Tractography-based targeting of the ventral intermediate nucleus: accuracy and clinical utility in MRgFUS thalamotomy.
Tractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a novel method conferring patient-specific selection of VIM coordinates for tremor surgery; however, its accuracy and clinical utility in magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy compared to conventional indirect targeting has not been specifically addressed. This retrospective study sought to compare the treatment locations and potential adverse effect profiles of T-VIM with indirect targeting in a large cohort of MRgFUS thalamotomy patients. T-VIM was performed using diffusion tractography outlining the pyramidal and medial lemniscus tracts in 43 MRgFUS thalamotomy patients. T-VIM coordinates were compared with the indirect treatment coordinates used in the procedure. Thalamotomy lesions were delineated on postoperative T1-weighted images and displaced ("translated") by the anteroposterior and mediolateral difference between T-VIM and treatment coordinates. Both translated and actual lesions were normalized to standard space and subsequently overlaid with areas previously reported to be associated with an increased risk of motor and sensory adverse effects when lesioned during MRgFUS thalamotomy. T-VIM coordinates were 2.18 mm anterior and 1.82 mm medial to the "final" indirect treatment coordinates. Translated lesions lay more squarely within the boundaries of the VIM compared to nontranslated lesions and showed significantly less overlap with areas associated with sensory adverse effects. Translated lesions overlapped less with areas associated with motor adverse effects; however, this difference was not significant. T-VIM leads to the selection of more anterior and medial coordinates than the conventional indirect methods. Lesions moved toward these anteromedial coordinates avoid areas associated with an increased risk of motor and sensory adverse effects, suggesting that T-VIM may improve clinical outcomes.


Ureteroneocystostomy for treatment of struvite urolithiasis in a ferret.
To assess the clinical outcome of a ferret undergoing a ureteroneocystostomy for treatment of urolithiasis. A 10-month-old spayed female ferret. The ferret was evaluated for straining to urinate and defecate, hematochezia, and a rectal prolapse. Plain radiographs revealed large cystic and ureteral calculi. Clinicopathologic analyses indicated the ferret was anemic with an elevated creatinine concentration. Exploratory laparotomy defined bilateral ureteral calculi that were unable to be successfully moved into the bladder. A cystotomy was performed to remove a large cystic calculus. Serial abdominal ultrasonographic examinations showed progressive hydronephrosis of the left kidney and persistent pyelectasia of the right kidney secondary to bilateral ureteral calculi. This confirmed a left ureteral obstruction secondary to the distal calculus while the right ureter remained patent. A ureteroneocystostomy was performed to allow for left renal decompression. The ferret recovered well despite worsening hydronephrosis of the left kidney in the perioperative period. The ferret was discharged from the hospital 10 days after initial evaluation. At 3-week follow-up, abdominal ultrasonography confirmed resolution of hydronephrosis and ureteral dilation of the left kidney and ureter. A ureteroneocystostomy successfully allowed renal decompression and ureteral patency in a ferret with urolithiasis. To the authors' knowledge, this is the first time this procedure has been reported in a ferret for treatment of a ureteral calculus obstruction and may result in good long-term outcome.


Cargo regulates clathrin-coated pit dynamics.
Clathrin-coated pits (CCPs) are generally considered a uniform population of endocytic machines containing mixed constitutive and regulated membrane cargo. Contrary to this view, we show that regulated endocytosis of G protein-coupled receptors (GPCRs) occurs preferentially through a subset of CCPs. Significantly, GPCR-containing CCPs are also functionally distinct, as their surface residence time is regulated locally by GPCR cargo via PDZ-dependent linkage to the actin cytoskeleton. Such cargo-regulated CCPs show delayed recruitment of dynamin and can undergo an abortive event in which clathrin coats separate from the plasma membrane without concomitant receptor endocytosis. Segregation of cargo into CCP subsets, combined with cargo-dependent control of CCP dynamics, suggests a simple kinetic mechanism to generate functional specialization early in the endocytic pathway and reduce competition between diverse endocytic cargo.


