acta Médica Portuguesa.


Parasite-accessory cell interactions in murine leishmaniasis. II. Leishmania donovani suppresses macrophage expression of class I and class II major histocompatibility complex gene products.
In the present study, we examined the modulation of MHC class II and class I gene products on BALB/c macrophages infected with the obligate intracellular protozoan Leishmania donovani. Our findings indicated that this organism suppressed macrophage expression of both classes of MHC antigens. These effects varied somewhat, depending on whether cells were in the basal state or were stimulated with interferon-gamma. Thus, class II density on interferon-gamma-treated infected macrophages was suppressed by as much as 90%, relative to lymphokine-stimulated control cells. Induction of H-2K and H-2D by lymphokine treatment of infected macrophages was also markedly reduced. In the basal (non-lymphokine-treated) state, infected cells also showed reduced expression of H-2K and H-2D, but not I-A or I-E. The latter result was related to minimal levels of class II molecules on normal, in vitro cultured macrophages. Suppression of MHC gene products correlated with both the duration and intensity of leishmania infection and could not be overcome by increasing doses of interferon-gamma. Culture of cells under conditions of cyclooxygenase inhibition completely abolished elevated synthesis of prostaglandin E2 by infected macrophages and augmented their responsiveness to lymphokine induction of class II antigens by 60 to 80%. These results indicate that L. donovani is capable of subverting a critical macrophage accessory function required for the induction of T lymphocyte immunity. This mechanism could account, at least in part, for defective parasite-specific cell-mediated immunity seen during infections with this protozoan.


Ashkenazi Jewish population frequency of the Bloom syndrome gene 2281 delta 6ins7 mutation.
Bloom syndrome is an autosomal recessive disorder characterized clinically by small size, sun-sensitive facial erythema, and immunodeficiency, and cytogenetically by increased chromosome breakage and sister chromatid exchange. Genomic instability renders Bloom syndrome patients at elevated risk for multiple cancers. Bloom syndrome occurs most commonly in the Ashkenazi Jewish population due to an apparent founder effect. The BLM gene on chromosome 15q26.1 was identified to encode a RecQ DNA helicase. Multiple mutations were identified, with Ashkenazi Jewish Bloom syndrome patients almost exclusively homozygous for a complex frameshift mutation (6-bp deletion/7-bp insertion at BLM nucleotide 2,281). This molecular genetic study seeks to verify the Ashkenazi Jewish carrier frequency of the BLM 2281 delta 6ins7 allele using semiautomated allele-specific oligonucleotide (ASO) analysis. Anonymized DNA samples from 1,016 Ashkenazi Jewish individuals and 307 non-Jewish individuals were screened. Ten Ashkenazi heterozygote carriers for the 2281 delta 6ins7 mutation were identified, giving a carrier frequency estimate of 0.98%, or approximately 1 carrier out of 102 individuals in the Ashkenazi Jewish population. These results are consistent with previous estimates, and combining our findings with the published molecular data collectively yields an Ashkenazi Jewish carrier frequency of approximately 1 in 104. Given its high population frequency and detection rate among Ashkenazi Jewish patients, the blmAsh mutation constitutes an appropriate addition to screening panels for Ashkenazi Jewish disease testing.


Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis.
This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models-S. cerevisiae, five cancer cell lines, and the parasite L. mexicana-were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.


Progress bias versus status quo bias in the ethics of emerging science and technology.
How should we handle ethical issues related to emerging science and technology in a rational way? This is a crucial issue in our time. On the one hand, there is great optimism with respect to technology. On the other, there is pessimism. As both perspectives are based on scarce evidence, they may appear speculative and irrational. Against the pessimistic perspective to emerging technology, it has been forcefully argued that there is a status quo bias (SQB) fuelling irrational attitudes to emergent science and technology and greatly hampering useful development and implementation. Therefore, this article starts by analysing the SQB using human enhancement as a case study. It reveals that SQB may not be as prominent in restricting the implementation of emergent technologies as claimed in the ethics literature, because SQB (a) is fuelled by other and weaker drivers than those addressed in the literature, (b) is at best one amongst many drivers of attitudes towards emergent science and technology, and (c) may not be a particularly prominent driver of irrational decision-making. While recognizing that SQB can be one driver behind pessimism, this article investigates other and counteracting forces that may be as strong as SQB. Progress bias is suggested as a generic term for the various drivers of unwarranted science and technology optimism. Based on this analysis, a test for avoiding or reducing this progress bias is proposed. Accordingly, we should recognize and avoid a broad range of biases in the assessment of emerging and existing science and technology in order to promote an open and transparent deliberation.


Consistency across repeated eyewitness interviews: contrasting police detectives' beliefs with actual eyewitness performance.
In the legal system, inconsistencies in eyewitness accounts are often used to discredit witnesses' credibility. This is at odds with research findings showing that witnesses frequently report reminiscent details (details previously unrecalled) at an accuracy rate that is nearly as high as for consistently recalled information. The present study sought to put the validity of beliefs about recall consistency to a test by directly comparing them with actual memory performance in two recall attempts. All participants watched a film of a staged theft. Subsequently, the memory group (N = 84) provided one statement immediately after the film (either with the Self-Administered Interview or free recall) and one after a one-week delay. The estimation group (N = 81) consisting of experienced police detectives estimated the recall performance of the memory group. The results showed that actual recall performance was consistently underestimated. Also, a sharp decline of memory performance between recall attempts was assumed by the estimation group whereas actual accuracy remained stable. While reminiscent details were almost as accurate as consistent details, they were estimated to be much less accurate than consistent information and as inaccurate as direct contradictions. The police detectives expressed a great concern that reminiscence was the result of suggestive external influences. In conclusion, it seems that experienced police detectives hold many implicit beliefs about recall consistency that do not correspond with actual recall performance. Recommendations for police trainings are provided. These aim at fostering a differentiated view on eyewitness performance and the inclusion of more comprehensive classes on human memory structure.


Steroid therapy of chronic hepatitis: characteristics associated with response in anti-hepatitis C virus-positive and -negative patients.
The goals of this study were to examine responses to corticosteroid-containing therapy in non-B chronic hepatitis patients with different anti-hepatitis C virus (HCV), autoantibody, and biochemical test results and to determine what factors correlate with response. Patients with a prior or current history of steroid therapy for putative autoimmune or chronic non-A, non-B hepatitis were assessed. Responses during the first 6 months of therapy were categorized as "complete" (normal aminotransferases for > or = 1 month), "partial" ( > 50% reduction), or "no response." Sufficient data available to permit evaluation in 32 patients. Complete responses were noted in 17, partial responses in 12, and no response in three subjects. By multivariate analysis, only absence of anti-HCV and presence of cirrhosis were independent predictors of response. Nonresponders were found to have lower scores in a proposed autoimmune hepatitis scoring system, but scores of complete and partial responders were not significantly different. Despite a lower likelihood of a complete response, 80% (12/15) of patients with multiantigen positive anti-HCV tests had either partial or complete initial responses to corticosteroid-containing therapy, and, in nine patients, aminotransferases fell to < 2 times the upper limit of normal. All 15 anti-HCV-negative patients, but only three of 15 anti-HCV-positive patients, entered complete responses that were sustained (aminotransferases < twofold abnormal) on regimens containing < 20 mg/day or prednisolone or prednisone. Although anti-HCV-positive patients frequently exhibit partial initial responses to immunosuppressive therapy, the absence of specific anti-HCV antibodies was better as a predictor of completeness of response than assessment of autoantibodies or degree of biochemical abnormalities.


Vibration Monitoring Using Fiber Optic Sensors in a Lead-Bismuth Eutectic Cooled Nuclear Fuel Assembly.
Excessive fuel assembly vibrations in nuclear reactor cores should be avoided in order not to compromise the lifetime of the assembly and in order to prevent the occurrence of safety hazards. This issue is particularly relevant to new reactor designs that use liquid metal coolants, such as, for example, a molten lead-bismuth eutectic. The flow of molten heavy metal around and through the fuel assembly may cause the latter to vibrate and hence suffer degradation as a result of, for example, fretting wear or mechanical fatigue. In this paper, we demonstrate the use of optical fiber sensors to measure the fuel assembly vibration in a lead-bismuth eutectic cooled installation which can be used as input to assess vibration-related safety hazards. We show that the vibration characteristics of the fuel pins in the fuel assembly can be experimentally determined with minimal intrusiveness and with high precision owing to the small dimensions and properties of the sensors. In particular, we were able to record local strain level differences of about 0.2 μϵ allowing us to reliably estimate the vibration amplitudes and modal parameters of the fuel assembly based on optical fiber sensor readings during different stages of the operation of the facility, including the onset of the coolant circulation and steady-state operation.


[Digestive tract hemorrhage and recurrent ileus. Peutz-Jeghers syndrome-case report].
Authors describe a case of 24 years old woman with recurrent lower GI bleeding and mechanical obstruction. Crohn's disease was diagnosed at the beginning. It was impossible to treat the patient's profound anemia with blood transfusions due to her religion believes. The diagnosis of Peutz-Jeghers syndrome was made postoperatively. During operation mechanical obstruction (invagination of terminal ileum into ascending colon) was released. The invagination was caused by 3 cm large polyp localized in terminal ileum. Subsequently, 8 polyps (varying in size between 0.5 and 3 cm) in the small intestine were localized using intraoperative upper GI endoscopy and enteroscopy and finally surgically removed. Typical hamartomas were found on histopathological examination of removed polyps. Authors present modern attitude to Peutz-Jeghers syndrome--its diagnostics, treatment and follow-up.


