EMDR therapy vs. Supportive Therapy as adjunctive treatment in trauma-exposed bipolar patients: a randomized controlled trial.
Patients with Bipolar Disorder (BD) are frequently exposed to traumatic events which worsen disease course, but this study is the first multicentre randomised controlled trial to test the efficacy of a trauma-focused adjunctive psychotherapy in reducing BD affective relapse rates. This multicentre randomised controlled trial included 77 patients with BD and current trauma-related symptoms. Participants were randomised to either 20 sessions of trauma-focused Eye Movement Desensitization and Reprocessing (EMDR) therapy for BD, or 20 sessions of supportive therapy (ST). The primary outcome was relapse rates over 24-months, and secondary outcomes were improvements in affective and trauma symptoms, general functioning, and cognitive impairment, assessed at baseline, post-treatment, and at 12- and 24-month follow-up. The trial was registered prior to starting enrolment in clinical trials (NCT02634372) and carried out in accordance with CONSORT guidelines. There was no significant difference between treatment conditions in terms of relapse rates either with or without hospitalization. EMDR was significantly superior to ST at the 12-month follow up in terms of reducing depressive symptoms (p=0.0006, d=0.969), manic symptoms (p=0.027, d=0.513), and improving functioning (p=0.038, d=0.486). There was no significant difference in dropout between treatment arms. Although the primary efficacy criterion was not met in the current study, trauma-focused EMDR was superior to ST in reducing of affective symptoms and improvement of functioning, with benefits maintained at six months following the end of treatment. Both EMDR and ST reduced trauma symptoms as compared to baseline, possibly due to a shared benefit of psychotherapy. Importantly, focusing on traumatic events did not increase relapses or dropouts, suggesting psychological trauma can safely be addressed in a BD population using this protocol.


The utility of positron emission tomography/computed tomography in target delineation for stereotactic body radiotherapy for liver metastasis from primary gastric cancer: an illustrative case report and literature review.
The liver is a common site for metastatic disease for many cancers. Radiation therapy is one means of treatment for liver metastases, especially for patients unable to undergo surgery or ineligible for systemic chemotherapy. In particular, stereotactic body radiotherapy (SBRT) has become an important option in the treatment of metastatic disease in the liver. SBRT delivers ablative doses of radiation in relatively few fractions. As such, precise and clear imaging plays an important role in maximizing disease control while minimizing normal tissue toxicity. We present a case that highlights the importance of using multiple imaging modalities for target volume delineation in stereotactic radiation treatment of liver metastases.


S protein modulates the heparin-catalyzed inhibition of thrombin by antithrombin III. Evidence for a direct interaction of S protein with heparin.
The interference of S protein with the heparin-catalyzed inhibition of thrombin by antithrombin III was studied in a purified system and in plasma. The effect of S protein to counteract heparin activity was documented by kinetic analysis of the initial phase of the inhibition reaction. Addition of S protein induced a concentration-dependent reduction of the inhibition rate, reflected in a decrease of the apparent pseudo-first-order rate constant by a factor of 5-8 in the presence of a twofold molar excess of S protein over antithrombin III. A non-competitive interaction of S protein with the thrombin--antithrombin-III--heparin inhibition reaction with Ki = 0.6 microM was found. While the association constant of thrombin--antithrombin III in the presence of 0.05 U/ml heparin amounted to 2.5 X 10(8) M-1, an approximately 200-fold decrease of this value was observed in the presence of S protein. The fast formation of the covalent complex between thrombin and antithrombin III in the presence of heparin was impaired as a result of the presence of S protein, as was shown by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. In the absence of heparin the inhibition of thrombin by antithrombin III alone was not influenced by S protein. The heparin-counteracting activity of S protein was found to be mainly expressed in the range of 0.01-0.1 U/ml heparin, thereby shifting the point of 50% inhibition of thrombin from 0.003 U/ml to 0.1 U/ml heparin with a second-order rate constant of k2 = 1.4 X 10(6) M-1. A direct interaction of S protein with heparin was demonstrated by crossed immunoelectrophoresis with purified proteins as well as in plasma and serum. The analysis of plasma and serum by crossed immunoelectrophoresis against rabbit anti-(human S protein) serum revealed an additional cathodal peak in the serum sample, resulting from the interaction of S protein with serum components. These findings not only indicate a direct interaction of S protein with heparin in the onset of the inhibition of thrombin by antithrombin-III--heparin, but also a contribution of S protein during enzyme-inhibitor complex formation.


The reaction of singlet oxygen with proteins, with special reference to crystallins.
Photosensitized oxidation of the eye lens proteins, the crystallins, is thought to lead to protein crosslinks and high molecular weight aggregates. Such protein modifications may be important factors in the formation of lens opacities or cataracts. We focus attention here on type 2 photo-oxidation involving the reaction of singlet oxygen (1O2) with crystallins and some "control" proteins. We find that: (1) trp residues are oxidized to N-formyl kynurenine and related products, but this in itself does not lead to the production of high molecular weight protein aggregates of the protein; (2) tyr residues react with 1O2 but we do not detect dihydroxyphenylalanine or bityrosine nor are protein crosslinks formed as a result; (3) oxidation of his residues appears necessary for high molecular weight protein covalent aggregates to form. Proteins devoid of his, e.g. melittin or bovine pancreatic trypsin inhibitor, do not form high molecular weight products upon reaction with 1O2. Prior reaction and blocking of his inhibits the crosslinking reactions. (4) The oxidized protein is seen to be more acidic than the parent and has an altered tertiary structure. (5) Among the crystallins, reactivity towards 1O2 varies in the order gamma greater than beta greater than alpha and also gamma A/E greater than gamma D greater than gamma B crystallin.


Enhancing Electrocatalytic Water Oxidation of NiFe-LDH Nanosheets via Bismuth-Induced Electronic Structure Engineering.
The design and synthesis of high-efficiency electrocatalysts are of great practical significance in electrocatalytic water splitting, specifically in accelerating the slow oxygen evolution reaction (OER). Herein, a self-supported bismuth-doped NiFe layered double hydroxide (LDH) nanosheet array for water splitting was successfully constructed on nickel foam by a one-step hydrothermal strategy. Benefiting from the abundant active sites of two-dimensional nanosheets and electronic effect of Bi-doped NiFe LDH, the optimal Bi0.2NiFe LDH electrocatalyst exhibits excellent OER performance in basic media. It only requires an overpotential of 255 mV to drive 50 mA cm-2 and a low Tafel slope of 57.49 mV dec-1. The calculation of density functional theory (DFT) further shows that the incorporation of Bi into NiFe LDH could obviously overcome the step of H2O adsorption during OER progress. This work provides a simple and effective strategy for improving the electrocatalytic performance of NiFe LDHs, which is of great practical significance.


[Clinical and morphological characteristics and peculiarities of differentiated thyroid gland cancer course].
221 patients were operated for cancer of the thyroid gland during the last 12 years. Adequate preoperative diagnosis including ultrasound examination, and fine needle aspiration biopsy made it possible to operate 88.7% of patients at earlier (I and II) stages of the disease. Long term results of radical surgical treatment have been studied in 197 (89.1%) patients followed up 5 to 16 years, 49.2% of patients being followed up for no less than 10 years. Majority of patients (95.9%) had differentiated forms of tumors, medullar cancer was detected in 4.1% of patients. Clinical and morphological analysis of differentiated thyroid cancer was carried out in 212 patients. Metastases to lymph nodes of the neck occur more frequently in younger patients, and extracapsular spread of the tumor was revealed in aged persons. Risk factors were male sex, old age, follicular cancer and growth of the tumor through the capsule of the gland. The minimal procedure in case of location of the differentiated tumor in a single lobe of thyroid is extrafascial hemithyreoidectomy with resection of the istmus. Prognosis in radically operated patients is relatively favourable, 5-year survival rate made up 97.5%.


Balance training improves static stability and gait in chronic incomplete spinal cord injury subjects: a pilot study.
Walking is considered the most important goal after an incomplete spinal cord injury (SCI). Only recently it has been demonstrated that balance is a key factor of walking recovery, but no data on the efficacy of balance training in supporting walking function in SCI subjects are available. The object of the study was to determine the efficacy of visual biofeedback task-specific balance training (vBFB) in improving balance performance and gait in SCI subjects compared with conventional over-ground rehabilitation (Rehab). Open-case study with retrospective matched control. Chronic SCI outpatients and healthy subjects (H). Twelve SCI subjects with ASIA impairment scale grade D-6 in the vBFB group (EXP) and 6 in the Rehab group (CTRL)-and 6 H. Data from H were used as reference for physiological balance and gait parameters. CTRL and EXP groups underwent 8 weeks of rehabilitation 5 times/week (CTRL group: 60 minutes devoted to Rehab; EXP group: 40 minutes of Rehab plus 20 of vBFB). At baseline (T0), every 10 vBFB sessions (T1-T2-T3), at the end of training (T4) and 1 and 2 months after vBFB was halted, data on the following parameters were collected and compared between groups and training steps: Berg Balance Scale, Walking Index for Spinal Cord Injury, 6-minute walking, 10-meter walk and timed up and go tests, balance performance (assessed with a stabilometric platform), and kinematic spatio-temporal gait parameters (collected using a 2-dimensional motion analysis system). At T4, only the EXP group experienced a significant improvement in balance and gait demonstrated by clinical and instrumental evaluation; the improvement was maintained at follow-up examinations. Further, in the EXP group, the enhancement in balance that existed at T1 preceded the improvement in gait, and significant correlations between the improvements in gait and balance were observed. In comparison with H data, vBFB treatment demonstrated a significant higher level of effectiveness than conventional Rehab. vBFB training is effective in improving balance and gait in chronic SCI subjects. Inclusion of vBFB in rehabilitation protocols for chronic SCI subjects effects greater improvements in gait than conventional rehabilitation alone.