TARDBP in amyotrophic lateral sclerosis: identification of a novel variant but absence of copy number variation.
Mutations in the gene encoding TDP-43 have been identified in both familial and sporadic amyotrophic lateral sclerosis (ALS). A mutation screen and copy number analysis in a motor neuron disease clinic cohort was conducted to characterise the genetic contribution of TARDBP. A novel missense mutation in a highly conserved region of TDP-43 was identified in a patient with sporadic ALS. The mutation is in close vicinity to previously identified changes. Copy number variation abnormalities were not detected. The findings stress the importance of TDP-43 in the pathogenesis of sporadic ALS.


Cold interactions and chemical reactions of linear polyatomic anions with alkali-metal and alkaline-earth-metal atoms.
We consider collisional studies of linear polyatomic ions immersed in ultracold atomic gases and investigate the intermolecular interactions and chemical reactions of several molecular anions (OH-, CN-, NCO-, C2H-, C4H-) with alkali-metal (Li, Na, K, Rb, Cs) and alkaline-earth-metal (Mg, Ca, Sr, Ba) atoms. State-of-the-art ab initio techniques are applied to compute the potential energy surfaces (PESs) for these systems. The coupled cluster method restricted to single, double, and noniterative triple excitations, CCSD(T), is employed and the scalar relativistic effects in heavier metal atoms are modeled within the small-core energy-consistent pseudopotentials. The leading long-range isotropic and anisotropic induction and dispersion interaction coefficients are obtained within the perturbation theory. The PESs are characterized in detail and their universal similarities typical for systems dominated by the induction interaction are discussed. The two-dimensional PESs are provided for selected systems and can be employed in scattering calculations. The possible channels of chemical reactions and their control are analyzed based on the energetics of the reactants. The present study of the electronic structure is the first step towards the evaluation of prospects for sympathetic cooling and controlled chemistry of linear polyatomic ions with ultracold atoms.


Tuberculosis testing. Physician attitudes and practice.
To assess physician agreement with and adoption of American Academy of Pediatrics' (AAP) recommendations on tuberculosis screening in children. Survey of a random sample of 1272 community pediatricians and family physicians (excluding academic institutions) in 4 mid-Atlantic states and the District of Columbia. The response rate was 66%. Seventy-five percent of the respondents were aware of the 1994 AAP screening recommendations. Most (64%) test children at low risk periodically (at age 1 year, preschool age, and adolescent age), and 81% test children at high risk annually. Eighty-one percent of the respondents estimated that 10% or less of their patients were at high risk for tuberculosis. Most use patient-specific factors, geographic or community prevalence, or both as principal criteria to determine risk. Eighty-seven percent used multiple-puncture tests in 1993; this declined to 55% in 1994. Multiple-puncture tests are still used exclusively by 29% of the respondents. Ninety-one percent of those using multiple-puncture tests and 19% of those using the Mantoux test allow parents to read the test reaction. Forty-six percent of the respondents believed that if a return visit was required for reading the test reaction, 50% or less of their patients would return. Only 22% of the respondents adhere to the 1994 AAP recommendations regarding frequency, testing method, and reading the test reaction. Factors associated with adherence to AAP recommendations included physician and practice characteristics and knowledge of AAP recommendations. Physician practice of tuberculosis testing varies widely; most do not adhere to the 1994 AAP recommendations. Most physicians vary the frequency and testing method based on a patient's risk status. The use of multiple-puncture tests has declined, although they are still widely used. Accurate reading of screening tests remains a major concern.