Human CtIP mediates cell cycle control of DNA end resection and double strand break repair.
In G(0) and G(1), DNA double strand breaks are repaired by nonhomologous end joining, whereas in S and G(2), they are also repaired by homologous recombination. The human CtIP protein controls double strand break (DSB) resection, an event that occurs effectively only in S/G(2) and that promotes homologous recombination but not non-homologous end joining. Here, we mutate a highly conserved cyclin-dependent kinase (CDK) target motif in CtIP and reveal that mutating Thr-847 to Ala impairs resection, whereas mutating it to Glu to mimic constitutive phosphorylation does not. Moreover, we show that unlike cells expressing wild-type CtIP, cells expressing the Thr-to-Glu mutant resect DSBs even after CDK inhibition. Finally, we establish that Thr-847 mutations to either Ala or Glu affect DSB repair efficiency, cause hypersensitivity toward DSB-generating agents, and affect the frequency and nature of radiation-induced chromosomal rearrangements. These results suggest that CDK-mediated control of resection in human cells operates by mechanisms similar to those recently established in yeast.


Parental Knowledge and Recall of Concussion Discharge Instructions.
Children increasingly are being seen in the emergency department for a concussion, or mild traumatic brain injury (mTBI). A key aim of the ED visit is to provide discharge advice that can help parents to identify an evolving neurosurgical crisis, facilitate recovery, and prevent reinjury. The present study examined parents' knowledge of symptoms and recall of discharge instructions after their adolescent's mTBI and the effect of supplementing written discharge instructions with verbal instruction and reinforcement. We performed a nested observational study of parents/caregivers of patients who participated in a larger mTBI study. After their adolescent's mTBI, parents were given verbal and standardized written instructions. The ED discharge process was observed using a structured checklist, and parents were surveyed 3 days after discharge on knowledge and recall of discharge instructions. Ninety-three parents completed the postsurvey. Nearly 1 in 5 parents were confused about when to return to the emergency department after evaluation for head injury. Up to 1 in 4 parents could not recall specific discharge advice related to concussion. Parents who received verbal reinforcement of written discharge instructions were more likely to recall them. Emergency nurses and clinicians should strive to utilize both verbal and written discharge instructions with families to help increase understanding.


Fluorescence labelling of NADPH-cytochrome P-450 reductase with the monobromomethyl derivative of syn-9,10-dioxabimane.
The kinetics of thiol-group alkylation in NADPH-cytochrome P-450 reductase during its inactivation by monobromobimane has been studied using the fluorimetric determination of S-bimane-L-cysteine by high-performance liquid chromatography. Loss of activity during the reaction of NADPH-cytochrome P-450 reductase with monobromobimane is caused by the alkylation of one single critical cysteine residue, which can be protected against thiol-specific reagents by NADP(H). The chemical stability of the bimane group allows the digestion of bimane-labelled NADPH-cytochrome P-450 reductase by CNBr. The critical cysteine residue could be located in a CNBr-cleaved peptide purified to homogeneity with Mr 10 500 +/- 1 000 and valine as N-terminus.


Partial inversion of the initiation-promotion sequence of multistage tumorigenesis in the skin of NMRI mice.
Alterations in NMRI mouse skin induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate in "stage I of tumor promotion" are slowly reversible, and this reversibility has a half-time of 10 to 12 weeks. The tumor response observed in the course of an initiation-promotion experiment in vivo is independent of whether stage I of promotion occurs before or after initiation. Since the time interval between treatment with the promoter, and subsequent initiation can be extended up to at least 6 weeks, an enhancement of initiation because of promoter-induced cellular DNA synthesis seems to be unlikely. This result may be inconsistent with the two-stage model of tumor promotion because it indicates that in skin the existence of initiated cells is not required for the induction of cellular alterations that are essential for the stage of skin tumorigenesis called stage I of promotion.


RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities.
In fast neutron therapy, the relative biological effectiveness (RBE) of a given beam varies to a large extent with the neutron energy spectrum. This spectrum depends primarily on the energy of the incident particles and on the nuclear reaction used for neutron production. However, it also depends on other factors which are specific to the local facility, eg, target, collimation system, etc. Therefore direct radiobiological intercomparisons are justified. The present paper reports the results of an intercomparison performed at seven neutrontherapy centres: Orléans, France (p(34)+Be), Riyadh, Saudi Arabia (p(26)+Be), Ghent, Belgium (d(14.5)+Be), Faure, South Africa (p(66)+Be), Detroit, USA (d(48)+Be), Nice, France (p(65)+Be) and Louvain-la-Neuve, Belgium (p(65)+Be). The selected radiobiological system was intestinal crypt regeneration in mice after single fraction irradiation. The observed RBE values (ref cobalt-60 gamma-rays) were 1.79 +/- 0.10, 1.84 +/- 0.07, 2.24 +/- 0.11, 1.55 +/- 0.04, 1.51 +/- 0.03, 1.50 +/- 0.04 and 1.52 +/- 0.04, respectively. When machine availability permitted, additional factors were studied: two vs one fraction (Ghent, Louvain-la-Neuve), dose rate (Detroit), influence of depth in phantom (Faure, Detroit, Nice, Louvain-la-Neuve). In addition, at Orléans and Ghent, RBEs were also determined for LD50 at 6 days after selective abdominal irradiation and were found to be equal to the RBEs for crypt regeneration. The radiobiological intercomparisons were always combined with direct dosimetric intercomparisons and, when possible in some centres, with microdosimetric investigations.


Socio-geographical factors in vulnerability to dengue in Thai villages: a spatial regression analysis.
Focusing on the socio-geographical factors that influence local vulnerability to dengue at the village level, spatial regression methods were applied to analyse, over a 5-year period, the village-specific, cumulative incidence of all reported dengue cases among 437 villages in Prachuap Khiri Khan, a semi-urban province of Thailand. The K-order nearest neighbour method was used to define the range of neighbourhoods. Analysis showed a significant neighbourhood effect (ρ = 0.405, P <0.001), which implies that villages with geographical proximity shared a similar level of vulnerability to dengue. The two independent social factors, associated with a higher incidence of dengue, were a shorter distance to the nearest urban area (β = -0.133, P <0.05) and a smaller average family size (β = -0.102, P <0.05). These results indicate that the trend of increasing dengue occurrence in rural Thailand arose in areas under stronger urban influence rather than in remote rural areas.


Effect of estrogen on serum DHEA in younger and older women and the relationship of DHEA to adiposity and gender.
This case-controlled study consisted of 2 parts. The objective of part 1 was to determine the relationship between DHEA, body mass index (BMI), and age in young males, young females, and postmenopausal (PM) females. Part 2 examined the effects of estrogen on DHEA by analyzing the relationship between DHEA and age in young females on and off oral contraceptives (OCs) and PM females on and off estrogen or hormone replacement therapy (ERT/HRT). The study was performed at the Obstetrics and Gynecology Clinic, Texas Tech Health Sciences Center-Amarillo, Exercise Physiology Laboratory at Southeastern Louisiana University, and Woman's Health Research Institute, Woman's Hospital, Baton Rouge, LA. Part 1 groups consisted of: (1) young males between the ages of 18 to 40 years; (2) normally cycling females off OCs, ages 18 to 40 years; and (3) PM females older than 40 years not receiving ERT/HRT. Part 2 groups consisted of: (1) normally cycling females on OCs, ages 18 to 40 years;, (2) normally cycling females off OCs, ages 18 to 40 years; (3) PM females 50 years or older not receiving ERT/HRT; and (4) PM females 50 years or older receiving ERT/HRT. The main outcome measure was serum DHEA concentrations. For part 1, there were significant (P <.05) inverse relationships between DHEA and age for young males; young females, off OCs; PM females, no ERT/HRT r = -.44, -.26, and -.25, respectively. There were no significant relationships between DHEA and BMI for any of the groups. DHEA concentrations were significantly higher in young males than young females even after accounting for age. For part 2, DHEA concentrations were significantly higher in young females off OCs compared with young females on OCs, and significantly higher in PM women off ERT/HRT than those on ERT\HRT. There were significant inverse relationships between DHEA and age for young females and PM females on and off ERT/HRT. From these findings, we conclude that there is an inverse relationship between DHEA and age for young males, young females off OCs, and PM females, no ERT/HRT. No relationship between BMI and DHEA was observed in these same 3 groups. These results agree with previous findings in young men, but differ from previous findings in obese young females. The data also suggest that estrogen treatment (OCs and ERT/HRT) suppresses DHEA concentrations in premenopausal and PM females, and that DHEA declines with age in PM females regardless of estrogen treatment.