BOOP and COP.
BOOP and COP are essentially the same condition and represent one of many ways in which the lung may respond to an inflammatory stimulus. Some underlying causes of BOOP have been identified but in many cases no cause can be found. The clinical and radiological features are of a pneumonic illness that responds to corticosteroids rather than antibiotics, but as milder cases are being identified the clinical spectrum is widening. Most cases can be confidently diagnosed only by open lung biopsy, but bacteriological lavage and transbronchial biopsy followed by a trial of steroids may sometimes be considered.


Exploring mHealths Fit to Workflow in Homecare - A Case Study in Sweden.
With an ageing population and limited resources in healthcare, many high-income countries such as Sweden see an increase in homecare and mobile work for healthcare professionals. In this case study, we explore how mHealth services can support the everyday work for healthcare professionals when delivering home care in rural areas in Sweden. The studied mHealth application had failed to be adopted among district nurses, despite a great expressed need for mobile tools. The results indicate that the mHealth solution did not live up the healthcare professionals' expectations in terms of providing the same functions as the regular electronic health record systems, and with poor integration into the existing eco-system of eHealth applications. In conclusion, in order for a mHealth application to be successfully implemented in a context where many digital services are already in use, it is not enough to support important activities in the current workflow. The mHealth application will need to be carefully integrated into the existing eco-system of healthcare applications to increase the chances of adoption.


A tool for assessing perineal trauma.
The initial aim of this study was to develop a reliable visual tool to assist in the assessment of the severity of oedema and bruising in perineal trauma, using a categorical scale of 'none', 'mild', 'moderate' and 'severe'. A standardised set of photographs was selected by 10 clinically experienced midwives to represent these categories. The tool was tested in a clinical trial involving 77 women, recording and monitoring changes in the level of oedema and bruising during the first 48 hours following suturing of an episiotomy. The results demonstrated a statistically significant change for both oedema and bruising. However, the less experienced assessors reported some uncertainties in assessing a small proportion of women. A combined method, using this tool with a categorical scoring scale, was used to minimise difficulties in the assessment. Two pairs of midwives, one pair very experienced in assessing perineal trauma and the other less experienced, evaluated the combined method. The results showed a high level of agreement. The standard set of photographs and categorical scoring scale together resulted in a reliable and sensitive assessment tool to evaluate severity of perineal trauma.


A Qualitative Survey Study of United States Burn Units: Pathways to a Career in Burn Surgery.
With current changes in training requirements, it is important to understand the venues in the United States for a general surgery (GS) and plastic surgery (PS) resident interested in pursuing a burn surgery career. The study aims to evaluate the pathways to a career in burn surgery and the current state of leadership. A cross-sectional study was conducted between August and September 2017. A 12-question survey was sent to all burn unit directors in the United States, asking about their background, who manages various aspects of burn care and the hiring requirements. Responses were received from 55 burn unit directors (47% response rate). Burn units are lead most commonly by physicians who received GS training (69%), but the majority either did not undergo fellowship training (31%) or completed a burn surgery fellowship (29%). While surgical care (GS = 51%, PS = 42%) and wound care (GS = 51%, PS = 42%) were predominantly managed by GS- or PS-trained burn teams, management of other aspects of burn care varied depending on the institution, demonstrating that a shift in burn care management. The desired hiring characteristics, including GS (67%) or PS residency (44%) and a burn surgery (55%), trauma surgery (15%), or critical care (44%) fellowship. Directors' training significantly influenced their preferences for hiring requirements. While leadership in burn surgery is dominated by GS-trained physicians, the surgical and wound care responsibilities are shared among PS and GS. Although one third of current directors did not undergo fellowship training, aspiring surgeons are advised to obtain a burn surgery and/or critical care fellowship.


Deregulated expression of miR-107 inhibits metastasis of PDAC through inhibition PI3K/Akt signaling via caveolin-1 and PTEN.
Pancreatic ductal adenocarcinoma (PDAC) displays a highly aggressive malignancy and is considered to be an incurable and rapidly lethal disease. MicroRNAs (miRNAs) are small non-coding RNAs of approximately nucleotides that regulate several aspects of tumors pathogenesis, including migration, invasion, metastasis and epithelial-mesenchymal transition. We have found that miR-107 was significantly high expression in PDAC tissues and cells. High miR-107 expression is associated with poor clinicopathological parameters and prognosis in PDAC patients. Deregulated expression of miR-107 in PDAC cells (AsPC-1 and Panc-1) is sufficient to reduce cell migration and invasion, and to induce upregulation of epithelial markers (β-catenin, ZO-1 and E-cadherin) and a decrease of mesenchymal marker expression (ZEB-1 and vimentin). We also found that the caveolin-1, PTEN and p-Akt expression are modulated by miR-107 in PDAC cells. Moreover, our study clearly demonstrated that deregulated expression of miR-107 inhibited cell migration and invasion and EMT by up-regulation of caveolin-1 and PTEN, and inhibition of PI3K/Akt signaling in PDAC cells. Our study suggested that miR‑107 expression might both be a useful indicator of the metastatic potential and provided a new potential therapeutic target in PDAC.


Regional differences and correlates of leisure time physical activity in Brazil: results from the Brazilian National Health Survey-2013.
To analyze the regional differences and factors associated with physical activity during the leisure time in the adult participants of the National Health Survey, 2013. This study was carried out with the data from the National Health Survey, conducted in 2013 with an approximate sample of 63,000 adults (18+ years). For each of the five regions of Brazil, the prevalence of physically active adults during the leisure time was calculated, and the participants were classified as active if they practiced at least 150 minutes per week of physical activity during leisure time. The prevalence of individuals who were active during the leisure time varied from 21.9% in the south to 24.4% in the midwest. The men were 1.48 (95%CI 1.40-1.57) times more active than women, with the northern region showing the highest difference between the sexes. The prevalence of active individuals was 67% lower among those aged 75+ years when compared with the 18-24 age group, and this difference was more marked in the north. Those with higher levels of education were on average three times more active than the participants with lower education levels. In terms of education level, the lowest difference was observed in the northeast. Despite the slight variations in the prevalence of physical activity during the leisure time among the regions, when population subgroups are considered, important differences were observed. These results suggest the need for promotion initiatives on physical activity with different approaches in each of the five regions of Brazil.


Bio-electro-Fenton process driven by microbial fuel cell for wastewater treatment.
In this study, we proposed a new concept of utilizing the biological electrons produced from a microbial fuel cell (MFC) to power an E-Fenton process to treat wastewater at neutral pH as a bioelectro-Fenton (Bio-E-Fenton) process. This process can be achieved in a dual-chamber MFC from which electrons were generated via the catalyzation of Shewanella decolorationis S12 in its anaerobic anode chamber and transferred to its aerated cathode chamber equipped with a carbon nanotube (CNT)/gamma-FeOOH composite cathode. In the cathode chamber, the Fenton's reagents including hydrogen peroxide (H(2)O(2)) and ferrous irons (Fe(2+)) were in situ generated. This Bio-E-Fenton process led to the complete decolorization and mineralization of Orange II at pH 7.0 with the apparent first-order rate constants, k(app) = 0.212 h(-1) and k(TOC) = 0.0827 h(-1), respectively, and simultaneously produced a maximum power output of 230 mW m(-2) (normalized to the cathode surface area). The apparent mineralization current efficiency was calculated to be as high as 89%. The cathode composition was an important factor in governing system performance. When the ratio of CNT to gamma-FeOOH in the composite cathode was 1:1, the system demonstrated the fastest rate of Orange II degradation, corresponding to the highest amount of H(2)O(2) formed.


Targeting telomerase via its key RNA/DNA heteroduplex.
Telomerase is a promising "universal" anticancer target. It has been demonstrated that inhibition of telomerase leads to mortalization and death of previously immortal cell lines. We are interested in targeting telomerase by binding to the RNA/DNA duplex that forms during its catalytic cycle. The RNA strand of this duplex is a component of telomerase and acts as a template to direct the synthesis of the single-stranded DNA telomere. We have hypothesized that molecules that bind to this duplex will inhibit the enzyme by either preventing strand dissociation or by sufficiently distorting the substrate, thereby causing a misalignment of key catalytic residues. To test this hypothesis we have examined the activity of telomerase in the presence of a range of intercalating molecules, known for their broad duplex binding properties. Of the nine compounds we examined, four show promising lead activity in the low micromolar range. A kinetic analysis of the telomeric products suggests that these compounds do not act by stabilizing G-quartets, thereby supporting the telomeric RNA/DNA heteroduplex as the site of action. We anticipate using these lead compounds as the basis for combinatorial variation to increase the affinity and specificity for the target telomerase.


New Onset Focal Stabbing Headache Associated With Peripheral Vertigo: A Case Report.
We present a novel case of a focal stabbing headache sharing features of primary stabbing headache that started and resolved with the onset and resolution of a course of self-limiting peripheral vertigo. The association of onset and improvement of the stabbing headaches support the trigeminal and vestibular reciprocal relationships. Vestibular input may be the driving force and a potential target for treatment.


Redox dyshomeostasis modulation of the tumor intracellular environment through a metabolic intervention strategy for enhanced photodynamic therapy.
Rationale: Photodynamic therapy (PDT) is a clinically approved anticancer treatment with a promising therapeutic prospect, however, usually suffers from the unfavorable intracellular environment including cellular hypoxia and excessive glutathione (GSH). Comprehensive and long-term modulation of tumor intracellular environment is crucial for optimizing therapeutic outcomes. However, current strategies do not enable such requirements, mainly limited by flexible networks of intracellular metabolic avenues. Methods: A metabolic pre-intervention (MPI) strategy that targets critical pathways of cellular metabolism, ensuring long-term modulation of the intracellular environment. A versatile lipid-coating photosensitive metal-organic framework (MOF) nano-vehicle encapsulating aerobic respiration inhibitor metformin (Met) and GSH biosynthesis inhibitor buthionine sulfoximine (BSO) (termed PBMLR) was developed for comprehensive sustainable hypoxia alleviation and GSH downregulating. Results: Since MPI could effectively circumvent the compensatory accessory pathway, PBMLR, therefore functioned as an efficient singlet oxygen (1O2) radical generator during the subsequent laser irradiation process and enhanced PDT anti-tumor efficiency. We emphasized the concordance of long-term hypoxia alleviation, persistent GSH depletion, and tumor enrichment of photosensitizers, which is very meaningful for a broad therapeutic time window and the successful enhancement of PDT. Conclusion: Our findings indicate that maintaining the sensitivity of tumor cells via MPI could enhance anti-tumor PDT, and may be applied to other dynamic therapies such as radiodynamic therapy and sonodynamic therapy.