Angioedema.
Angioedema is characterized by a well-demarcated swelling on the skin, oropharyngolaryngeal tissue, or the gastrointestinal wall. Underlying mechanisms may include IgE-mediated reactions, complement activation, inhibition of the cyclo-oxygenase pathway of arachidonic acid metabolism, direct release of mediators from mast cells, and activation of the kinin-forming system. Foods, drugs, inhalants, insect bites, blood transfusion, collagen vascular disease, infections, physical factors, neoplasms, and hereditary factors can cause angioedema through one or more of these mechanisms. Chronic angioedema lasts more than 6 weeks or recurs during this period. Acute angioedema is a self-limited disorder and resolves spontaneously, or with simple therapy, in several days; the patient rarely requires a complete work-up. Chronic angioedema may necessitate a detailed history, physical examination, and limited clinical or laboratory tests to exclude serious underlying illnesses. The H1 antihistamines are used for the treatment of both acute and chronic angioedema. An H2 antihistamine, a second H1 antihistamine, or rarely even a low dose of corticosteroid may be added to the regimen if H1 antihistamine alone fails to control chronic angioedema. Hereditary angioedema is an autosomal dominant disease that is caused by C1INH deficiency. In patients with this disorder, swelling of the lip, pharynx, and extremities may follow trauma to soft tissue. Other clinical manifestations include abdominal pain, nausea, vomiting, and suffocation because of laryngeal swelling. Diagnosis can be confirmed by the finding of low levels of C4 and C2 and the absence of nonfunction of C1INH. Androgens reverse the biochemical defects.


Current pharmacological approaches to the therapy of varicella zoster virus infections: a guide to treatment.
Varicella zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella, chickenpox) as well as reactivation (zoster, shingles) infections. In immunocompetent patients, the course of varicella is generally benign. For varicella zoster, post-herpetic neuralgia is the most common complication. In immunocompromised patients (particularly those with AIDS), transplant recipients and cancer patients, VZV infections can be life-threatening. For these patients and also for immunocompetent patients at risk such as pregnant women or premature infants, the current treatment of choice is based on either intravenous or oral aciclovir (acyclovir). The low oral bioavailability of aciclovir, as well as the emergence of drug-resistant virus strains, have stimulated efforts towards the development of new compounds for the treatment of individuals with VZV infections. Among these new compounds, penciclovir, its oral prodrug form famciclovir and the oral pro-drug form of aciclovir (valaciclovir), rank among the most promising. As with aciclovir itself, all of these drugs are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation (phosphorylation), and, upon conversion to their triphosphate form, they act as inhibitors/alternative substrate of the viral DNA polymerase. Therefore, cross-resistance to these drugs may be expected for those virus mutants that are TK-deficient and thus resistant to aciclovir. Other classes of nucleoside analogues dependent for their phosphorylation on the viral TK that have been pursued for the treatment of VZV infections include sorivudine, brivudine, fialuridine, fiacitabine and netivudine. Among oxetanocins, which are partially dependent on viral TK, lobucavir is now under clinical evaluation. Foscarnet, which does not require any previous metabolism to interact with the viral DNA polymerase, is used in the clinic when TK-deficient VZV mutants emerge during aciclovir treatment. TK-deficient mutants are also sensitive to the acyclic nucleoside phosphonates (i.e. [s]-1-[3-hydroxy-2-phosphonylmethoxypropyl]cytosine; HPMPC); these agents do not depend on the virus-encoded TK for their phosphorylation but depend on cellular enzymes for conversion to their diphosphoryl derivatives which then inhibit viral DNA synthesis. Vaccination for VZV has now come of age. It is recommended for healthy children, patients with leukaemia, and patients receiving immunosuppressive therapy or those with chronic diseases. The protection induced by the vaccine seems, to some extent, to include zoster and associated neuralgia. Passive immuniatin based on specific immunoglobulins does not effectively prevent VZV infection and is therefore restricted to high risk individuals (i.e. immunocompromised children and pregnant women).


Cloning and expression of gene 2, required for the protein-primed initiation of the Bacillus subtilis phage phi 29 DNA replication.
A phi 29 DNA fragment containing gene 2, coding for a phi 29-specific DNA polymerase required for the formation of the terminal protein p3-dAMP initiation complex, the first step in phi 29 DNA replication, has been cloned in plasmid pPLc28 under the control of the pL promoter of bacteriophage lambda. Four polypeptides of Mr 68 000, 5800 and 3400 and less than 2000 were labelled with [35S]methionine after heat induction. The protein of Mr 68 000 had the size expected for protein p2 and it accounted for about 2% of the de novo synthesized protein. Protein p2 synthesized in Escherichia coli was shown to be stable and biologically active. Its enzymatic activity could be assayed by the in vitro formation of the protein p3-dAMP initiation complex when complemented with extracts from Bacillus subtilis infected with a phi 29sus2 mutant or with extracts from E. coli harbouring gene 3-containing recombinant plasmids. Moreover, protein p2-containing E. coli extracts could catalyze the initiation reaction in vitro when complemented with highly purified protein p3.