Facial clefts and facial dysplasia: revisiting the classification.
Most craniofacial malformations are identified by their appearance. The majority of the classification systems are mainly clinical or anatomical, not related to the different levels of development of the malformation, and underlying pathology is usually not taken into consideration. In 1976, Tessier first emphasized the relationship between soft tissues and the underlying bone stating that "a fissure of the soft tissue corresponds, as a general rule, with a cleft of the bony structure". He introduced a cleft numbering system around the orbit from 0 to 14 depending on its relationship to the zero line (ie, the vertical midline cleft of the face). The classification, easy to understand, became widely accepted because the recording of the malformations was simple and communication between observers facilitated. It represented a great breakthrough in identifying craniofacial malformations, named clefts by him. In the present paper, the embryological-based classification of craniofacial malformations, proposed in 1983 and in 1990 by us, has been revisited. Its aim was to clarify some unanswered questions regarding apparently atypical or bizarre anomalies and to establish as much as possible the moment when this event occurred. In our opinion, this classification system may well integrate the one proposed by Tessier and tries at the same time to find a correlation between clinical observation and morphogenesis.Terminology is important. The overused term cleft should be reserved to true clefts only, developed from disturbances in the union of the embryonic facial processes, between the lateronasal and maxillary process (or oro-naso-ocular cleft); between the medionasal and maxillary process (or cleft of the lip); between the maxillary processes (or cleft of the palate); and between the maxillary and mandibular process (or macrostomia).For the other types of defects, derived from alteration of bone production centers, the word dysplasia should be used instead. Facial dysplasias have been ranged in a helix form and named after the site of the developmental arrest. Thus, an internasal, nasal, nasomaxillary, maxillary and malar dysplasia, depending on the involved area, have been identified.The classification may provide a useful guide in better understanding the morphogenesis of rare craniofacial malformations.


Four-dimensional dynamics of MAPK information processing systems.
Mitogen activated protein kinase (MAPK) cascades process a myriad of stimuli received by cell-surface receptors and generate precise spatio-temporal guidance for multiple target proteins, dictating receptor-specific cellular outcomes. Computational modelling reveals that the intrinsic topology of MAPK cascades enables them to amplify signal sensitivity and amplitude, reduce noise and display intricate dynamic properties, which include toggle switches, excitation pulses and oscillations. Specificity of signaling responses can be brought about by signal-induced feedback and feedforward wiring imposed on the MAPK cascade backbone. Intracellular gradients of protein activities arise from the spatial separation of opposing reactions in kinase-phosphatase cycles. The membrane confinement of the initiating kinase in MAPK cascades and cytosolic localization of phosphatases can result in precipitous gradients of phosphorylated signal-transducers if they spread solely by diffusion. Endocytotic trafficking of active kinases driven by molecular motors and traveling waves of protein phosphorylation can propagate phosphorylation signals from the plasma membrane to the nucleus, especially in large cells, such as Xenopus eggs.


Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: A case series.
Obtaining a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) can decrease hepatic complications and be curative, however, extrahepatic manifestations including mixed cryoglobulinemia (MCN) may persist with interferon-based therapy. Our objective was to review our experience in treating patients with new oral antiviral agents and to assess common factors associated with MCN persistence despite SVR. We analyzed a case series of five patients with genotype one chronic HCV complicated by MCN who had persistence of cryoglobulins despite completion of triple therapy with oral antiviral agents (boceprivir, telaprivir or sofosbuvir). Patients with cirrhosis appear to have a decreased ability to clear immune complexes. We observed that early viral response by week 8 of therapy and longer periods of undetectable virus on treatment correlated with eventual clearance of serum cryoglobulins in patients without cirrhosis. Two patients were treated with anti-B-cell agent rituximab prior to starting therapy for HCV; this did not lead to a more effective clearance of cryoglobulins. We suggest that a longer treatment course than the standard 24 weeks with triple therapy could aid in the clearance of these immune complexes and cryoglobulins in cirrhotics. More studies to determine the ideal duration of treatment for chronic HCV and coincident MCN are needed, especially in light of the new all oral direct-acting antiviral regimens that are now recommended for HCV treatment.


Emphysematous Cystitis. Case report and imaging features.
Emphysematous cystitis is a rare bacterial infection of the bladder which results in presence of gas in the bladder wall, lumen, and surrounding tissues. The most important factors involved in this disease are diabetes mellitus, dysuria and neurogenic bladder, with predominance of female gender.We present a case of a 64 years old female patient, with diabetes mellitus tip 2, who presented in our emergency department with fever, abdominal complaint, olyguria for the last one month. Abdominal CT (computer tomography) revealed gas in the bladder with thickening of bladder wall and formation of an air-fluid level. Laboratory test showed anemia and leukocytosis. Urine culture showed elevated growth of Escherichia coli (E. coli). The diagnosis was emphysematous cystitis and patient started the antibiotic specific therapy.


Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes.
Suppression of tumor-specific T cell sensitization is a predominant mechanism of tumor escape. To identify tumor-induced suppressor cells, we transferred spleen cells from mice bearing progressive MCA205 sarcoma into sublethally irradiated mice. These mice were then inoculated subdermally with tumor cells to stimulate T cell response in the tumor-draining lymph-node (TDLN). Tumor progression induced splenomegaly with a dramatic increase (22.1%) in CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC) compared with 2.6% of that in normal mice. Analyses of therapeutic effects by the adoptive immunotherapy revealed that the transfer of spleen cells from tumor-bearing mice severely inhibited the generation of tumor-immune T cells in the TDLN. We further identified MDSC to be the dominant suppressor cells. However, cells of identical phenotype from normal spleens lacked the suppressive effects. The suppression was independent of CD4(+)CD25(+) regulatory T cells. Intracellular IFN-gamma staining revealed that the transfer of MDSC resulted in a decrease in numbers of tumor-specific CD4(+) and CD8(+) T cells. Transfer of MDSC from MCA207 tumor-bearing mice also suppressed the MCA205 immune response indicating a lack of immunologic specificity. Further analyses demonstrated that MDSC inhibited T cell activation that was triggered either by anti-CD3 mAb or by tumor cells. However, MDSC did not suppress the function of immune T cells in vivo at the effector phase. Our data provide the first evidence that the systemic transfer of MDSC inhibited and interfered with the sensitization of tumor-specific T cell responses in the TDLN.


Electrocardiographic changes in 1000 highly trained junior elite athletes.
To evaluate the spectrum of electrocardiographic (ECG) changes in 1000 junior (18 or under) elite athletes. A total of 1000 (73% male) junior elite athletes (mean (SD) age 15.7 (1.4) years (range 14-18); mean (SD) body surface area 1.73 (0.17) m2 (range 1.09-2.25)) and 300 non-athletic controls matched for gender, age, and body surface area had a 12 lead ECG examination. Athletes had a significantly higher prevalence of sinus bradycardia (80% v 19%; p<0.0001) and sinus arrhythmia (52% v 9%; p<0.0001) than non-athletes. The PR interval, QRS, and QT duration were more prolonged in athletes than non-athletes (153 (20) v 140 (18) milliseconds (p<0.0001), 92 (12) v 89 (7) milliseconds (p<0.0001), and 391 (27) v 379 (29) milliseconds (p = 0.002) respectively). The Sokolow voltage criterion for left ventricular hypertrophy (LVH) and the Romhilt-Estes points score for LVH was more common in athletes (45% v 23% (p<0.0001) and 10% v 0% (p<0.0001) respectively), as were criteria for left and right atrial enlargement (14% v 1.2% and 16% v 2% respectively). None of the athletes with voltage criteria for LVH had left axis deviation, ST segment depression, deep T wave inversion, or pathological Q waves. ST segment elevation was more common in athletes than non-athletes (43% v 24%; p<0.0001). Minor T wave inversion (less than -0.2 mV) in V2 and V3 was present in 4% of athletes and non-athletes. Minor T wave inversion elsewhere was absent in non-athletes and present in 0.4% of athletes. ECG changes in junior elite athletes are not dissimilar to those in senior athletes. Isolated Sokolow voltage criterion for LVH is common; however, associated abnormalities that indicate pathological hypertrophy are absent. Minor T wave inversions in leads other than V2 and V3 may be present in athletes and non-athletes less than 16 but should be an indication for further investigation in older athletes.


Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex.
Carney complex (CNC) is characterized by lentiginosis and myxomatosis together with a variety of endocrine, neural crest-derived, and other tumors, including primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors, including the myxomas and PPNAD, are unclear. In this study, seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with CNC were stained with antisera for synaptophysin (SYN), neuron-specific enolase, chromogranin A, tyrosine hydroxylase, and the neural cell adhesion molecule (NCAM). In addition, one PPNAD specimen and one myxoma were analyzed by electron microscopy. The results showed that chromogranin A and tyrosine hydroxylase stained adrenomedullary tissue, but not the PPNAD nodules or the extranodular adrenal cortex. SYN, neuron-specific enolase, and NCAM also stained the medulla. PPNAD nodules and the PPNAD cell line, but not the extranodular adrenal cortex, stained intensely for SYN. The myxoma cell line, but not normal fibroblasts, stained for SYN and NCAM. Ultrastructural analysis of a PPNAD tumor and a skin myxoma revealed a well developed rough endoplasmic reticulum, prominent mitochondria, and vesicle-like structures dispersed throughout the cytoplasm. We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue and can be helpful in the detection of small nodules in apparently unaffected cortex. The cells of a cutaneous myxoma were also stained positive by two of the three neuroendocrine markers. Finally, both PPNAD and myxoma cells demonstrated ultrastructural features suggestive of neuroendocrine properties. These results support the previously suggested hypothesis that the genetic mechanism leading to CNC involves genes with a neuroendocrine role.