[Determination of the stable mitochondrial factor in vivo].
We have determined a release of a stable mitochondrial factor (SMF) into the outflowing blood in vivo. That effect was induced by ischemia/reperfusion or phenylarsin oxide (PAO)--the activators of the mitochondrial permeability transition pore (MPTP) and the oxidative stress. The SMF was measured by a spectrophotometer in the range of wave-lengths 230-260 nm with the absorption maximum of 240-250 nm. The SMF release was accompanied with a decrease in the myocardial contractility, disturbances in cardiodynamics and regional blood circulation. The data obtained have demonstrated that the SMF can be used as a marker of MPTP opening in vivo.


Paving the way for electronic medical records.
This article explores the reasons why electronic medical records have not become widely deployed in the health care industry. Y2K moved to center stage and fears of computer meltdowns became the single greatest obstacle to overcome before considering new technology possibilities. Almost every other information technology initiative in health care was delayed or suspended, while the issues of compatibility with four-digit dates were examined. Finding systems and devices that weren't Y2K compliant and replacing or working around their deficiencies left precious few resources available for other tasks. Another issue is standardization. The potential and promise of electronic records can only be realized if a standard way to describe clinical information can be agreed upon and implemented in practice situations. Clients have been reluctant to purchase electronic records while vendors are offering nonstandard solutions. Obstacles and benefits to implementing EMR systems are outlined. Despite some of the barriers to implementing EMRs, the future is bright for their widespread deployment.


SiRNA directed against NF‑κB inhibits mononuclear macrophage cells releasing proinflammatory cytokines in vitro.
Acute lung injury (ALI) is a condition of acute respiratory failure, characterized by diffuse pulmonary infiltrates and severe hypoxemia. During ALI, the acute phase of inflammation induces the recruitment of activated inflammatory cells, including macrophages and lymphocytes, to the damaged lesions. Nuclear factor (NF)‑κB is a key protein in many signal transduction pathways, over‑activation of which is followed by an approach of inflammation cells and release of pre‑inflammation cytokines. The aim of the present study was to explore the effect of NF‑κB P65 siRNA retroviruses on the activation of NF‑κB signaling pathway and release of pro‑inflammatory cytokines in THP‑1 cells. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were used to detect the NF‑κB p65 mRNA and protein expression at different times in THP‑1 cells infected by p65 siRNA retroviruses. The results revealed that p65 siRNA retroviruses could significantly inhibit the expression levels of NF‑κB p65 mRNA and protein at different times. In addition, to further investigate the effect of p65 siRNA retroviruses on the pro‑inflammatory cytokines release stimulated by LPS, the expression of IL‑1β in THP‑1 cells and TNF‑α in THP‑1/M cells was also detected using RT‑qPCR and ELISA. As a result, the level of released proinflammatory cytokine interleukin‑1β and tumor necrosis factor‑α stimulated was significantly inhibited at different times infected by p65 siRNA retroviruses, while increased at different times infected by siControl retroviruses in THP‑1 and THP‑1/M cells stimulated by LPS. In summary, the present study demonstrated that p65 siRNA retroviruses could suppress the activation of NF‑κB signal pathway and release of pro‑inflammatory cytokines in THP‑1 cells which provided a clinically plausible method to inhibit the inflammation for ALI/ARDS utilizing RNA interference technology.


Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma.
The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics. The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype. We performed SNaPshot genotyping on a panel of 129 FVPTCs of ≥1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes. We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARγ. BRAF mutation was significantly associated with unencapsulated tumor status. These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARγ. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes.


Serological diagnosis of the porcine proliferative enteropathies: implications for aetiology and epidemiology.
Campylobacter mucosalis and C hyointestinalis have been associated with the proliferative enteropathies of pigs. An examination of the antibody response to these organisms and to the intracellular campylobacter-like organism was undertaken. Antibody to the campylobacter-like organism was predominantly IgM, short lived, and could be detected by an immunofluorescence test using bacteria released from lesions as antigen. The majority (75 per cent) of pigs with proliferative enteropathy at necropsy were antibody positive and a small number (4 per cent) of pigs in which lesions were not observed were found to have antibody. Antibody appeared to be correlated with the presence of lesions rather than with exposure to infection and was independent of the presence of antibody to C mucosalis or C hyointestinalis. In natural outbreaks of the disease antibody to the campylobacter-like organism was more prevalent than clinical signs in the affected animals.


Comparative pathogenicity of early and recent isolates of avian metapneumovirus subtype C in turkeys.
The objective of the present study was to compare the pathogenicity of early and recent isolates of avian metapneumovirus subtype-C (aMPV-C) in turkeys. Two-week-old turkeys were inoculated with early and recent isolates of aMPV-C. Clinical signs were monitored. Tissues were examined for viral ribonucleic acid (RNA), lesions, and viral antigen by reverse transcription-polymerase chain reaction (RT-PCR), histopathology and immunohistochemistry, respectively. Birds infected with the recent isolate had higher clinical sign scores than those infected with the early isolate. Only the recent isolate produced a multifocal loss of cilia in the nasal turbinate of infected birds. Immunohistochemistry revealed intense staining of aMPV antigen in turbinate and trachea of birds infected with the recent isolate. The findings indicate that the recent isolate produced more severe clinical signs and lesions in turkeys compared to the early isolate. The recent isolate could be ideal for the development of a challenge model for aMPV infection in turkeys.


Determining magnitude of benefit from poly(ADP-ribose) polymerase inhibitors in prostate cancer.
The treatment landscape for castration-resistant prostate cancer (mCRPC) is undergoing significant advancements, particularly with the emergence of poly(ADP-ribose) polymerase inhibitors and their recent US FDA authorizations. The combination of olaparib with abiraterone and prednisone/prednisolone has gained approval for mCRPC patients harboring confirmed BRCA mutations. Subsequently, talazoparib in combination with enzalutamide was approved for patients with mutations in homologous recombination repair genes. Nevertheless, emerging evidence suggests that these treatments may confer benefits irrespective of specific biomarkers. While the understanding of biomarkers in therapy selection for mCRPC is expanding, further data are warranted to provide comprehensive elucidation for guiding clinical practice.


Achilles: A Homeric hero enamoured with the absolute.
This article explores through a psychoanalytical lens the character of Achilles in Homer's Iliad, the matrix behind the Western conception of heroism. The contribution reveals the psychological link binding the words and acts of the most valiant of warriors in Antiquity, which is situated in myth and termed "the Eros of the absolute." The paroxystic ideality underlying the aforementioned myth, which is rooted in the anthropological need to believe, is at the origin of Achilles' legendary μῆνις, that is, the flood of rage triggered by contests for supremacy, aggravated by the loss of his war comrade, aroused by the drama of aging and death, and then transfigured through song and memory. The main claim of the author is that Iliad, despite its seeming lack of attention to interiority, is launched by the archetypal emotion of wrath and owes its appeal to its hero's embrace of heroic idealism in an excessive, radical and absolute way that results in a captivating narcissism and sadomasochistic antithesis of ideality. This argument leads to the conclusion that Homer is the Father of the "primitive horde" of affects.


[Risk factors of postoperative meningitis in patients with chiasm-sellar tumors].
Postoperative intracranial infectious complications are one of the most topical problems of neurosurgical intensive care due to theirs significant capability to impair outcomes of the main disease. To define the risk factors of postoperative meningitis in patients with chiasm-sellar tumors. 1. to define the effect of somatic and intracranial risk factors on occurrence of postoperative meningitis in patients after transsphenoidal and transcranial approaches to the tumor. 2. To define the effect of postoperative meningitis on outcomes of treatment in patients after transsphenoidal and transcranial approaches to the tumor. Somatic and intracranial risk factors of occurrence of postoperative meningitis (pneumonia, urinary tract infection, sepsis, intra-abdominal hypertension, the presence of external ventricular and lumbar drainage, monitoring of intracranial pressure, cerebrospinal fluid, and reoperation) were fixed every day. The study was conducted in the ICU of the Burdenko from October, 2010 to July, 2012. The 34 patients (19 males, 15 females) were included in the study (average age 47.5 years). The patients were divided into two groups; 17 patients each group. The group-1 included patients after transcranial approach to the tumor and the group-2 included patients after transsphenoidal approach. In the group-1 a meningitis occurred in 3 patients (17.6% +/- 9.2%, DI [-0.4 - 35.6]). In the group-2 a meningitis occurred in 7 patients (41.2% +/- 11.9) DI 95% [17.8 - 64.4]. Accumulation of cerebrospinal fluid under the skin flap authentically increased a risk of a meningitis occurrence in patients after transcranial approach to the tumor (p = 0.031). There was no defined statistical significance of other risk factors. But there was defined a trend of the increasing of meningitis occurrence in patients after transsphenoidal approach in case of lumbar drainage or reoperation. Duration of mechanical ventilation and ICU stay in patients with meningitis was authentically longer than in patients without meningitis in both groups. In the group-2 the duration of mechanical ventilation and ICU stay was significantly shorter than in the group-1. Meningitis is not a typical complication of postoperative period in patients with transcranial approach to the tumor. After transsphenoidal approach a meningitis occurrence is likely in case of postoperative liquorrhea, lumbar drainage or reoperation. Subcutaneous accumulation of cerebrospinal fluid is a single defined statistically significant risk factor of meningitis. Postoperative meningitis impairs a condition of patients with chiasm-sellar tumors, increases the duration of mechanical ventilation and impairs treatment outcomes.