Consultation request patterns, patient characteristics, and utilization of services within a Veterans Affairs medical center chiropractic clinic.
A retrospective review of completed chiropractic consultations in 2006 (N = 354) was carried out to investigate consultation request patterns, patient characteristics, and the utilization of chiropractic services within the Department of Veterans Affairs of Western New York Health Care System. Primary care was the main source of patients with variation in the volume of consultation requests among providers. The average chiropractic patient was a 55-year-old male with low back pain who was overweight or obese with 27.43% service-connected disability. Post-traumatic stress disorder was diagnosed in 16.44%. The mean number of patient visits was minimized by following outcome-based practice parameters. Management consisted mainly of spinal manipulative therapy and mobilization techniques. Veteran chiropractic patients differed demographically from those in the general public who are predominantly female and younger. The implications of these differences on clinical outcomes and chiropractic clinical education are unclear and serve as the stimulus for additional research.


Scientific impact of studies published in temporarily available radiation oncology journals: a citation analysis.
The purpose of this study was to review all articles published in two temporarily available radiation oncology journals (Radiation Oncology Investigations, Journal of Radiosurgery) in order to evaluate their scientific impact. From several potential measures of impact and relevance of research, we selected article citation rate because landmark or practice-changing research is likely to be cited frequently. The citation database Scopus was used to analyse number of citations. During the time period 1996-1999 the journal Radiation Oncology Investigations published 205 articles, which achieved a median number of 6 citations (range 0-116). However, the most frequently cited article in the first 4 volumes achieved only 23 citations. The Journal of Radiosurgery published only 31 articles, all in the year 1999, which achieved a median number of 1 citation (range 0-11). No prospective randomized studies or phase I-II collaborative group trials were published in these journals. Apparently, the Journal of Radiosurgery acquired relatively few manuscripts that were interesting and important enough to impact clinical practice. Radiation Oncology Investigations' citation pattern was better and closer related to that reported in several previous studies focusing on the field of radiation oncology. The vast majority of articles published in temporarily available radiation oncology journals had limited clinical impact and achieved few citations. Highly influential research was unlikely to be submitted during the initial phase of establishing new radiation oncology journals.


T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment.
Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and aggressive non-Hodgkin's lymphomas. Despite progress in the last several years resulting in a deeper understanding of PTCL biology and pathogenesis, there is currently no accepted single standard of care for newly diagnosed patients, and for those with relapsed or refractory disease, prognosis is dismal. The National Cancer Institute convened a Clinical Trials Planning Meeting to advance the national clinical trial agenda in lymphoma. The objective was to identify unmet needs specific to five major lymphoma subtypes and develop strategies to address them. This consensus statement reviews recent advances in the molecular and genetic characterization of PTCL that may inform novel treatments, proposes strategies to test novel therapies in the relapsed setting with the hopes of rapid advancement into frontline trials, and underscores the need for the identification and development of active and biologically rational therapies to cure PTCL at higher rates, with iterative biomarker evaluation.