Topical verapamil and episcleral venous pressure.
To investigate the effect of a single-dose and 2-week administration of topical 0.25% verapamil on episcleral venous pressure (EVP) and intraocular pressure (IOP). A prospective, randomized, double-masked, crossover, and placebo-controlled study. One eye of each of 20 normal subjects received topical verapamil or placebo. The EVP was measured using a pressure chamber episcleral venomanometer. The IOP, EVP, heart rate (HR), and blood pressure (BP) were measured at baseline, 1.5 hours after a single drop, and after 2-week, three-times-a-day topical administration of 0.25% verapamil or placebo to one eye. After a 4-week washout period, the treatment to the study eye was reversed, and measurements of EVP, IOP, HR, and BP were repeated. The EVP, IOP, HR, and BP were measured. Ninety minutes after a single drop, the EVP in the verapamil-treated eyes was reduced by 4.8% (P = <0.001) and in the untreated fellow eyes by 2.4% (P = 0.032). After 2-week topical administration, the EVP was reduced by 9.5% (P = <0.0001) in the verapamil-treated eyes and by 4.8% (P = 0.001) in the fellow eyes. The EVP was unchanged in the treated and fellow eyes after a single drop or after a 2-week treatment with placebo. Ninety minutes after topical administration of 0.25% verapamil, the IOP decreased by 7.7% (P = <0.0001) in the treated eyes and decreased by 3.6% (P = 0.03) in the fellow eyes. After a 2-week administration of topical verapamil, the IOP decreased by 12% (P = 0.0001) in the treated eyes and by 7.2% (P = 0.0289) in the fellow eyes. The changes of IOP in the placebo-treated and fellow eyes were not statistically significant after a single-dose and 2-week administration. After topical administration of verapamil, a contralateral effect on IOP and EVP was observed in the fellow, untreated eye. No systemic effect on HR or BP was detected after a single-dose administration of topical verapamil. There were, however, significant reductions in HR and BP after a 2-week treatment with topical 0.25% verapamil. These results indicate that a single drop and a 2-week administration of topical 0.25% verapamil decrease IOP and EVP significantly, with more pronounced reduction after a 2-week treatment than after a single-dose treatment.


"Twin language": a risk factor for language impairment?
Retrospective parental report of earlier "twin language" was obtained for two groups of twins. Sample G consisted of 94 twin pairs between the ages of 7 and 13 years recruited through the school system as a general population sample. Sample L consisted of 82 twin pairs between the ages of 7 and 13 years who had been recruited for a genetic study; of these twin pairs at least one of the twins had a speech-language impairment persisting to school age. Parental report of twin language was higher (around 50%) for children with speech-language impairment than for those with normal language (11%). Consistent with this, children with twin language obtained significantly lower mean language scores than other children, although their mean nonverbal IQ was equivalent. The exceptions were a handful of children whose parents described use of a "private language" that coexisted alongside normal use of English. These findings are consistent with the view that what is described as twin language is usually use of immature or deviant language by two children at the same developmental level.


Assessing Prevalence of Temporomandibular Disorders among University Students: A Questionnaire Study.
The aim of this study is to assess the prevalence of temporomandibular disorders (TMDs) among university students. The etiology of TMD is of multifactorial, and our study is designed to assess the prevalence of TMD in an institution within a university. Various parameters including trauma, malocclusion, stress assessment - its correlation with the timing, the duration of TMD in meeting the deadlines, and examinations have been assessed. A standard questionnaire-based study with modified Fonseca anamnestic index is used. The questionnaire study was conducted with a statistically calculated sample size of 402 students within a university. The data were analyzed statistically for significance and correlations. Statistical analysis was performed using SPSS for Windows release 14.0 (SPSS Inc., Chicago, IL, USA). Differences at the 5% level were accepted as being statistically significant. TMD and its associated symptoms are frequent among students of health and science studies. Female predominance is seen. There was also an increased prevalence of symptoms in people who described themselves as being tense. The relationship between orthodontic therapy and TMDs were also evaluated, and the duration of therapy is found to be significant. There was a significant association between history of trauma and presence of TMDs. TMD and its associated symptoms are frequent among students of health and science studies. A simple anamnestic index is of use in identifying and classifying temporomandibular joint and TMD symptoms in patients according to the severity of the disorder. Females showed a greater prevalence of signs and symptoms of TMD than males. Longitudinal studies are recommended to identify and follow-up the prevalence and health-care needs of patients with TMDs.


Prospective association of serum androgens and sex hormone-binding globulin with subclinical cardiovascular disease in young adult women: the "Coronary Artery Risk Development in Young Adults" women's study.
The role of endogenous androgens and SHBG in the development of cardiovascular disease in young adult women is unclear. Our objective was to study the prospective association of serum androgens and SHBG with subclinical coronary and carotid disease among young to middle-aged women. This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort study with 20 yr of follow-up. Participants included 1629 women with measurements of serum testosterone and SHBG from yr 2, 10, or 16 and subclinical disease assessment at yr 20 (ages 37-52 yr). Coronary artery calcified plaques (CAC) and carotid artery intima-media thickness (IMT) were assessed at yr 20. The IMT measure incorporated the common carotid arteries, bifurcations, and internal carotid arteries. SHBG (mean of yr 2, 10, and 16) was inversely associated with the presence of CAC (multivariable adjusted odds ratio for women with SHBG levels above the median = 0.59; 95% confidence interval = 0.40-0.87; P = 0.008). SHBG was also inversely associated with the highest quartile of carotid-IMT (odds ratio for women with SHBG levels in the highest quartile = 0.56; 95% confidence interval = 0.37-0.84; P for linear trend across quartiles = 0.005). No associations were observed for total or free testosterone with either CAC or IMT. SHBG levels were inversely associated with subclinical cardiovascular disease in young to middle-aged women. The extent to which low SHBG is a risk marker or has its own independent effects on atherosclerosis is yet to be determined.


Do MRI agents cause or worsen acute pancreatitis?
Acute pancreatitis is still one of the challenging issues in general surgical practice in terms of diagnosis, management and follow-up. CT evaluation of the patients with acute pancreatitis gained popularity in order to document necrosis within the pancreatic tissue which is one of the most important factor linked to the morbidity and even mortality of the disease. Recent studies evidenced that agents used for CT evaluation might also contribute to pancreatic inflammation and cause necrosis. Recently, magnetic resonance imaging (MRI) with gadolinium has been speculated as a safer mean of providing optimum imaging of the pancreas than contrast enhanced CT. In this article we report an unusual case of acute pancreatitis which might have been initiated and/or worsened by gadolinium.


Meckel's diverticulum and mesenterium commune in a patient with gastrointestinal bleeding.
Lower gastrointestinal bleeding after aspirin intake was reported in a 64-year-old woman. Gastroscopy, colonoscopy and selective mesenteric angiography failed to reveal the source of hemorrhage; only a midgut malrotation was suggested by angiography. Small bowel enema finally demonstrated a blind sac on the antimesenteric border of the ileum, corresponding to a Meckel's diverticulum. This embryological remnant of the vitelline duct was associated with a mesenterium commune. Laparoscopy confirmed the small bowel study, and resection of the diverticulum was easily carried out. It is, to our knowledge, the first time that these developmental abnormalities have been preoperatively diagnosed together.


Variational learning of quantum ground states on spiking neuromorphic hardware.
Recent research has demonstrated the usefulness of neural networks as variational ansatz functions for quantum many-body states. However, high-dimensional sampling spaces and transient autocorrelations confront these approaches with a challenging computational bottleneck. Compared to conventional neural networks, physical model devices offer a fast, efficient and inherently parallel substrate capable of related forms of Markov chain Monte Carlo sampling. Here, we demonstrate the ability of a neuromorphic chip to represent the ground states of quantum spin models by variational energy minimization. We develop a training algorithm and apply it to the transverse field Ising model, showing good performance at moderate system sizes ( N ≤ 10 ). A systematic hyperparameter study shows that performance depends on sample quality, which is limited by temporal parameter variations on the analog neuromorphic chip. Our work thus provides an important step towards harnessing the capabilities of neuromorphic hardware for tackling the curse of dimensionality in quantum many-body problems.


Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.
Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n = 229]; Hannover, Germany [n = 171]; Lyon, France [n = 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P = 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P = 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P = 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P = 0.875) and did not influence clinical or biological variables. The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage.


Artificial multi-enzyme networks for the asymmetric amination of sec-alcohols.
Various artificial network designs that involve biocatalysts were tested for the asymmetric amination of sec-alcohols to the corresponding α-chiral primary amines. The artificial systems tested involved three to five redox enzymes and were exemplary of a range of different sec-alcohol substrates. Alcohols were oxidised to the corresponding ketone by an alcohol dehydrogenase. The ketones were subsequently aminated by employing a ω-transaminase. Of special interest were redox-neutral designs in which the hydride abstracted in the oxidation step was reused in the amination step of the cascade. Under optimised conditions up to 91 % conversion of an alcohol to the amine was achieved.