Selection of a water-extractable phosphorus test for manures and biosolids as an indicator of runoff loss potential.
The correlation of runoff phosphorus (P) with water-extractable phosphorus (WEP) in land-applied manures and biosolids has spurred wide use of WEP as a water quality indicator. Land managers, planners, and researchers need a common WEP protocol to consistently use WEP in nutrient management. Our objectives were to (i) identify a common WEP protocol with sufficient accuracy and precision to be adopted by commercial testing laboratories and (ii) confirm that the common protocol is a reliable index of runoff P. Ten laboratories across North America evaluated alternative protocols with an array of manure and biosolids samples. A single laboratory analyzed all samples and conducted a separate runoff study with the manures and biosolids. Extraction ratio (solution:solids) was the most important factor affecting WEP, with WEP increasing from 10:1 to 100:1 and increasing from 100:1 to 200:1. When WEP was measured by a single laboratory, correlations with runoff P from packed soil boxes amended with manure and biosolids ranged from 0.79 to 0.92 across all protocol combinations (extraction ratio, filtration method, and P determination method). Correlations with P in runoff were slightly lower but significant when WEP was measured by the 10 labs (r=0.56-0.86). Based on laboratory repeatability and water quality evaluation criteria, we recommend the following common protocol: 100:1 extraction ratio; 1-h shaking and centrifuge 10 min at 1500xg (filter with Whatman #1 paper if necessary); and determining P by inductively coupled plasma-atomic emission spectrometry or colorimetric methods.


Dominant gingers - Discovery and inheritance of a new shell polymorphism in the great pond snail Lymnaea stagnalis.
Color polymorphism is a classic study system for evolutionary genetics. One of the most color-polymorphic animal taxa is mollusks, but the investigation of the genetic basis of color determination is often hindered by their life history and the limited availability of genetic resources. Here, we report on the discovery of shell color polymorphism in a much-used model species, the great pond snail Lymnaea stagnalis. While their shell is usually beige, some individuals from a Greek population show a distinct red shell color, which we nicknamed Ginger. Moreover, we found that the inheritance fits simple, single-locus Mendelian inheritance with dominance of the Ginger allele. We also compared crucial life-history traits between Ginger and wild-type individuals, and found no differences between morphs. We conclude that the relative simplicity of this polymorphism will provide new opportunities for a deeper understanding of the genetic basis of shell color polymorphism and its evolutionary origin.


Clinical utility of antithrombotic prophylaxis in ART procedures: an Italian experience.
The usefulness of antithrombotic prophylaxis in management of Assisted Reproductive Technologies (ART) is questionable. We prospectively examined the contribution of an antithrombotic prophylaxis in influencing clinical pregnancy and live-birth in an unselected cohort of women approaching ART. 1107 women with fertility problems and a valid indication for ART were recruited. Baseline and follow-up information of obstetric outcomes and antithrombotic treatment were collected. Median follow-up time was 34.5 months (range: 2-143). During the follow-up period, 595 (53.8%) women underwent ART (total 1234 cycles); 202 (33.9%) women achieved a pregnancy for a total of 255 clinical pregnancies. The concomitant use of LMWH and aspirin was significantly associated with a higher rate of clinical pregnancies (p: 0.003, OR: 4.9, 95% CI: 1.7-14.2). The pregnancy rate was also significantly increased by the use of LMWH alone (p: 0.005, OR: 2.6, 95% CI: 1.3-5.0). Carriership of inherited or acquired thrombophilia did not affect clinical outcomes of the ART. The efficacy of antithrombotic treatment was confirmed when the outcome " live-birth" was considered. Present data suggest a potential benefit of antithrombotic prophylaxis during ART in improving the number of live-births.


Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities.
Friedreich's ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory-motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial chaperone protein required for incorporation of iron into iron-sulfur cluster and heme precursors. After the discovery of the molecular basis of FRDA in 1996, over two decades of research have been dedicated to understanding the temporal manifestations of disease both at the whole body and molecular level. Early research indicated strong cellular iron dysregulation in both human and yeast models followed by onset of oxidative stress. Since then, the pathophysiology due to dysregulation of intracellular iron chaperoning has become central in FRDA relative to antioxidant defense and run-down in energy metabolism. At the same time, limited consideration has been given to changes in cytoskeletal organization, which was one of the first molecular defects noted. These alterations include both post-translational oxidative glutathionylation of actin monomers and differential DNA processing of a cytoskeletal regulator PIP5K1β. Currently unknown in respect to FRDA but well understood in the context of FXN-deficient cell physiology is the resulting impact on the cytoskeleton; this disassembly of actin filaments has a particularly profound effect on cell-cell junctions characteristic of barrier cells. With respect to a neurodegenerative disorder such as FRDA, this cytoskeletal and tight junction breakdown in the brain microvascular endothelial cells of the blood-brain barrier is likely a component of disease etiology. This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.


Evaluation of Motor Skills in Children with Rubinstein-Taybi Syndrome.
Rubinstein-Taybi syndrome (RTS) is a rare genetic disease that associates intellectual disability with somatic characteristics. We have conducted a study of the overall motor abilities of RTS participants. Static postural performance as well as gait parameters were somewhat decreased, although not significantly compared to typically developing (TD) participants. In contrast, the motor skills requiring a high level of visuomotor coordination were considerably degraded in RTS participants compared to TD participants. We also found that cognitive status was significantly correlated with performance for tasks requiring a higher level of visuomotor coordination in RTS but not TD participants. Our study demonstrates a reduction in the motor performance of RTS participants and a link between the level of intellectual disability and motor capacities.


Pancreatitis--a retrospective study.
A retrospective study has been made of all adult patients admitted to Manchester Royal Infirmary with exocrine pancreatic disease between 1968 and 1974, in order to define the factors which influence the variable mortality and morbidity rates in published accounts of patients with acute pancreatitis. The most plausible explanation is that some series with low mortality rates include a variable number of patients with relapsing acute pancreatitis and acute exacerbations of chronic pancreatitis. Both these pathological entities have a negligible mortality and morbidity rate compared with single attacks of acute pancreatitis. The difficulties encountered by the clinician in determining the prognosis of acute pancreatitis at the time of admission to hospital are discussed. Attention is drawn to the differing role of alcohol as an aetiological factor in relapsing chronic pancreatitis and acute pancreatitis.


Lymph drainage in pregnant women.
Aim. The aim of this study was to evaluate the efficacy of lymph drainage to reduce edema of pregnant women. Method. Pregnant women (30 limbs) from the Obstetrics Outpatient Clinic of the Medical School of Santa Casa in São Paulo in the period December 2009 to May 2010 were enrolled in this quantitative, prospective study. The patients, in the 5th to 8th months of gestation, were submitted to one hour of manual lymph drainage of the legs. The volume of the legs was measured by water displacement volumetry before and after one hour of drainage using the Godoy & Godoy manual lymph drainage technique. The paired t-test was used for statistical analysis with an alpha error of 5% being considered significant. Results. Manual lymph drainage significantly reduced swelling of the legs of pregnant women during the day (P = 0.04). Conclusion. Manual lymph drainage helps to reduce limb size during the day of pregnant women.


Treatment of severe reflux esophagitis with cimetidine and metoclopramide.
Reflux esophagitis may be unresponsive to standard medical therapy with an H2-receptor antagonist drug. Twenty-five patients with chronic reflux esophagitis, refractory to cimetidine treatment alone, were randomly assigned in a double-blind design to receive cimetidine (1200 mg/d), in combination with metoclopramide (40 mg/d) or placebo. Nine of twelve patients receiving cimetidine with metoclopramide had significant symptomatic improvement at the end of the 8-week study period, compared with 3 of 12 patients receiving cimetidine with placebo (p less than 0.02). Endoscopic appearance improved in 9 patients receiving metoclopramide and in 4 patients receiving placebo (p less than 0.05). Neither group had significant improvement in lower esophageal sphincter pressure, 24-hour esophageal pH recordings, and esophageal histologic findings. Side effects were common with cimetidine and metoclopramide but were rarely disabling. This combination is efficacious in the management of chronic reflux esophagitis but, because of frequent side effects, should be reserved for patients refractory to treatment with cimetidine alone.


Unraveling Adhesion Strength between Gas Hydrate and Solid Surfaces.
Natural gas hydrate is a promising future energy source, but it also poses a huge threat to oil and gas production due to its ability to deposit within and block pipelines. Understanding the atomistic mechanisms of adhesion between the hydrate and solid surfaces and elucidating its underlying key determining factors can shed light on the fundamentals of novel antihydrate materials design. In this study, large-scale molecular simulations are employed to investigate the hydrate adhesion on solid surfaces, especially with focuses on the atomistic structures of intermediate layer and their influences on the adhesion. The results show that the structure of the intermediate layer formed between hydrate and solid surface is a competitive equilibrium of induced growth from both sides, and is regulated by the content of guest molecules. By comparing the fracture behaviors of the hydrate-solid surface system with different intermediate structures, it is found that both the lattice areal density of water structure and the adsorption of guest molecules on the interface together determine the adhesion strength. Based on the analysis of the adhesion strength distribution, we have also revealed the origins of the drastic difference in adhesion among different water structures such as ice and hydrate. Our simulation indicates that ice-adhesion strength is approximately five times that of lowest hydrate adhesion strength. This finding is surprisingly consistent with the available experimental results.