Life Cycle Exposure to Environmentally Relevant Concentrations of Diphenyl Phosphate (DPhP) Inhibits Growth and Energy Metabolism of Zebrafish in a Sex-Specific Manner.
Due to commercial uses and environmental degradation of aryl phosphate esters, diphenyl phosphate (DPhP) is frequently detected in environmental matrices and is thus of growing concern worldwide. However, information on potential adverse effects of chronic exposure to DPhP at environmentally realistic concentrations was lacking. Here, we investigated the effects of life cycle exposure to DPhP on zebrafish at environmentally relevant concentrations of 0.8, 3.9, or 35.6 μg/L and employed a dual-omics approach (metabolomics and transcriptomics) to characterize potential modes of action. Exposure to DPhP at 35.6 μg/L for 120 days resulted in significant reductions in body mass and length of male zebrafish, but did not cause those same effects to females. Predominant toxicological mechanisms, including inhibition of oxidative phosphorylation, down-regulation of fatty acid oxidation, and up-regulation of phosphatidylcholine degradation, were revealed by integrated dual-omics analysis and successfully linked to adverse outcomes. Activity of succinate dehydrogenase and protein content of carnitine O-palmitoyltransferase 1 were significantly decreased in livers of male fish exposed to DPhP, which further confirmed the proposed toxicological mechanisms. This study is the first to demonstrate that chronic, low-level exposure to DPhP can retard growth via inhibiting energy output in male zebrafish.


Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.
This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.


Supporting evidence-based practice for nurses through information technologies.
To evaluate the usability of mobile information terminals, such as personal digital assistants (PDAs) or Tablet personal computers, to improve access to information resources for nurses and to explore the relationship between PDA or Tablet-supported information resources and outcomes. The authors evaluated an initiative of the Nursing Secretariat, Ontario Ministry of Health and Long-Term Care, which provided nurses with PDAs and Tablet PCs, to enable Internet access to information resources. Nurses had access to drug and medical reference information, best practice guidelines (BPGs), and to abstracts of recent research studies. The authors took place over a 12-month period. Diffusion of Innovation theory and the Promoting Action on Research Implementation in Health Services (PARIHS) model guided the selection of variables for study. A longitudinal design involving questionnaires was used to evaluate the impact of the mobile technologies on barriers to research utilization, perceived quality of care, and on nurses' job satisfaction. The setting was 29 acute care, long-term care, home care, and correctional organizations in Ontario, Canada. The sample consisted of 488 frontline-nurses. Nurses most frequently consulted drug and medical reference information, Google, and Nursing PLUS. Overall, nurses were most satisfied with the Registered Nurses Association of Ontario (RNAO) BPGs and rated the RNAO BPGs as the easiest resource to use. Among the PDA and Tablet users, there was a significant improvement in research awareness/values, and in communication of research. There was also, for the PDA users only, a significant improvement over time in perceived quality of care and job satisfaction, but primarily in long-term care settings. It is feasible to provide nurses with access to evidence-based practice resources via mobile information technologies to reduce the barriers to research utilization.


Do women prefer care from female or male obstetrician-gynecologists? A study of patient gender preference.
To determine whether men should be encouraged to enter the medical specialty of obstetrics and gynecology. A self-administered survey was designed for and distributed to patients (N=264) in 13 obstetrics and gynecology waiting rooms in Connecticut. The survey was used to determine whether there were any patient preferences with regard to the gender of physicians providing obstetric and gynecologic care within this population. In addition, the rationale for any preferences was analyzed. The majority of patients (66.6%) had no gender bias when selecting an obstetrician-gynecologist, and an even larger majority (198, 80.8%) felt that physician gender does not influence quality of care. There was no statistical difference in patient satisfaction based on physician sex. Respondents self-reporting gender bias rarely selected obstetrician-gynecologists based solely on this factor and frequently choose physicians of the sex that was not their indicated preference, suggesting that several factors other than gender preference are more important in physician selection. The majority of women surveyed did not select their obstetrician-gynecologists based solely on physician gender. Although a small percentage of survey respondents did indicate a gender preference, it rarely influenced physician selection and was only a minor consideration when compared with other desirable physician attributes.