Pediatric trauma triage: A Pediatric Trauma Society Research Committee systematic review.
Significant variability exists in the triage of injured children with most systems using mechanism of injury and/or physiologic criteria. It is not well established if existing triage criteria predict the need for intervention or impact morbidity and mortality. This study evaluated existing evidence for pediatric trauma triage. Questions defined a priori were as follows: (1) Do prehospital trauma triage criteria reduce mortality? (2) Do prehospital trauma scoring systems predict outcomes? (3) Do trauma center activation criteria predict outcomes? (4) Do trauma center activation criteria predict need for procedural or operative interventions? (5) Do trauma bay pediatric trauma scoring systems predict outcomes? (6) What secondary triage criteria for transfer of children exist? A structured, systematic review was conducted, and multiple databases were queried using search terms related to pediatric trauma triage. The literature search was limited to January 1990 to August 2019. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was applied with the methodological index for nonrandomized studies tool used to assess the quality of included studies. Qualitative analysis was performed. A total of 1,752 articles were screened, and 38 were included in the qualitative analysis. Twelve articles addressed questions 1 and 2, 21 articles addressed question 3 to 5, and five articles addressed question 6. Existing literature suggest that prehospital triage criteria or scoring systems do not predict or reduce mortality, although selected physiologic parameters may. In contrast, hospital trauma activation criteria can predict the need for procedures or surgical intervention and identify patients with higher mortality; again, physiologic signs are more predictive than mechanism of injury. Currently, no standardized secondary triage/transfer protocols exist. Evidence supporting the utility of prehospital triage criteria for injured children is insufficient, while physiology-based trauma system activation criteria do appropriately stratify injured children. The absence of strong evidence supports the need for further prehospital and secondary transfer triage-related research. Systematic review study, level II.


The impact of profitability of hospital admissions on mortality.
Fiscal constraints faced by Medicare are leading to policies designed to reduce expenditures. Evidence of the effect of reduced reimbursement on the mortality of Medicare patients discharged from all major hospital service lines is limited. We modeled risk-adjusted 30-day mortality of patients discharged from 21 hospital service lines as a function of service line profitability, service line time trends, and hospital service line and year-fixed effects. We simulated the effect of alternative revenue-neutral reimbursement policies on mortality. Our sample included all Medicare discharges from PPS-eligible hospitals (1997, 2001, and 2005). The results reveal a statistically significant inverse relationship between changes in profitability and mortality. A $0.19 average reduction in profit per $1.00 of costs led to a 0.010-0.020 percentage-point increase in mortality rates (p < .001). Mortality in newly unprofitable service lines is significantly more sensitive to reduced payment generosity than in service lines that remain profitable. Policy simulations that target service line inequities in payment generosity result in lower mortality rates, roughly 700-13,000 fewer deaths nationally. The policy simulations raise questions about the trade-offs implicit in universal reductions in reimbursement. The effect of reduced payment generosity on mortality could be mitigated by targeting highly profitable services only for lower reimbursement.


Assaultive behavior. Does provocation begin in the front office?
1. Provocation is an important risk predictor because these issues can be recognized, assessed, and appropriate interventions can be implemented to reduce the associated risks. It is only by the reduction of such "non-fixed" risk factors that any reduction of assaults can be accomplished. 2. Involuntary admission, patients with dementia or organic brain disorder, physical or verbal limits, staff attitude, denial of the possibility of assaults, and the educational level and clinical experience of the staff may help provoke an assaultive episode. 3. An important step is assessing the assault to identify provocation due to certain medical causes, and to document the extent of degeneration in patients with dementia or organic brain disorder. Medical intervention would be indicated and would appropriately address the causes of some violent episodes.


Feasibility and Safety of Laparoscopic Radical Distal Pancreatosplenectomy with Adrenalectomy in Advanced Pancreatic Cancer.
Pancreatic adenocarcinoma is a lethal condition with poor outcomes and an increasing incidence.1 However, recent meta-analysis reported improved survival and R0 resection rate following neoadjuvant chemotherapy with subsequent surgery in initially unresectable pancreatic cancer.2 In addition, as a result of technological advances during the past 2 decades, even in pancreatic cancers, minimally invasive surgery (MIS) approaches are being used more frequently and safely.3-5 This video shows the feasibility and safety of laparoscopic resection in advanced left-sided pancreatic cancer. The patient was a 63-year-old male with hypertension and diabetes. Initial computed tomography (CT) scan showed a 31 mm-sized pancreatic tail cancer with celiac artery and left adrenal gland abutment. The patient underwent neoadjuvant chemotherapy due to the risk of retroperitoneal cancer infiltration. After four cycles of FOLFIRINOX chemotherapy, follow-up CT scan showed the tumor decreased to 2.6 cm and celiac artery abutment became less prominent. Based on the CT scan, laparoscopic radical distal pancreatosplenectomy with left adrenalectomy was planned. A five-port laparoscopic approach was performed, including three 12 mm trocars and an additional two 5 mm trocars. Initial intra-abdominal exploration showed no peritoneal seeding or micro liver metastasis. Gastric wedge resection was added due to cancer invasion for margin-negative resection. Operation time was 215 min and estimated blood loss was 200 cc without transfusion. The patient was discharged on postoperative day 6 without any complications, including postoperative pancreatic fistula. Laparoscopic distal pancreatosplenectomy can be technically feasible and safe to obtain negative resection margins in well-selected patients following neoadjuvant therapy in locally advanced pancreatic cancer.6.


Electrical stimulation modulates the amphetamine-induced hemodynamic changes: an fMRI study to compare the effect of stimulating locations and frequencies on rats.
Our previous fMRI and microdialysis measurements showed that electroacupuncture (EA) at LI4 was effective in alleviating excessive cerebral dopamine release induced by d-amphetamine (AMPH) in rats. We now compare the effect of EA in adjusting excess dopamine release at two stimulating frequencies (2 Hz versus 100 Hz at LI4) and at two acupoints (forepaw (LI4) versus hindpaw (ST36), at 2 Hz). fMRI measurements of relative cerebral blood volume (rCBV) were used to monitor the brain activity of "rest", followed by AMPH challenge, 10 min "rest", and then 20 min of EA. EA at LI4 and ST36 significantly attenuated the AMPH-induced rCBV increases in the striatum, S1 cortex, and thalamus. Frequency: EA at 100 Hz induced greater attenuation of rCBV than EA at 2 Hz in the S1, insula, anterior cingulate cortices, dorsolateral striatum, and thalamus. Acupoints: EA at LI4 modulated a broader area in the medial anterior striatum while EA at ST36 modulated a more site-specific area in the dorsolateral striatum. In the thalamus, EA at LI4 showed greater attenuating effect than EA at ST36 did. However, in the insular cortex, EA at ST36 showed stronger attenuation. EA at both LI4 and ST36 was effective in restoring dopamine homeostasis from an excess state, with the most effective response at LI4 with 100 Hz, while the responses to 2Hz EA at LI4 and ST36 showed slightly different spatial distribution of MR signal. This therefore provided insight into the neurophysiological basis of electroacupuncture effects in cortical and subcortical circuits.


Cross-linking of CD32 induces maturation of human monocyte-derived dendritic cells via NF-kappa B signaling pathway.
Dendritic cells (DC) represent a unique set of APCs that initiate immune responses through priming of naive T cells. Maturation of DC is a crucial step during Ag presentation and can be induced by triggering a broad spectrum of DC surface receptors. Although human DC express several receptors for the Fc portion of IgG which were described to play an important role in Ag internalization, little is known about the effects of IgG or immune complexes on DC maturation. In this study, we show that cross-linking of FcgammaR-type II (CD32) with immobilized IgG (imIgG) can induce maturation of human monocyte-derived DC via the NF-kappaB signaling pathway. IgG-mediated maturation was accompanied by a moderate increase of IL-10 secretion, whereas no IL-12 production was observed. Involvement of CD32 was further supported by experiments with the anti-CD32 mAb, which blocked IgG-triggered DC maturation and cytokine secretion significantly. Furthermore, DC cultivated in the presence of imIgG induced allogeneic T cell proliferation. Because this imIgG-induced maturation was considerably impaired in monocyte-derived DC from systemic lupus erythematosus patients, we suggest that DC, which matured in the presence of immune complexes, may contribute to prevention of pathological immune responses.