Longitudinal Associations between Homelessness and Substance Use: Investigating Demographic Differences for Young Adults in Treatment.
Objective: To examine prospective, bidirectional associations between homelessness and substance use frequency among young adults receiving substance use treatment in the United States. We also investigated potential differences across demographic subgroups. Methods: Young adults (N = 3717, Mage = 20.1, 28% female, 7.3% sexual/gender minority, and 37% non-Hispanic White) receiving substance use treatment in the U.S. completed assessments at intake, 3 months, 6 months, and 12 months post-intake. Latent growth curve models with structured residuals (LGC-SR) were used to examine cross-lagged associations between homeless days and frequency of substance use and associated problems. Models were stratified by sex, race/ethnicity, and sexual and/or gender minority status. Results: Overall, days spent homeless (μslope= -0.19, p = 0.046) and substance use frequency (μslope1= -6.19, p < 0.001) significantly decreased during treatment, with no significant cross-lagged associations between homeless days and substance use frequency. However, results differed by race and ethnicity. For non-Hispanic White young adults, greater substance use at treatment entry was associated with steeper declines in homeless days between-persons (ϕstandardized = -0.14, p = 0.04). For African Americans, homeless days at treatment entry were associated with greater increases in substance use between-persons (ϕstandardized = 0.29, p = 0.04). No significant differences were found by sex or sexual/gender minority status. Conclusions: Despite overall declines in homelessness and substance use during treatment, these outcomes may unfold differently for non-Hispanic White and African American young adults. More support may be needed for African American young adults reporting homelessness at treatment entry.


Scoring performance on computer-based patient simulations: beyond value of information.
As computer based clinical case simulations become increasingly popular for training and evaluating clinicians, approaches are needed to evaluate a trainee's or examinee's solution of the simulated cases. In 1997 we developed a decision analytic approach to scoring performance on computerized patient case simulations, using expected value of information (VOI) to generate a score each time the user requested clinical information from the simulation. Although this measure has many desirable characteristics, we found that the VOI was zero for the majority of information requests. We enhanced our original algorithm to measure potential decrements in expected utility that could result from using results of information requests that have zero VOI. Like the original algorithm, the new approach uses decision models, represented as influence diagrams, to represent the diagnostic problem. The process of solving computer based patient simulations involves repeated cycles of requesting and receiving these data from the simulations. Each time the user requests clinical data from the simulation, the influence diagram is evaluated to determine the expected VOI of the requested clinical datum. The VOI is non-zero only it the requested datum has the potential to change the leading diagnosis. The VOI is zero when the data item requested does not map to any node in the influence diagram or when the item maps to a node but does not change the leading diagnosis regardless of it's value. Our new algorithm generates a score for each of these situations by modeling what would happen to the expected utility of the model if the user changes the leading diagnosis based on the results. The resulting algorithm produces a non-zero score for all information requests. The score is the VOI when the VOI is non-zero It is a negative number when the VOI is zero.


Intramedullary spinal cord metastases: clinical features and treatment outcome.
Our objective was to delineate clinical features and treatment outcome of patients with intramedullary spinal cord metastasis (ISCM). There are no reports of a large experience with this rare cancer complication. We reviewed records retrospectively from 1980 to 1993 to identify patients with histologically confirmed systemic cancer, clinical features of myelopathy, and either tissue-proven ISCM or abnormal neuroimaging findings consistent with ISCM. We identified 40 patients who fulfilled these criteria. In nine, ISCM was the initial presentation of cancer. Nineteen patients had lung primaries (small cell in 12). Twenty-one patients had pain, 35 had demonstrable sensory loss, 37 had weakness, and 25 had urinary incontinence at presentation. Nine patients had true Brown-Séquard syndrome and nine others had pseudo-Brown-Séquard syndrome. Median duration of symptoms at diagnosis was 28 days (range 3 days to 18 months). Thirteen patients had prior brain metastasis, nine had brain metastasis simultaneous with ISCM, and one had brain metastasis after ISCM; 11 had concomitant leptomeningeal metastases. Spinal magnetic resonance findings were abnormal in 30/30 patients, myelographic results were abnormal in 16/20, and eight had pathologic confirmation of ISCM. Thirty-five patients had radiotherapy and five had surgery; four were untreated or treated elsewhere. Median survival was 4 months for patients receiving radiotherapy and 2 months for patients not receiving radiotherapy. Eleven patients survived > 6 months. Twenty-three were ambulatory at ISCM diagnosis, and 21 were ambulatory at letest follow-up. We conclude that ISCM as the initial presentation of malignancy is not rare, and hemicord syndromes occur frequently. Although long-term survival is poor, treatment preserves ambulation in most patients still ambulatory at diagnosis. Focal radiotherapy is indicated in most patients.


Information-Seeking on the Internet.
The Internet is used by young people at risk of self-harm to communicate, find information, and obtain support. We aimed to identify and analyze websites potentially accessed by these young people. Six search terms, relating to self-harm/suicide and depression, were input into four search engines. Websites were analyzed for access, content/purpose, and tone. In all, 314 websites were included in the analysis. Most could be accessed without restriction. Sites accessed by self-harm/suicide search terms were mostly positive or preventive in tone, whereas sites accessed by the term ways to kill yourself tended to have a negative tone. Information about self-harm methods was common with specific advice on how to self-harm in 15.8% of sites, encouragement of self-harm in 7.0%, and evocative images of self-harm/suicide in 20.7%. Advice on how to get help was given in 56.1% of sites. Websites relating to suicide or self-harm are easily accessed. Many sites are potentially helpful. However, a significant proportion of sites are potentially harmful through normalizing or encouraging self-harm. Enquiry regarding Internet use should be routinely included while assessing young people at risk.


[Counseling: a tool for enhancing the communication with the patient].
Counseling is a technique used in psychology that has shown a major impact on health: in deep, it is the methodology recommended by the Worl Health Organization to help HIV-infected patients. Although it has been translated to spanish by assisted counseling or helping relationship, counseling covers a broader concept. It is defined as an interactive process based on communication in which the clinician helps the patients to think about their own health and to take appropiate decisions based on their values and interests. In short, counseling is a tool to enhance communication with the patient, resulting very useful during clinical interview in pharmaceutical care programs in order to improve pharmacotherapy and patient safety.


Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma.
The antiapoptotic Bcl-2 family member Bfl-1 is up-regulated in many human tumors in which nuclear factor-kappaB (NF-kappaB) is implicated and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-kappaB induces transcription of bfl-1 and that the Bfl-1 protein is also regulated by ubiquitin-mediated proteasomal degradation. However, the role that dysregulation of Bfl-1 turnover plays in cancer is not known. Here we show that ubiquitination-resistant mutants of Bfl-1 display increased stability and greatly accelerated tumor formation in a mouse model of leukemia/lymphoma. We also show that tyrosine kinase Lck is up-regulated and activated in these tumors and leads to activation of the IkappaB kinase, Akt, and extracellular signal-regulated protein kinase signaling pathways, which are key mediators in cancer. Coexpression of Bfl-1 and constitutively active Lck promoted tumor formation, whereas Lck knockdown in tumor-derived cells suppressed leukemia/lymphomagenesis. These data demonstrate that ubiquitination is a critical tumor suppression mechanism regulating Bfl-1 function and suggest that mutations in bfl-1 or in the signaling pathways that control its ubiquitination may predispose one to cancer. Furthermore, because bfl-1 is up-regulated in many human hematopoietic tumors, this finding suggests that strategies to promote Bfl-1 ubiquitination may improve therapy.


Bacterial profile and antimicrobial susceptibility pattern of isolates among burn patients at Yekatit 12 Hospital Burn Center, Addis Ababa, Ethiopia.
Infection is a common cause of morbidity and mortality in burn patients. Clinical diagnosis of bacteremia and/or sepsis in burn patients is difficult for a number of reasons. It could be symptomatic and/or asymptomatic as a result of immune deficiency secondary to thermal injury. A cross sectional study was conducted at Yekatit 12 Hospital Burn Center. Blood specimen and wound swab were collected from burn patients and were cultured by conventional method. Sensitivity/susceptibility pattern of the isolates was determined by disc diffusion method. Some of the risk factors of bacteremia like prior antibiotic use and total body surface area burn were also determined. Fifty patients were enrolled in the study of whom 21(42%) were found bacteremic. Five different bacteria were isolated from blood specimen. Coagulase negative Staphylococci, 9(42.8%), S. aureus, 8(38.2%), Bacillus spps, 2(9.52%), K. pneumoniae, 1(4.8%), and P. aeruginosa, 1(4.8%), were frequent isolates. From wound swab, S. aureus, (34.04%), and P. aeruginosa, (31.8%), were predominant. Antimicrobial resistance was observed for Ampicillin, (77.4%), Doxycycline, (74.0), Nalidixic acid, (70.5%), Penicillin G, (68.2%), and tetracycline, (67.5%). Total body surface area of burn ≥ 15% was found as a risk factor for bacteremia. Bacteremia was detected at a rate of 42% among burn patients. Frequent isolates were S. aureus, (34.04%), and P. aeruginosa, (31.8%). About 82.16% of the isolates showed multiple resistances. In light of our findings, regular antibiotic resistance test has to be done for each patient in order to select an appropriate antimicrobial agent.


An electrochemically actuated MEMS device for individualized drug delivery: an in vitro study.
Individualized disease treatment is a promising branch for future medicine. In this work, we introduce an implantable microelectromechanical system (MEMS) based drug delivery device for programmable drug delivery. An in vitro study on cancer cell treatment has been conducted to demonstrate a proof-of-concept that the engineered device is suitable for individualized disease treatment. This is the first study to demonstrate that MEMS drug delivery devices can influence the outcome of cancer drug treatment through the use of individualized disease treatment regimes, where the strategy for drug dosages is tailored according to different individuals. The presented device is electrochemically actuated through a diaphragm membrane and made of polydimethylsiloxane (PDMS) for biocompatibility using simple and cost-effective microfabrication techniques. Individualized disease treatment was investigated using the in vitro programmed delivery of a chemotherapy drug, doxorubicin, to pancreatic cancer cell cultures. Cultured cell colonies of two pancreatic cancer cell lines (Panc-1 and MiaPaCa-2) were treated with three programmed schedules and monitored for 7 days. The result shows that the colony growth has been successfully inhibited for both cell lines among all the three treatment schedules. Also, the different observations between the two cell lines under different schedules reveal that MiaPaCa-2 cells are more sensitive to the drug applied. These results demonstrate that further development on the device will provide a promising novel platform for individualized disease treatment in future medicine as well as for automatic in vitro assays in drug development industry.