Anal cytological abnormalities and epidemiological correlates among men who have sex with men at risk for HIV-1 infection.
The incidence of anal cancer, a Human Papillomavirus (HPV)-related neoplasia, has been increasing in recent decades, mainly in men who have sex with men (MSM). Cytological changes of the anal epithelium induced by HPV can be detected through an anal pap smear. This study aimed to evaluate the prevalence and epidemiological correlates of anal cytological abnormalities among relatively young MSM at risk for HIV-1 infection, to help clarify whether or not this population deserves further investigation to assess the presence of anal cancer precursor lesions. MSM were recruited among attendees of a large STI clinic for a HIV-1 screening program. Anal samples, collected with a Dracon swab in PreservCyt, were used both for liquid-based cytology and HPV testing by the Linear Array HPV Genotyping Test. Data regarding socio-demographic characteristics and sexual behavior were collected in face-to-face interviews. A total of 346 MSM were recruited (median age 32 years). Overall, 72.5% of the individuals had an anal HPV infection, with 56.1% of them being infected by oncogenic HPV genotypes. Anal cytological abnormalities were found in 29.8% of the cases (16.7% ASC-US and 13.1% L-SIL). Presence of ASC-US+ was strongly associated with infection by any HPV type (OR = 4.21, 95% CI: 1.97-9.23), and particularly by HPV 16 and/or 18 (OR = 5.62, 95% CI: 2.33-13.81). A higher proportion of ASC-US+ was found in older MSM, in those with a higher number of lifetime partners and in those with a history of ano-genital warts. However, none of these variables or the others analyzed showed any significant association with abnormal cytological findings. The presence of anal cytological abnormalities in about one third of the recruited MSM and their strong association with HPV infection, in particular that caused by HPV 16 and/or 18, might provide a further complement to the data that now support the introduction of HPV vaccination among MSM to protect them from the development of HPV-associated diseases. Additional studies are needed to determine whether and how screening for anal cancer precursor lesions should be performed in younger MSM.


Recombinant expression of Epinephelus lanceolatus serum amyloid A (ElSAA) and analysis of its macrophage modulatory activities.
Serum amyloid A (SAA) is an acute-phase protein that plays a crucial role in the inflammatory response. In this study, we identified an SAA homolog from Epinephelus lanceolatus (ElSAA). Molecular characterization revealed that ElSAA contains a fibronectin-like motif that is typical of SAAs. Recombinant ElSAA protein (rElSAA) was produced in E. coli BL21 (DE3) cells and purified as a soluble protein. To analyze its biological activity, mouse Raw264.7 macrophage cells were treated with various concentrations of rElSAA. Expression of several inflammation-related cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-10, was induced by rElSAA. This protein also triggered macrophage differentiation, as evidenced by increases in cell size and complexity. To determine whether rElSAA regulates macrophage polarization, we assessed gene expression of M1 and M2 markers. The results demonstrated that rElSAA induced the expression of both M1 and M2 markers, suggesting that it promotes the differentiation of macrophages into a mixed M1/M2 phenotype. To evaluate whether rElSAA enhances phagocytosis via an opsonization-dependent mechanism, GFP-labeled E. coli cells were pretreated with rElSAA, followed by incubation with Raw264.7 cells. Flow cytometry was used to monitor the phagocytic uptake of GFP-labeled E. coli by macrophages. Surprisingly, incubating E. coli with rElSAA did not enhance bacterial uptake by macrophages. However, preincubating Raw264.7 cells with various concentrations of rElSAA, followed by infection with E. coli (multiplicity of infection = 20 or 40), resulted in a clear enhancement of macrophage phagocytic capacity. In conclusion, we have identified SAA from E. lanceolatus and have demonstrated that rElSAA promotes inflammatory cytokine production and macrophage differentiation. In addition, rElSAA enhances phagocytosis of bacteria by macrophages via an opsonization-independent mechanism.


Innovations in problem-based learning: what can we learn from recent studies?
This article aims at discussing the six papers included in this special issue on innovations in Problem-based learning (PBL). The papers address different aspects related to the implementation and the development of PBL. This discussion article highlights the relevance of the theme explored by each of the papers, the contributions emerging from the study to what is already known about that topic, and its limitations, particularly those that suggest directions for future research. Emphasis is given to new insights brought by the papers for better understanding tutorial group processes and self-study phase in PBL. The contributions provided by the papers are discussed in the light of pertinent literature and also in relation to their companion articles in this issue when indicated.