Milk plasmin, N-acetyl-beta-D-glucosaminidase, and antitrypsin as determinants of bacterial replication rates in whey.
Quarter milk samples were collected monthly on a selected herd of 80 Ayrshire cows having a high frequency of subclinical mastitis. Analysis of bacterial growth rates in milk showed that whey prepared from infected or inflamed quarters stimulated bacterial growth. Milk N-acetyl-beta-D-glucosaminidase, antitrypsin, and plasmin activities all showed positive correlations with bacterial replication rates (Staphylococcus aureus and Escherichia coli) in respective whey samples as determined by a turbidometric micro-technique. Increased bacterial replication rates in mastitic whey represent an increased yield of the key nutrients for bacteria. Bacterial growth enhancement can be partly explained by proteose-peptone originating from plasmin activation and casein degradation. However, as multiple regression analysis showed that a combination of the predictor variables: antitrypsin, N-acetyl-beta-D-glucosaminidase and plasmin explained enhancement of bacterial growth better than plasmin alone, other factors connected with inflammation should be sought when searching for growth-enhancing factors in whey. Milk plasmin activities showed increasing activities toward end of lactation (before drying off) as well as during later lactation (age of cow in years minus 2). Bacterial replication was enhanced in parallel with these changes in plasmin activities.


APOE ε4 positive patients suffering severe traumatic head injury are more prone to undergo decompressive hemicraniectomy.
In this paper we tested the hypothesis if patients with severe traumatic brain injury and presence of the apolipoprotein E (APOE) ε4 allele are more prone to undergo the surgical procedure decompressive hemicraniectomy (DC) in order to bring the intracranial pressure (ICP) under control. In this prospective consecutive study patients with sTBI were enrolled (n=48). Inclusion criteria were arrival to our level one trauma university hospital within 24h after trauma, patient age between 15 and 70years, Glasgow Coma Scale (GCS) score ≤8 at the time of intubation and sedation, an initial cerebral perfusion pressure >10mmHg. Venous blood was sampled for APOE genotype determination. Clinical outcome at 6months after injury was assessed with the Extended Glasgow Outcome Scale (GOSE). All surgical procedures needed for each patient were registered. Patients with the APOE ε4 allele were significantly overrepresented in the DC group. In the APOE ε4+DC group, ICPmax and ICPmean during the first 36h were significantly higher and GOSE was significantly worse at 6months. Our data suggest that patients with the APOE ε4 allele are predisposed for the need of DC more often than patients without the APOE ε4 allele. Thus, it seems to be of importance to consider the APOE genotype in patients suffering severe traumatic brain injury in order to forecast the need for a more exquisite intensive care.


Receptor activator of NF-kappaB ligand enhances breast cancer-induced osteolytic lesions through upregulation of extracellular matrix metalloproteinase inducer/CD147.
Breast cancer shows a strong predilection to metastasize to bone. Cell surface glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147 induces metalloproteinases (MMP) and vascular endothelial growth factor (VEGF), which may support osteoclastic activity and increased incidence of breast cancer bone metastases. In support of this hypothesis, we observed that MDA-MB-231 human breast tumor cells engineered to overexpress EMMPRIN strongly induced osteolytic lesions in immunodeficient mice, which was blunted by in vivo treatment with an EMMPRIN blocking antibody. Similarly, these cells exhibited increased expression of MMP-9 and VEGF relative to control cells. Treatment of MDA-MB-231 cells with the osteoclastogenic cytokine receptor activator of NF-kappaB ligand (RANKL) upregulated EMMPRIN expression with a parallel increase of MMP-9 and VEGF. Conditioned medium from osteoblasts similarly increased EMMPRIN, MMP-9, and VEGF expression in cells. Osteoblast treatment with the RANKL decoy receptor osteoprotegerin abolished this effect. EMMPRIN overexpression stimulated MDA-MB-231 cell invasion but not proliferation. Conversely, small interfering RNA-mediated knockdown of EMMPRIN downregulated MMP-9 and VEGF basal expression and RANKL-stimulated expression, and reduced cell invasion. Our results argue that EMMPRIN drives breast cancer-induced osteolytic lesions and that activation of the RANKL pathway increases EMMPRIN in osteotropic tumor cells, in turn enhancing tumor-induced bone resorption.


Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute Simian Immunodeficiency Virus Infection in a Pigtailed Macaque Model of Human Immunodeficiency Virus.
Although social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health outcomes in general [1] and in the context of infectious disease, such as human immunodeficiency virus (HIV) [2, 3]. A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection. To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n = 35) and socially (n = 41) housed simian immunodeficiency virus (SIV)-infected pigtailed macaques (Macaca nemestrina). Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T-cell declines and more CD4 and CD8 T-cell activation compared with socially housed macaques throughout acute SIV infection. These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections.


Identification of Whole-Blood DNA Methylation Signatures and Rules Associated with COVID-19 Severity.
Different severities of coronavirus disease 2019 (COVID-19) cause different levels of respiratory symptoms and systemic inflammation. DNA methylation, a heritable epigenetic process, also shows differential changes in different severities of COVID-19. DNA methylation is involved in regulating the activity of various immune cells and influences immune pathways associated with viral infections. It may also be involved in regulating the expression of genes associated with the progression of COVID-19. In this study, a sophisticated machine-learning workflow was designed to analyze whole-blood DNA methylation data from COVID-19 patients with different severities versus healthy controls. We aimed to understand the role of DNA methylation in the development of COVID-19. The sample set contained 101 negative controls, 360 mildly infected individuals, and 113 severely infected individuals. Each sample involved 768,067 methylation sites. Three feature-ranking algorithms (least absolute shrinkage and selection operator (LASSO), light gradient-boosting machine (LightGBM), and Monte Carlo feature selection (MCFS)) were used to rank and filter out sites highly correlated with COVID-19. Based on the obtained ranking results, a high-performance classification model was constructed by combining the feature incremental approach with four classification algorithms (decision tree (DT), k-nearest neighbor (kNN), random forest (RF), and support vector machine (SVM)). Some essential methylation sites and decision rules were obtained. The genes (IGSF6, CD38, and TLR2) of some essential methylation sites were confirmed to play important roles in the immune system.


Use of chemostat cultures mimicking different phases of wine fermentations as a tool for quantitative physiological analysis.
Saccharomyces cerevisiae is the most relevant yeast species conducting the alcoholic fermentation that takes place during winemaking. Although the physiology of this model organism has been extensively studied, systematic quantitative physiology studies of this yeast under winemaking conditions are still scarce, thus limiting the understanding of fermentative metabolism of wine yeast strains and the systematic description, modelling and prediction of fermentation processes. In this study, we implemented and validated the use of chemostat cultures as a tool to simulate different stages of a standard wine fermentation, thereby allowing to implement metabolic flux analyses describing the sequence of metabolic states of S. cerevisae along the wine fermentation. Chemostat cultures mimicking the different stages of standard wine fermentations of S. cerevisiae EC1118 were performed using a synthetic must and strict anaerobic conditions. The simulated stages corresponded to the onset of the exponential growth phase, late exponential growth phase and cells just entering stationary phase, at dilution rates of 0.27, 0.04, 0.007 h-1, respectively. Notably, measured substrate uptake and product formation rates at each steady state condition were generally within the range of corresponding conversion rates estimated during the different batch fermentation stages.Moreover, chemostat data were further used for metabolic flux analysis, where biomass composition data for each condition was considered in the stoichiometric model. Metabolic flux distributions were coherent with previous analyses based on batch cultivations data and the pseudo-steady state assumption. Steady state conditions obtained in chemostat cultures reflect the environmental conditions and physiological states of S. cerevisiae corresponding to the different growth stages of a typical batch wine fermentation, thereby showing the potential of this experimental approach to systematically study the effect of environmental relevant factors such as temperature, sugar concentration, C/N ratio or (micro) oxygenation on the fermentative metabolism of wine yeast strains.


ALOX12 mutation in a family with dominantly inherited bleeding diathesis.
The arachidonic acid (AA) cascade plays a significant role in platelet aggregation. AA released from membrane phospholipids is metabolized by cyclooxygenase (COX) pathway to thromboxane A2 (TXA2) or by 12S-lipoxygenase (ALOX12) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE). In contrast to a well-known role of the COX pathway in platelet aggregation, the role of ALOX12 is not well understood. Platelets of ALOX12-deficient mice exhibit increased sensitivity for ADP-induced aggregation. However, recent evidence strongly suggests a significant role of ALOX12 in platelet aggregation and calcium signaling. 12-HPETE potentiates thrombin- and thromboxane-induced platelet aggregation, and calcium signaling. Inhibition experiments of ALOX12 demonstrated decreased platelet aggregation and calcium signaling in stimulated platelets. We studied a family with a dominantly inherited bleeding diathesis using next-generation sequencing analysis. Platelet aggregation studies revealed that the proband's platelets had defective aggregation responses to ADP, TXA2 mimetic U46619, collagen, and AA, normal affinity of TXA2 receptor for U46619, and normal induction of GTPase activity upon stimulation with U46619. However, the production of inositol 1,4,5-triphosphate (IP3) was only increased up to 30% of the control upon U46619 stimulation, suggesting a defect in phospholipase C-β2 (PLCB2) activation downstream from TXA2 receptors. Affected family members had no mutation of PLCB2, but had a heterozygous c.1946A > G (p.Tyr649Cys) mutation of ALOX12. ALOX12 activity in platelets from the affected members was decreased to 25-35% of the control. Our data strongly suggested that a heterozygous c.1946A > G ALOX12 mutation was a disease-causing mutation; however, further experiments are required to confirm the pathogenesis of ALOX12 mutation in platelet aggregation.