Activity of quinone alkylating agents in quinone-resistant cells.
The role of the quinone group in the antitumor activity of quinone alkylating agents, such as mitomycin C and 2,5-diaziridinyl-3,5-bis(carboethoxyamino)-1,4-benzoquinone, is still uncertain. The quinone group may contribute to antitumor activity by inducing DNA strand breaks through the formation of free radicals and/or by influencing the alkylating activity of the quinone alkylators. The cytotoxic activity and DNA damage produced by the model quinone alkylating agents, benzoquinone mustard and benzoquinone dimustard, were compared in L5178Y murine lymphoblasts sensitive and resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard. The resistant cell lines, L5178Y/HBM2 and L5178Y/HBM10, have increased concentrations of glutathione and elevated catalase, superoxide dismutase, glutathione S-transferase, and DT-diaphorase activity. L5178Y/HBM2 and L5178Y/HBM10 cells were 7.4- and 8.5-fold less sensitive to benzoquinone mustard and 1.7- and 4.3-fold less sensitive to benzoquinone dimustard, respectively, compared with sensitive cells, but showed no resistance to the non-quinone alkylating agent, aniline mustard. The formation of DNA double strand breaks by benzoquinone mustard was reduced by 2- and 8-fold in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, while double strand break formation by benzoquinone dimustard was reduced only in the L5178Y/HBM10 cells. The number of DNA-DNA cross-links produced by benzoquinone mustard was 3- and 6-fold lower, and the number produced by benzoquinone dimustard was 35% and 2-fold lower in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, compared with L5178Y parental cells. In contrast, cross-linking by aniline mustard was unchanged in sensitive and resistant cells. Dicoumarol, an inhibitor of DT-diaphorase, increased the cytotoxic activity of both benzoquinone mustard and benzoquinone dimustard in L5178Y/HBM10 cells. This study provides evidence that elevated DT-diaphorase activity in the resistant cells contributes to resistance to benzoquinone mustard and benzoquinone dimustard, possibly by decreasing the formation of the semiquinone intermediates of these agents. The altered reduction of the quinone groups in the resistant cells may be responsible for the decreased DNA-DNA cross-linking and lowered induction of DNA strand breaks by the quinone alkylating agents. These findings demonstrate that the quinone group can modulate the activity of quinone alkylating agents. The study also suggests that the semiquinone intermediates of benzoquinone mustard and benzoquinone dimustard may be the active alkylating species of these two agents.


From pancreatic islets to central nervous system, the importance of glutamate dehydrogenase for the control of energy homeostasis.
Glutamate dehydrogenase (GDH) is a mitochondrial enzyme linking the Krebs cycle to the multifunctional amino acid glutamate. Thereby, GDH plays a pivotal role between carbohydrate and protein metabolisms, controlling production and consumption of the messenger molecule glutamate in neuroendocrine cells. GDH activity is under the control of several regulators, conferring to this enzyme energy-sensor property. Indeed, GDH directly depends on the provision of the co-factor NADH/NAD(+), rendering the enzyme sensitive to the redox status of the cell. Moreover, GDH is allosterically regulated by GTP and ADP. GDH is also regulated by ADP-ribosylation, mediated by a member of the energy-sensor family sirtuins, namely SIRT4. In the brain, GDH ensures the cycling of the neurotransmitter glutamate between neurons and astrocytes. GDH also controls ammonia metabolism and detoxification, mainly in the liver and kidney. In pancreatic β-cells, the importance of GDH as a key enzyme in the regulation of insulin secretion is now well established. Inhibition of GDH activity decreases insulin release, while activating mutations are associated with a hyperinsulinism syndrome. Although GDH enzyme catalyzes the same reaction in every tissue, its function regarding metabolic homeostasis varies greatly according to specific organs. In this review, we will discuss specificities of GDH regulation in neuroendocrine cells, in particular pancreatic islets and central nervous system.


[Cyclic nucleotides in the regulation system of cell proliferation and differentiation].
The paper deals with certain aspects in the role of cyclic nucleotides in cell differentiation and proliferation. The content of cyclic nucleotides and activity of protein kinases are determined for the cell cycle stages of a synchronous plasmodium culture of true myxomycete Physarum polycephalum. Studies in the biological role of the brain cAMP-dependent protein kinase show that during phosphorylation of nuclei from the brain and subsequent isolation of chromatin its matrix activity is higher than the control one. When a regulatory subunit is added to the standard RNA-polymerase reaction, the total level of transcription increases for eucaryote RNA-polymerase. The constant of the regulatory subunit binding with chromatin from the brain is 10(10) M-1. Studies in translocation of tritium-labelled cAMP-dependent protein kinase and its subunits to interphase nuclei and in acception of these proteins by metaphase chromosomes in different cell cultures state that sAMP-dependent protein kinase penetrates into the nucleus in the dissociated state. It is established that disturbance of the regulatory subunits translocation into the nucleus and its acception by chromosomes when cell are transformed by SV40 virus is completely restored by adding cAMP. For cells, which suffered the malignant transformation of another type (spontaneous human cancer--KB, HeLa), and essential nuclear translocation and a complete absence of acception by chromosomes for the regulatory subunit are found. An assumption is made that compartmentation of cAMP-dependent protein kinase, in particular of its regulatory subunit, plays an important role in the organism vital activity and disturbances arising in neoplastic transformation are connected with changes in translocation and acception of the regulatory subunit in the nucleus.


Direct oral anticoagulant agents attenuate temporary aortic occlusion-induced renal oxidative and inflammatory responses in rats.
This study aims to investigate the effects of different direct oral anticoagulants on experimental renal injury induced by temporary infrarenal aortic occlusion. A total of 35 male Wistar rats (250 to 350 g) were randomly allocated to any of the five groups: sham, ischemia-reperfusion, rivaroxaban, dabigatran, and apixaban groups. Sham group underwent median laparotomy. Ischemia-reperfusion group was given saline gavage for one week. Animals in the other groups received rivaroxaban (3 mg/kg), dabigatran (15 mg/kg), or apixaban (10 mg/kg) daily once for one week via oral gavage. The infrarenal abdominal aorta was clamped for 60 min, and reperfusion was maintained for 120 min in the ischemia-reperfusion, rivaroxaban, dabigatran, and apixaban groups. At the end of reperfusion, kidneys were harvested for biochemical and histopathological analysis. Renal total antioxidant capacity was reduced, and total oxidant status, interleukin-1 beta, and tumor necrosis factor-alpha were elevated in the ischemia-reperfusion group, compared to the sham group (p<0.005). Histological damage scores were also higher in the ischemia-reperfusion group (p<0.005). Administration of direct oral anticoagulants caused an increase of total antioxidant capacity and reduction of total oxidant status, tumor necrosis factor-alpha, and interleukin-1 beta in the rivaroxaban, dabigatran, and apixaban groups compared to the ischemia-reperfusion group (p<0.005). Histological damage scores were lower in the rivaroxaban and dabigatran groups than the ischemia-reperfusion group scores (p<0.005). Direct oral anticoagulants reduce aortic clamping-induced renal tissue oxidation and inflammation. Rivaroxaban and dabigatran attenuate ischemia-reperfusion-related histological damage in kidneys.


Inhibition of poly (ADP-Ribose) polymerase-1 in telomerase deficient mouse embryonic fibroblasts increases arsenite-induced genome instability.
The telomerase enzyme is a viable target for anti-cancer therapy given the innate differences in telomerase activity between tumour cells and normal somatic cells. However, the time lag between telomerase inhibition and telomeres becoming critically short to trigger cell death, allows cancer cells to acquire drug resistance. Inhibition of DNA repair pathways along with telomerase could be an alternative strategy to enhance anti-tumour effects and circumvent the possibility of drug resistance. Poly (ADP-Ribose) Polymerase-1 (PARP-1), an important DNA damage sensor and a DNA repair factor, has important roles in maintaining telomeres and chromosomal stability. In this study, the effects of combined inhibition of PARP-1 and telomerase in mouse embryonic fibroblasts (MEFs) following sodium arsenite exposure (a carcinogen and potent DNA damaging agent), were evaluated. Inhibition of PARP in telomerase deficient MEFs induced an increase in arsenite-induced DNA damage as compared to control cells. Combined inhibition also resulted in enhanced genomic instability, demonstrated by elevated micronuclei induction and chromosomal aberrations with decreased cell survival. In addition, telomerase inhibition in PARP-1 deficient MEFs led to greater telomere shortening and increased genomic instability. Our study demonstrated that the co-inhibition of PARP-1 and telomerase in MEFs rendered cells more susceptible to DNA damaging agents. Hence, these results offer support for the use of combined inhibition of PARP-1 and telomerase as a strategy to minimise the problems associated with long-term telomerase inhibition in cancer therapeutics.


Role of Physical Activity in Lowering Risk of End-Stage Renal Disease.
To investigate the association between the amount and intensity of leisure-time physical activity (LTPA) and the risk of end-stage renal disease (ESRD). The study examined a cohort of 543,667 participants aged 20 years and older who participated in a health screening program from January 1, 1996, through December 31, 2017. We identified 2520 individuals undergoing dialysis or who had a kidney transplant by linking participants' encrypted personal identification with the registry for ESRD with a median follow-up of 13 years. We classified participants into 5 categories measured by metabolic equivalent of tasks. Within each category, we analyzed the effect of moderate- and vigorous-intensity LTPA in reducing risk of ESRD. We used a Cox proportional hazards model to calculate hazard ratios (HRs). We observed a dose-response relationship between LTPA and the risk of ESRD. The fully active group had a 12% lower hazard of ESRD compared with the no reported LTPA group (HR, 0.88; 95% CI, 0.80 to 0.98) adjusting for covariates including baseline estimated glomerular filtration rate and proteinuria. Within the same category of LTPA, vigorous-intensity exercise carried a 35% lower HR for ESRD compared with moderate-intensity exercise (HR, 0.65; 95% CI, 0.52 to 0.81). The effect was observed stronger among men, younger participants, and participants with diabetes or hyperlipidemia. Sustained LTPA (≥ 150 minutes per week), particularly with vigorous intensity, significantly lowered the ESRD risk, even among individuals with comorbidities such as diabetes or hyperlipidemia. This finding suggested that patients with no reported LTPA with cardiovascular risks should engage in more LTPA to lower their risk of ESRD.