Renewable energy.
The Energy Committee of the Royal Swedish Academy of Sciences has in a series of projects gathered information and knowledge on renewable energy from various sources, both within and outside the academic world. In this article, we synthesize and summarize some of the main points on renewable energy from the various Energy Committee projects and the Committee's Energy 2050 symposium, regarding energy from water and wind, bioenergy, and solar energy. We further summarize the Energy Committee's scenario estimates of future renewable energy contributions to the global energy system, and other presentations given at the Energy 2050 symposium. In general, international coordination and investment in energy research and development is crucial to enable future reliance on renewable energy sources with minimal fossil fuel use.


Energy balance-related behaviours associated with overweight and obesity in preschool children: a systematic review of prospective studies.
The current review aimed to systematically identify dietary, physical activity and sedentary behaviours in preschool children (4-6 years of age) that are prospectively related to overweight or obesity later in childhood. Prospective studies published between January 1990 and June 2010 were selected from searches in PubMed, EMBASE, PsycINFO, CINAHL and Cochrane Library. Studies examining the prospective association between at least one relevant behaviour measured during preschool period (children aged 4-6 years at baseline) in relation to at least one anthropometric measurement at follow-up (age <18 years) were included. Harvest plots were used to summarize the results and draw conclusions from the evidence. Of the 8,718 retrieved papers, 23 papers reporting on 15 different study samples were included in this review. Strong evidence was found for an inverse association between total physical activity and overweight. Moderate evidence was observed for a positive association between television viewing and overweight. Because of the heterogeneity in the assessed dietary behaviours, insufficient evidence was found for an association between dietary intake or specific dietary behaviours and overweight. These results suggest that interventions aiming to prevent overweight among preschool children should focus on promotion of total physical activity and limitation of screen time and that further research is needed to establish whether and which dietary behaviours are important for obesity prevention in this age group. However, despite the lack of evidence for dietary behaviours from the present review, future interventions may already target specific dietary behaviours that are highly prevalent and for which there a clear rationale as well as preliminary evidence that these behaviours are associated with overweight.


Improvement after constraint-induced movement therapy: recovery of normal motor control or task-specific compensation?
Constraint-induced movement therapy (CIMT) has proven effective in increasing functional use of the affected arm in patients with chronic stroke. The mechanism of CIMT is not well understood. To demonstrate, in a proof-of-concept study, the feasibility of using kinematic measures in conjunction with clinical outcome measures to better understand the mechanism of recovery in chronic stroke patients with mild to moderate motor impairments who undergo CIMT. A total of 10 patients with chronic stroke were enrolled in a modified CIMT protocol over 2 weeks. Treatment response was assessed with the Action Research Arm Test (ARAT), the Upper-Extremity Fugl-Meyer score (FM-UE), and kinematic analysis of visually guided arm and wrist movements. All assessments were performed twice before the therapeutic intervention and once afterward. There was a clinically meaningful improvement in ARAT from the second pre-CIMT session to the post-CIMT session compared with the change between the 2 pre-CIMT sessions. In contrast, FM-UE and kinematic measures showed no meaningful improvements. Functional improvement in the affected arm after CIMT in patients with chronic stroke appears to be mediated through compensatory strategies rather than a decrease in impairment or return to more normal motor control. We suggest that future large-scale studies of new interventions for neurorehabilitation track performance using kinematic analyses as well as clinical scales.


Short-term and long-term impact of the central line workshop on resident clinical performance during simulated central line placement.
The Central Line Workshop (CLW) was introduced at our institution to better train residents in safe placement of the central venous catheter (CVC). This study sought to determine if immediate performance improvements from the CLW are sustained 3 months after the training for residents with various levels of experience. Twenty-six emergency medicine residents completed the CLW, which includes online modules and experiential sessions in anatomy, ultrasound, sterile technique, and procedural task training. Demonstration of the synthesis of these skills including placement of both internal jugular and subclavian CVCs was assessed using a task trainer. Each resident was also tested approximately 3 months before and 3 months after the CLW. Residents were assessed using a validated CVC proficiency scale. Residents' CVC proficiency scores (percentage of items performed correctly during the assessment station) improved after CLW (0.6 vs. 0.93, P < 0.05). At 3 months after CLW testing, there was apparent skill decay from the CLW but overall improvement compared with baseline testing (0.6 vs. 0.8, P < 0.05). There was no significant difference in procedure time after CLW training. The postgraduate year 1 group showed the greatest improvement of CVC skill after CLW training. Resident CVC placement performance improved immediately after the CLW. Although performance 3 months after the CLW revealed evidence of skill decay, it was improved when compared with initial baseline assessment. Novice learners had the greatest benefit from the CLW.