The evaluation of skin lesions, according to the Toven Method - an interprofessional communication tool.
In the wound care field, effective communication within the interdisciplinary staff is essential and the use of tools that foster it is important. The use of a common language among professionals in the assessment and monitoring process, along with documentation of the outcome, avoids the useless repetition of performances by professionals, with a considerable save of time. One year after its publication, we wanted to evaluate the effectiveness of the Toven Evaluation Form as an interdisciplinary communication tool, for the assessment of cutaneous lesions, according to the Toven Method. The instrument got under observation also allows the graphic recording of the characteristics of the skin lesions (size, wound conditions, undermining and perilesional skin) according to specific pre-established rules, in an easy and intuitive way for the evaluator and the rest of the multidisciplinary team. It is an integral part of the Toven File. An anonymous, specially created questionnaire containing 20 questions was used for its evaluation. A fact-finding inquiry was initiated by recruiting a multidisciplinary sample of 101 professionals who managed skin lesions in their activity. Before completing the form, all the participants attended a two-hour training course, which took place through a lecture and a practical session. Sample composition: 76.2% females, 23.8% males; 63.4% nurses, 10.9% Wound Care Specialist nurses; 16,8% doctors; 8.9% physiotherapists. Of these, 69.3% had work experience >5 years. The technical quality of the instrument was considered excellent by 83.2% of professionals and good by 16.8% of them. The data recorded with the aid of the instrument were considered complete by 100% of the sample. Furthermore, 99% of the sample interviewed declared that the tool is easy to use and would be interested in including it in daily practice; 100% declares that the use of the form can facilitate its work, which can be easily understood and used by the entire multidisciplinary team and which can be an effective tool for the improvement of interdisciplinary communication.


A Multi-modal Teacher-student Framework for Improved Blood Pressure Estimation.
Blood pressure (BP) is a critical vital sign that hypertensive patients regularly measure. In this study, we propose a novel BP estimation framework to distill the knowledge from a multi-modal model to a uni-modal BP estimation model through teacher-student training. The multi-modal BP estimation model consists of three components: first, a gated recurrent unit network that generates features from photoplethysmogram, electrocardiogram, age, height, and weight; second, an attention mechanism that integrates each feature into joint embeddings; and third, a regression layer that estimates BP from the joint embeddings. The uni-modal BP estimation model has similar components to the multi-modal model but uses only PPG signal. BP is predicted by the embeddings extracted from the uni-modal model, and these embeddings are trained to be as similar as possible to the joint embeddings extracted from the multi-modal model. The proposed method demonstrates absolute prediction errors of 5.24±6.41 and 3.49±3.85 mmHg for systolic blood pressure and diastolic blood pressure in the MIMIC-III dataset, satisfying the AAMI standard.


Pediatric HIV infection. An update.
Human immunodeficiency virus infection is a leading cause of immunodeficiency in children. The epidemic in children parallels that in women since most infected women are in the child-bearing age groups. The risk of vertical transmission of HIV from an infected mother to her infant ranges from 13% to 39%. Diagnosis of infection in the infant is complicated by the passive transfer of antibody across the placenta, making the use of standard serologic tests to confirm infection difficult. In children less than 15 months of age, a positive p24 core antigen test, a positive viral culture or AIDS defining criteria with immune abnormalities are required for diagnosis. HIV infection in children is chronic and multisystem characterized by immunologic and clinical deterioration with a higher incidence of serious bacterial infections, neurologic disease, and lymphoid interstitial pneumonitis. The cornerstones of management include close medical follow-up, good nutrition, and prompt diagnosis and treatment of infections. Certain children will benefit from therapeutic modalities such as Pneumocystis carinii pneumonia prophylaxis and/or intravenous gamma globulin. The antiretroviral drugs have improved the quality of life and increased survival. Several newer antiviral agents are presently in clinical trials.


Ultrastructural analysis and TUNEL demonstrate motor neuron apoptosis in Werdnig-Hoffmann disease.
Werdnig-Hoffmann disease (WHD) is the most severe clinical type of spinal muscular atrophy characterized by loss of lower motor neurons and paralysis. We examined the hypothesis that disease pathogenesis is based on an inappropriate persistence of normally occurring motor neuron programmed cell death. The diagnosis of WHD was made on the basis of clinical findings, electromyoneurography, and biopsy, and further confirmed by mutation analysis of the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes using PCR. We used ultrastructural analysis as well as TUNEL and ISEL methods to assess DNA fragmentation, and immunocytochemistry to identify expression of the apoptosis-related proteins bcl-2 and p53. A significant number of motor neurons in the spinal cord of children with WHD were shown to die by apoptosis. As revealed by TUNEL, dying neurons in WHD patients comprised 0.2%-6.4% of the neuron numbers counted. This finding contradicts earlier studies that failed to find such evidence and suggests that early blockade of prolonged motor neuron apoptosis may be a potential therapeutic strategy for WHD.


Colon-Targeted Release of Turmeric Nonextractable Polyphenols and Their Anticolitis Potential via Gut Microbiota-Dependent Alleviation on Intestinal Barrier Dysfunction in Mice.
Solid evidence has emerged supporting the role of nonextractable polyphenols (NEPs) and dietary fibers (DFs) as gut microbiota modulators. This study aims to elucidate gut microbiota-dependent release of turmeric NEPs and examine the possible anti-inflammatory mechanism in the dextran sulfate sodium-induced ulcerative colitis (UC) model. 1.5% DSS drinking water-induced C57BL/6J mice were fed a standard rodent chow supplemented with or without 8% extractable polyphenols (EPs), NEPs, or DFs for 37 days. The bound curcumin, demethoxycurcumin, and bisdemethoxycurcumin in NEPs were released up to 181.5 ± 10.6, 65.2 ± 6.0, and 69.5 ± 7.6 μg/mL by in vitro gut microbiota-simulated fermentation and released into the colon of NEP-supplemented mice by 5.7-, 11.0-, and 7.8-fold higher than pseudo germ-free mice, respectively (p < 0.05). NEPs also enhanced the colonic microbiota-dependent production of short-chain fatty acids in vitro and in vivo (p < 0.05). Interestingly, NEP feeding significantly improved the DSS-caused gut microbiota disorder, epithelial barrier damage, and inflammation of UC mice better than EPs or DFs (p < 0.05). Meanwhile, the pseudo germ-free mice supplemented with NEPs failed to ameliorate UC symptoms. These findings manifest that turmeric NEPs as macromolecular carriers exert the target delivery of polyphenols into the colon for regulating gut microbiota to restore the impaired gut barrier function for alleviation of inflammation.


[Prospective epidemiologic study of arterial hypertension in an organized male population].
The effect of active arterial-hypertension preventive programs on the epidemiologic situation was studied over a nine-year period, 1977 through 1985. In the first five years, the number of effectively treated cases increased, while essential hypertension morbidity associated with temporary disability diminished, as did mortality and the incidence of myocardial infarction and cerebral accidents among 40- to 54-year-old male industrial workers. After an active preventive program was abandoned at one factory, the parameters examined deteriorated considerably, and a sample selected for comparison showed an abrupt drop in treatment efficiency within three years after annual screenings were discontinued.


Engineering and the law-how is an anesthesia machine like a lawnmower? The problem of the learned intermediary.
This article is the first in a series about the dilemmas posed by products-liability law. The authors point out that manufacturers of complex medical devices may have an unrealistic expectation about user expertise, the lack of which often causes injury to patients, thereby leading to litigation over the devices. The learned-intermediary problem arises when engineers and lawyers disagree over whether a device is designed for a sophisticated rather than unsophisticated user. The authors discuss why the law assumes that anesthesia machines are like lawnmowers, which are usually operated by untrained users, rather than airplanes. However, they argue that anesthesia machines, being complicated to understand as well as dangerous, are much more like airplanes. They conclude that medical-device manufacturers must develop strategies to assure that legally risky devices are restricted to competent users; otherwise, innovation will suffer and legal costs will destroy the competitiveness of the US medical device manufacturers.


Genetic aspects of unconventional virus infections: the basis of the virino hypothesis.
The properties of genes involved directly or indirectly in the pathogenesis of scrapie and other unconventional (UCV) virus infections are reviewed. Reasons are presented for assigning paramount importance to the Sinc gene in mice and the Sip gene in sheep (the likely homologue of Sinc). The rationale is given for concluding that the agents of UCV infections have their own genomic molecules coding for strain differences. The virino hypothesis, which proposes that the infective form of the agent is an informational hybrid between the agent's genome and protective host proteins, is presented in detail, with an explanation of the postulated role of Sinc.