Lessons from the Oslo Study Diet and Anti-smoking Trial: a qualitative study of long-term behaviour change.
The aim of this study was to identify factors associated with sustainable behaviour change among persons at increased risk for future cardiovascular disease. A qualitative approach based on focus group interviews was used. Twenty-five men aged 62-71 years who participated in the Oslo Study Diet and Anti-smoking Trial were interviewed in four focus groups. The study identified five categories of factors linked to the process of lifestyle changes: the doctor-patient relationship, significant others, motivators, barriers, and empowerment. A strong personal attachment to the principal investigator of the Oslo Study was revealed. The relationship was described as friendly and supportive. The family based approach and the impact of spouses, in particular, was emphasized by the participants. Somatic symptoms and fear often acted as motivators to behavioural change. Individual feedback was also identified as an important motivator. Psychological resistance to external pressure, concerns regarding behaviour change, and benefits from current (unhealthy) behaviour were identified as barriers. Participants reported a process of empowerment and personal control as an important element of sustainable change. The importance of the unique relationship with a certain provider has implications for future healthcare planning. This factor may also limit the external validity of studies of human behaviour.


Isolation and purification of alkaloids from lotus leaves by ionic-liquid-modified high-speed countercurrent chromatography.
An effective high-speed countercurrent chromatography method was successfully established by using ionic liquids as the modifier of the two-phase solvent system. Adding a small amount of ionic liquids significantly shortens the separation time and improves the separation efficiency. The conditions of ionic-liquid-modified high-speed countercurrent chromatography including solvent systems, types and content of added ionic liquids, and ionic liquids posttreatment were investigated. The established method was successfully applied to separate alkaloids from lotus leaves using a two-phase solvent system composed of petroleum ether/ethyl acetate/methanol/water/[C4 mim][BF4 ] (1:5:1:5:0.15, v/v/v/v/v). Four alkaloids pronuciferine (1.7 mg), N-nornuciferine (4.3 mg), nuciferine (3.1 mg), and roemerine (2.1 mg) were obtained with the purities of 90.53, 92.25, 99.86, and 98.63%, respectively, from 100 mg crude extract of lotus leaves. The results indicated that the ionic-liquid-modified high-speed countercurrent chromatography method was suitable for alkaloid separation from lotus leaves and would be a promising method for the separation of alkaloids from other natural products.


Expression of cancer-testis antigens (MAGE-A1, MAGE-A3/6, MAGE-A4, MAGE-C1 and NY-ESO-1) in primary human uveal and conjunctival melanoma.
Metastatic disease in ocular melanoma remains untreatable, is associated with late detection and is resistant to conventional systemic therapies. Many tumours including cutaneous melanoma express specific cancer-testis (CT) antigens and vaccines targeting these antigens can induce T-cell-mediated and humoural immune responses. The authors examined primary uveal and conjunctival melanomas for expression of CT antigens to assess their potential as targets for ocular melanoma immunotherapy. Paraffin-embedded uveal (n=32) and conjunctival (n=15) melanomas were assessed by immunohistochemistry for melanocyte differentiation antigens (gp100, Melan-A/MART-1 and tyrosinase), and CT antigens (MAGE-A1, MAGE-A3/6, MAGE-A4, MAGE-C1 and NY-ESO-1). Melanoma differentiation antigens, gp100, Melan-A/MART1 and tyrosinase, were expressed in >75% of tumour cells in all uveal and conjunctival melanomas tested. Expression of all five CT antigens tested was low in uveal melanomas, and when present, stained <25% of the tumour cells. MAGE-A1, MAGE-A4 and NY-ESO-1 were expressed in <10% of tumour cells in conjunctival melanomas, while MAGE-C1 and MAGE-A3/6 were expressed in ∼20% and ∼35% of tumour cells in this malignancy, respectively, with variable expression levels. Uveal and conjunctival melanomas consistently expressed high levels of the differentiation antigens (gp100, Melan-A/MART1 and tyrosinase). However, compared with other tumours, including cutaneous melanoma, only low levels of CT antigens were found in ocular melanomas. These observations suggest that immunotherapy directly targeting the CT antigens studied may not be effective for ocular melanoma.


Opportunities and challenges of self-binding directives: A comparison of empirical research with stakeholders in three European countries.
Self-binding directives (SBDs) are psychiatric advance directives that include a clause in which mental health service users consent in advance to involuntary hospital admission and treatment under specified conditions. Medical ethicists and legal scholars identified various potential benefits of SBDs but have also raised ethical concerns. Until recently, little was known about the views of stakeholders on the opportunities and challenges of SBDs. This article aims to foster an international exchange on SBDs by comparing recent empirical findings on stakeholders' views on the opportunities and challenges of SBDs from Germany, the Netherlands, and the United Kingdom. Comparisons between the empirical findings were drawn using a structured expert consensus process. Findings converged on many points. Perceived opportunities of SBDs include promotion of autonomy, avoidance of personally defined harms, early intervention, reduction of admission duration, improvement of the therapeutic relationship, involvement of persons of trust, avoidance of involuntary hospital admission, addressing trauma, destigmatization of involuntary treatment, increase of professionals' confidence, and relief for proxy decision-makers. Perceived challenges include lack of awareness and knowledge, lack of support, undue influence, inaccessibility during crisis, lack of cross-agency coordination, problems of interpretation, difficulties in capacity assessment, restricted therapeutic flexibility, scarce resources, disappointment due to noncompliance, and outdated content. Stakeholders tended to focus on practical challenges and did not often raise fundamental ethical concerns. Stakeholders tend to see the implementation of SBDs as ethically desirable, provided that the associated challenges are addressed.


Feasibility and safety of vNOTES for gynecological procedures in obese patients.
This study aimed to determine the feasibility and safety of transvaginal natural orifice transluminal endoscopic surgery (vNOTES) to treat benign and malign gynecological conditions in obese patients. We analyzed data from 79 obese patients with a body mass index (BMI) > 30 Kg/m2 operated by vNOTES for gynecological conditions between May 2020 and April 2023. The primary outcome was the feasibility of performing the surgery as initially planned. Data were presented for subgroups of patients with obesity class I (BMI 30.1 - 34.9 Kg/m2), class II (BMI 35.0 - 39.9 Kg/m2), and class III (BMI ≥ 40.0 Kg/m2). Patients presented obesity class I in 39 cases (49.4 %), class II in 27 cases (34.2 %), and class III in 13 cases (16.4 %). Fifty-two patients (65.8 %) underwent vNOTES hysterectomy, 26 patients (32.9 %) underwent procedures limited to the adnexa, and 1 patient (1.3 %) underwent myomectomy. The conversion rate was 0 %, 11.1 %, and 7.7 % in obesity class I, II, and III, respectively. Intraoperative bladder injury was observed in 1 case (1.3 %) and rectal serosal tear in 2 cases (2.5 %). Postoperatively, we observed 3 cases (3.8 %) of wound infection, 2 cases (2.5 %) of cystitis, and 1 case (1.3 %) of deep vein thrombosis. This study demonstrated the feasibility and safety of performing gynecological vNOTES procedures in obese patients. However, obesity could be associated with longer and more complex interventions, especially in obesity class II and III patients.


Classifications and comparisons of multilocus recombination distributions.
Various classifications and representations of multilocus recombination structures are delineated based on generalized notions of linkage values and recombination rates. An important class of recombination distributions (called the count-location chiasma process) is parameterized by a distribution of the number of crossover events and, for each such crossover count, by a conditional distribution of crossover locations. A number of properties of this recombination structure are developed. A multilocus definition of a "natural" recombination range is set forth. Orderings among recombination distributions in the multilocus setting are also discussed. Comparisons are made in terms of complete linkage, free assortment and noninterference schemes serving as standards.


Interaction of acetyl phosphate and carbamyl phosphate with plant phosphoenolpyruvate carboxylase.
Acetyl phosphate produced an increase in the maximum velocity (Vmax. for the carboxylation of phosphoenolpyruvate catalysed by phosphoenolpyruvate carboxylase. The limiting Vmax. was 22.2 mumol X min-1 X mg-1 (185% of the value without acetyl phosphate). This compound also decreased the Km for phosphoenolpyruvate to 0.18 mM. The apparent activation constants for acetyl phosphate were 1.6 mM and 0.62 mM in the presence of 0.5 and 4 mM-phosphoenolpyruvate respectively. Carbamyl phosphate produced an increase in Vmax. and Km for phosphoenolpyruvate. The variation of Vmax./Km with carbamyl phosphate concentration could be described by a model in which this compound interacts with the carboxylase at two different types of sites: an allosteric activator site(s) and the substrate-binding site(s). Carbamyl phosphate was hydrolysed by the action of phosphoenolpyruvate carboxylase. The hydrolysis produced Pi and NH4+ in a 1:1 relationship. Values of Vmax. and Km were 0.11 +/- 0.01 mumol of Pi X min-1 X mg-1 and 1.4 +/- 0.1 mM, respectively, in the presence of 10 mM-NaHCO3. If HCO3- was not added, these values were 0.075 +/- 0.014 mumol of Pi X min-1 X mg-1 and 0.76 +/- 0.06 mM. Vmax./Km showed no variation between pH 6.5 and 8.5. The reaction required Mg2+; the activation constants were 0.77 and 0.31 mM at pH 6.5 and 8.5 respectively. Presumably, carbamyl phosphate is hydrolysed by phosphoenolpyruvate carboxylase by a reaction the mechanism of which is related to that of the carboxylation of phosphoenolpyruvate.


Physical activity advice: short report from a population-based study in Brazil.
To evaluate the prevalence of physical activity advice, the source of the information, and the types of recommendation in a population-based sample of adults living in South Brazil. Population-based study including 972 adults living in Pelotas, Brazil. The outcome variable was based on the following question: "Has anyone ever recommended you to practice physical activity"? If the answer was positive, we asked who was responsible for the prescription (an open question, which was categorized later) and which recommendation was done. The prevalence of physical activity advice was 56.2% (95% CI 52.3-60.1). Physical activity advice was mostly done by physicians (92.5%). Walking was, by far, the most frequent recommendation. Females were more likely to receive advice for physical activity practice than males (OR 1.74; 95% CI 1.30-2.31). Age, economic level, body mass index and leisure-time physical activity were positively associated with physical activity advice, while self-reported health presented an inverse association with the outcome. The prevalence of physical activity advice was high in this sample, suggesting that the Brazilian health system is incorporating physical activity in its routine.


Disparities in Access to Radiotherapy Among Hispanic/Latinx Populations in the United States: How Far Have We Left to Go?
The Hispanic/Latinx population has consistently faced disparities in oncology access and outcomes with cancer being the leading cause of death in this population. We evaluate recent research in radiation therapy disparities among the Hispanic/Latinx population in the United States since our seminal analysis from 2017. A PubMed literature search was conducted for articles published from January 2017 through March 2023. Four term combinations were utilized, including: (1) "Hispanic" and "Radiotherapy" and "Disparities", (2) "Latino" and "Radiotherapy" and "Hispanic", (3) "Hispanic" and "Radiation" and "Disparities", and (4) "Latino" and "Radiation" and "Disparities." Included studies were those taking place in the United States, examined radiation oncology care, and examined health disparities. Fifty-eight of 245 articles returned met inclusion criteria and spanned 6 disparity-types: (1) Stage at Presentation, (2) Time to Treatment Initiation & Completion, (3) Receipt of Treatment and Guideline-Concordant Care, (4) Geography, (5) Clinical Trial Access and (6) Insurance Barriers and Treatment Center Type. The most common disparity was receipt of treatment and guideline-concordant care (n=39 studies), demonstrating that the Hispanic/Latinx population was less likely to receive guideline-concordant treatment or treatment at all. In additon, studies identified disparities in time to treatment and completion (n=12), geography (n=5), clinical trial access (n=3), and insurance and treatment center access (n=5). Disparities in radiotherapy access remain prominent for the Hispanic/Latinx population through a multitude of barriers, despite increasing interest in disparities research. Continued health care disparities research with tangible interventions are needed in radiation oncology to properly understand and address this problem.


Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma.
Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion. Patients with documented progressive disease and </=1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m(2)) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H(2) blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF. Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P = 0.002), and glucose levels were increased (P = 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P = 0.024), and plasma VEGF levels were elevated compared with pretherapy (P = 0.008). SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.


Postexercise hypotension is not sustained in normal and hypertensive humans.
Blood pressure falls after a single session of exercise. The duration for which this fall in blood pressure persists is not known. Sustained hypotension after a single session of exercise may have important implications in the treatment of patients with mild hypertension. We studied 24 subjects (12 normotensive subjects and 12 patients with mild or borderline hypertension). Blood pressure was measured in the laboratory for 30 minutes before and for an hour after graded bicycle exercise to maximal voluntary capacity. Subjects then left the hospital and measured their blood pressures at home (three measurements every 2 hours) following a strict measurement protocol for the rest of the day (usually between 8 and 12 hours). These home blood pressure measurements were compared with home blood pressure measurements recorded at the same times on a nonexercise control day. At 30 minutes after the graded maximal exercise test, the hypertensive patients experienced a fall in blood pressure from 142 +/- 3.5/93 +/- 6.5 mm Hg (mean +/- SEM) to 124 +/- 4.5/79 +/- 2.8 mm Hg (p less than 0.01). For the normotensive subjects, blood pressure after exercise fell from 117 +/- 3.1/70 +/- 2.1 mm Hg to 109 +/- 3.1/62 +/- 2.8 mm Hg (p less than 0.01). Despite these striking blood pressure reductions for the second half hour after exercise, blood pressure measurements recorded at home were not significantly different on the exercise and control days in either group. We conclude that although a single bout of exercise lowers blood pressure for a short (1-hour) period, this hypotension is not sustained.


Hepatic glycogen in humans. II. Gluconeogenetic formation after oral and intravenous glucose.
The amount of glycogen that is formed by gluconeogenetic pathways during glucose loading was quantitated in human subjects. Oral glucose loading was compared with its intravenous administration. Overnight-fasted subjects received a constant infusion or [3-3H]glucose and a marker for gluconeogenesis, [U-14C]lactate or sodium [14C]bicarbonate [14C]bicarbonate). An unlabeled glucose load was then administered. Postabsorptively, or after glucose infusion was terminated, a third tracer ([6-3H]glucose) infusion was initiated along with a three-step glucagon infusion. Without correcting for background stimulation of [14C]glucose production or for dilution of 14C with citric acid cycle carbon in the oxaloacetate pool, the amount of glycogen mobilized by the glucagon infusion that was produced by gluconeogenesis during oral glucose loading was 2.9 +/- 0.7 g calculated from [U-14C]-lactate incorporation and 7.4 +/- 1.3 g calculated using [14C]bicarbonate as a gluconeogenetic marker. During intravenous glucose administration the latter measurement also yielded 7.2 +/- 1.1 g. When the two corrections above are applied, the respective quantities became 5.3 +/- 1.7 g for [U-14C]lactate as tracer and 14.7 +/- 4.3 and 13.9 +/- 3.6 g for oral and intravenous glucose with [14C]bicarbonate as tracer (P less than 0.05, vs. [14C]-lactate as tracer). When [2-14C]acetate was infused, the same amount of label was incorporated into mobilized glycogen regardless of which route of glucose administration was used. Comparison with previous data also suggests that 14CO2 is a potentially useful marker for the gluconeogenetic process in vivo.


Rolling Nagoya mouse strain (PROD-rol/rol) with classic piebald mutation.
Ataxic rolling Nagoya (PROD-rol/rol) mice, which carry a mutation in the α1 subunit of the Cav2.1 channel (Cacna1a) gene, were discovered in 1969. They show white spots on agouti coat and have a mutation in the piebald spotting (s) locus. However, mutation analysis of the s locus encoding the endothelin receptor type B (Ednrb) gene in PROD-rol/rol mice had not been performed. Here, we examined the genomic and mRNA sequences of the Ednrb gene in PROD-rol/rol and wild-type rolling Nagoya (PROD-s/s) and studied the expression patterns of Ednrb and Cacna1a genes in these mice in comparison with C57BL/6J mice. Polymerase chain reaction analyses revealed two silent nucleotide substitutions in the coding region and insertion of a retroposon-like element in intron 1 of the Ednrb gene. Expression analyses demonstrated similar localizations and levels of Ednrb and Cacna1a expression in the colon between PROD-rol/rol and PROD-s/s mice, but the expression levels of both genes were diminished compared with C57BL/6J mice. Microsatellite genotyping showed that at least particular regions of chromosome 14 proximal to the Ednrb locus of the PROD strain were derived from Japanese fancy piebald mice. These results indicated that PROD-rol/rol mice have two mutant genes, Ednrb and Cacna1a. As no PROD strain had an intact Ednrb gene, using congenic rolling mice would better serve to examine rolling Nagoya-type Cav2.1 channel dysfunctions.


Effect of Socioeconomic Status on Surgery Waiting Times and Mortality After Hip Fractures in Italy.
Reducing inequities is a main goal of the Italian healthcare system. We evaluated socioeconomic differences in delayed surgery and postoperative mortality after a hip replacement after a fracture in Piedmont Region (Italy). Cohort study including all people aged ≥65 years hospitalized for a hip fracture in 2007-2010 (n = 21,432). Study outcomes were the following: (1) surgery waiting times >2 days; (2) 30-day, 90-day, and 1-year mortality from admission. Log-binomial models were used to evaluate the effect of socioeconomic status on waiting time, adjusting for age, sex, comorbidities, biennium, and Local Health Unit. Logistic models were fitted for mortality, adjusting also for the type of intervention (prosthesis/reduction) and waiting time. Seventy percent of surgeries were performed beyond 2 days from admission; 30-day mortality was 4.1%, 90-day was 10.8%, and 1-year was 21.9%. Lower socioeconomic levels were associated with higher risk of waiting >2 days (Adjusted Relative Risk: 1.14) and higher odds for 90-day (Adjusted Odds Ratio: 1.18) and 1-year (Adjusted OR: 1.27) mortality. We found socioeconomic inequities in access to hip replacement and postoperative outcomes. Strengthening the connection between hospital, primary care and rehabilitation services, improving regional monitoring systems and taking into account quality of care in funding health system, may contribute to guarantee uniform levels of healthcare quality in Italy.


Periodontitis, edentulism and glycemic control in patients with type 2 diabetes: a cross-sectional study.
To compare the glycemic control in non-smoking patients with type 2 diabetes according to their periodontal and dental status. This cross-sectional study investigated patients previously diagnosed with type 2 diabetes and under antidiabetic medication. Clinical data and fasting blood glucose (FBG) levels were collected from medical and dental records. Patients were divided into three groups according to dental and periodontal diagnosis: no or mild periodontitis (NO/MILD, n=96), moderate or severe periodontitis (MOD/SEV, n=74) and edentulous (n=141). FBG levels were compared between groups. Logistic regression was also applied to estimate the OR of presenting hyperglycemia. Edentulous patients had significantly higher FBG levels of 155.7±70.9 (mean±SD mg/dL) than those in the MOD/SEV (136.6±33.8) and the NO/MILD (123.1±36.7) groups. Differences between the latter two groups were also significant. Edentulous patients had adjusted ORs of 4.53, 4.27 and 3.95 of having FBG≥126, ≥150 and ≥180 mg/dL, respectively, in comparison with NO/MILD group. The MOD/SEV group also presented significant odds of having FBG≥126 mg/dL (OR=2.66) and ≥150 mg/dL (OR=2.45) than the NO/MILD group. Patients in the MOD/SEV group had worse glycemic control than the ones in the NO/MILD group. However, edentulous patients presented higher glycemic levels than both dentate groups, and also presented with higher odds of having hyperglycemia.