Progressive stretch enhances growth and maturation of 3D stem-cell-derived myocardium.
Bio-engineered myocardium has great potential to substitute damaged myocardium and for studies of myocardial physiology and disease, but structural and functional immaturity still implies limitations. Current protocols of engineered heart tissue (EHT) generation fall short of simulating the conditions of postnatal myocardial growth, which are characterized by tissue expansion and increased mechanical load. To investigate whether these two parameters can improve EHT maturation, we developed a new approach for the generation of cardiac tissues based on biomimetic stimulation under application of continuously increasing stretch. Methods: EHTs were generated by assembling cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) at high cell density in a low collagen hydrogel. Maturation and growth of the EHTs were induced in a custom-made biomimetic tissue culture system that provided continuous electrical stimulation and medium agitation along with progressive stretch at four different increments. Tissues were characterized after a three week conditioning period. Results: The highest rate of stretch (S3 = 0.32 mm/day) increased force development by 5.1-fold compared to tissue with a fixed length, reaching contractility of 11.28 mN/mm². Importantly, intensely stretched EHTs developed physiological length-dependencies of active and passive forces (systolic/diastolic ratio = 9.47 ± 0.84), and a positive force-frequency relationship (1.25-fold contractility at 180 min-1). Functional markers of stretch-dependent maturation included enhanced and more rapid Ca2+ transients, higher amplitude and upstroke velocity of action potentials, and pronounced adrenergic responses. Stretch conditioned hiPSC-CMs displayed structural improvements in cellular volume, linear alignment, and sarcomere length (2.19 ± 0.1 µm), and an overall upregulation of genes that are specifically expressed in adult cardiomyocytes. Conclusions: With the intention to simulate postnatal heart development, we have established techniques of tissue assembly and biomimetic culture that avoid tissue shrinkage and yield muscle fibers with contractility and compliance approaching the properties of adult myocardium. This study demonstrates that cultivation under progressive stretch is a feasible way to induce growth and maturation of stem cell-derived myocardium. The novel tissue-engineering approach fulfills important requirements of disease modelling and therapeutic tissue replacement.


Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy.
The phenanthroindolizidine and phenanthroquinolizidine alkaloids, typified by tylophorine and cryptopleurine, are a family of plant-derived small molecules with significant therapeutic potential. The plant extracts have been used in herbal medicine and the isolated compounds have displayed a range of promising therapeutic activity such as anti-ameobicidal, anti-viral, anti-inflammatory and anti-cancer activity. Despite their therapeutic protential, no compounds in this class have fully passed clinical trials. Drawbacks include low in vivo anti-cancer activity, central nervous system toxicity and low natural availability. A number of biological effects of these compounds, such as protein and nucleic acid synthesis suppression, have been identified, but the specific biomolecular targets have not yet been identified. Significant effort has been expended in the synthesis and structure-activity-relationship (SAR) studies of these compounds with the hope that a new drug will emerge. This review will highlight important contributions to the isolation, synthesis, SAR and mechanism of action of the phenanthroindolizidine and pheanthroquinolizidine alkaloids.


Systemic immune changes following meal intake in humans.
Food intake represents a high intestinal antigen exposition requiring host defense. Besides local immune activation, this defense includes a coordinate systemic immune response, which may serve to support local immunity. This study examined influences of a standardized high-protein meal on peripheral blood mononuclear cell counts; on the in vitro mitogen-stimulated production of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interferon-gamma; on the in vivo plasma levels of tumor necrosis factor-alpha and interleukin-6; and on plasma concentrations of cortisol and growth hormone. Ten healthy men (18-35 yr) participated in two experimental sessions in a balanced order. On one occasion, subjects fasted; on the other, they received a high-protein meal at 1230. Blood was sampled every 15 min. Whereas the numbers of neutrophils and platelets were increased for more than 2.5 h after meal intake (P < 0.01) lymphocyte counts decreased (P < 0.01). Meal intake also decreased the production of interferon-gamma but did not affect the production and plasma levels of the other cytokines. Changes in immune cell distribution and function were accompanied by a strong postprandial rise in plasma cortisol concentrations. Some of the systemic immune changes, like the emigration of lymphocytes, probably into extravascular abdominal tissues, may serve to support local immune defense.


Synthesis of feedforward networks in supremum error bound.
The main result of this paper is a constructive proof of a formula for the upper bound of the approximation error in Linfinity (supremum norm) of multidimensional functions by feedforward networks with one hidden layer of sigmoidal units and a linear output. This result is applied to formulate a new method of neural-network synthesis. The result can also be used to estimate complexity of the maximum-error network and/or to initialize that network weights. An example of the network synthesis is given.


Highly redundant function of multiple AT-rich sequences as core promoter elements in the TATA-less RPS5 promoter of Saccharomyces cerevisiae.
In eukaryotes, protein-coding genes are transcribed by RNA polymerase II (pol II) together with general transcription factors (GTFs). TFIID, the largest GTF composed of TATA element-binding protein (TBP) and 14 TBP-associated factors (TAFs), plays a critical role in transcription from TATA-less promoters. In metazoans, several core promoter elements other than the TATA element are thought to be recognition sites for TFIID. However, it is unclear whether functionally homologous elements also exist in TATA-less promoters in Saccharomyces cerevisiae. Here, we identify the cis-elements required to support normal levels of transcription and accurate initiation from sites within the TATA-less and TFIID-dependent RPS5 core promoter. Systematic mutational analyses show that multiple AT-rich sequences are required for these activities and appear to function as recognition sites for TFIID. A single copy of these sequences can support accurate initiation from the endogenous promoter, indicating that they carry highly redundant functions. These results show a novel architecture of yeast TATA-less promoters and support a model in which pol II scans DNA downstream from a recruited site, while searching for appropriate initiation site(s).


Primer effects by conspecific odors in house mice: a new perspective in the study of primer effects on reproductive activities.
Half a century has passed since the first report of the influence of odors on mice. Odors are known to influence behavior (signaling effect) and affect the physiology (primer effect) of mice. This review focuses on summarizing the primer effects found so far in female and male mice. Odors from conspecifics of the opposite sex had the tendency to enhance reproductive activities, whereas odors from conspecifics of the same sex diminish them. Only 2,5-dimethylpyrazine, one of the odor components identified in group-housed females, has been reported to have a suppressive influence on both males and females by lowering reproductive activities. Studies showed progress from the discovery of phenomena to the identification of odor components that cause such changes in reproductive organs and related neuroendocrinological changes. Compared to studies on the mechanisms of primer effects in females, the mechanisms in males are not yet clarified, and detailed studies on effects on the reproductive organs are still in primitive stages especially for males. Hypotheses on the influence of changes in the concentration of testosterone, estrogen, and prolactin on spermatogenesis and sperm maturation after exposure to odors are discussed.


A combination of absorption and enzymatic biodegradation: phenol elimination from aqueous and organic phase.
Peroxidase from Brassica rapa was immobilized as cross-linked enzyme aggregates (CLEAs) and used to treat air containing phenol as a model molecule of volatile organic compounds (VOCs). Prior to an enzymatic treatment, phenol was absorbed into an aqueous or organic phase (silicone oil) to reach concentrations ranging from 20 to 160 mg/L. The process was carried out by introducing a desired weighing of BRP-CLEAs into preparations and reaction was started by injecting H2O2 solution to the medium. Optimization of the reaction conditions in the organic solvent revealed an optimal contact time of 60 min, 60 mg/L of phenol concentration and 3 mM H2O2, leading to a maximum removal yield of 70% for 3.4 UI/mL of BRP-CLEAs. These results were compared to those obtained in an aqueous medium that showed 90% of degradation yield after 40 min in the following conditions, 90 mg/L of initial phenol amount, 2 mM of H2O2 and 2.5 UI/mL of BRP-CLEAs. Parameters of the Michaelis-Menten model, Km and Vmax, were also determined for the reaction in both phases. Phenol removal by BRP-CLEAs in silicone oil succeeded with 70% of conversion yield. It is promising regarding the transposition of such enzymatic process to hydrophobic VOCs.


γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion.
Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell-intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4-10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.


Microstructural thalamic changes in schizophrenia: a combined anatomic and diffusion weighted magnetic resonance imaging study.
Several magnetic resonance imaging (MRI) and postmortem studies have supported the role of the thalamus in the pathophysiology of schizophrenia. Interestingly, a recent small diffusion weighted imaging (DWI) study showed abnormal thalamic microstructure in patients with schizophrenia. The objective of our study was to use structural MRI and DWI to explore for the first time both thalamic volumes and integrity in schizophrenia. We measured thalamic volumes and apparent diffusion coefficient (ADC) measures bilaterally in 71 patients with schizophrenia, representative of those living in the geographically defined catchment area of South Verona (i.e., 100 000 inhabitants), and 75 individuals without schizophrenia. The presence of the adhesio interthalamica was also detected. We found no significant differences in thalamus size between patients with schizophrenia and participants in the control group, with only a trend for decreased left volumes. No abnormal frequency of the adhesio interthalamica was found. In contrast, significantly increased thalamic ADC values were shown in schizophrenia patients. Age significantly inversely correlated with thalamic volumes in both groups and correlated positively with posterior ADCs in patients with schizophrenia. No significant associations between clinical variables and either volumes or ADC values were reported. Widespread altered microstructure integrity and partially preserved thalamus size were found in schizophrenia patients. Therefore, subtle thalamic structural abnormalities are present in schizophrenia, even with maintained volumes. This may result from disruption at the cytoarchitecture level, ultimately supporting corticothalamic misconnection. Future imaging studies should further explore thalamic tissue coherence and its role for cognitive disturbances in patients at high risk for schizophrenia and in first-degree relatives.