Longitudinal development of cancer-related fatigue and physical activity in childhood cancer patients.
Cancer-related fatigue is one of the most distressing side effects of childhood cancer treatment. Physical activity can decrease fatigue and has positive effects on other health outcomes. Most research on physical activity pertains to adults, and the few studies that focus on children have limited follow-up time. This study evaluates cancer-related fatigue in children and its association with physical activity over a one-year time period. Sixty-eight children with cancer (7-18 years) were recruited during or within the first year after treatment. Physical activity (Actical activity monitor) and cancer-related fatigue (Pediatric Quality-of-Life Questionnaire Multidimensional Fatigue Scale (PedsQL-MFS), self- and parent- reports) were assessed at baseline, 4 months, and 12 months. PedsQL-MFS scores were compared with Dutch norms. Longitudinal association of cancer-related fatigue with physical activity was evaluated (No. NTR 1531). Generally, PedsQL-MFS scores were worse than norms at baseline and 4 months, and recovered by 12 months except for the parent-proxy scores in adolescents. Younger children (≤12 years) self-reported comparable or better scores than norms. Physical activity generally improved over time, but patients mostly remained sedentary. During follow-up, increased physical activity was associated with less cancer-related fatigue. Cancer-related fatigue in children improves over time, and increased physical activity is associated with less cancer-related fatigue. Given the sedentary lifestyle of this population, the positive effect of physical activity on cancer-related fatigue, and the many other health benefits of an active lifestyle, it is important to stimulate physical activity in childhood cancer patients and survivors.


Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks.
Recruitment of 53BP1 to chromatin flanking double strand breaks (DSBs) requires γH2AX/MDC1/RNF8-dependent ubiquitination of chromatin and interaction of 53BP1 with histone H4 methylated on lysine 20 (H4K20me). Several histone methyltransferases have been implicated in 53BP1 recruitment, but their quantitative contributions to the 53BP1 response are unclear. We have developed a multi-photon laser (MPL) system to target DSBs to subfemtoliter nuclear volumes and used this to mathematically model DSB response kinetics of MDC1 and of 53BP1. In contrast to MDC1, which revealed first order kinetics, the 53BP1 MPL-DSB response is best fitted by a Gompertz growth function. The 53BP1 MPL response shows the expected dependency on MDC1 and RNF8. We determined the impact of altered H4K20 methylation on 53BP1 MPL response kinetics in mouse embryonic fibroblasts (MEFs) lacking key H4K20 histone methyltransferases. This revealed no major requirement for the known H4K20 dimethylases Suv4-20h1 and Suv4-20h2 in 53BP1 recruitment or DSB repair function, but a key role for the H4K20 monomethylase, PR-SET7. The histone methyltransferase MMSET/WHSC1 has recently been implicated in 53BP1 DSB recruitment. We found that WHSC1 homozygous mutant MEFs reveal an alteration in balance of H4K20 methylation patterns; however, 53BP1 DSB responses in these cells appear normal.


The role of Broca's area in speech perception: evidence from aphasia revisited.
Motor theories of speech perception have been re-vitalized as a consequence of the discovery of mirror neurons. Some authors have even promoted a strong version of the motor theory, arguing that the motor speech system is critical for perception. Part of the evidence that is cited in favor of this claim is the observation from the early 1980s that individuals with Broca's aphasia, and therefore inferred damage to Broca's area, can have deficits in speech sound discrimination. Here we re-examine this issue in 24 patients with radiologically confirmed lesions to Broca's area and various degrees of associated non-fluent speech production. Patients performed two same-different discrimination tasks involving pairs of CV syllables, one in which both CVs were presented auditorily, and the other in which one syllable was auditorily presented and the other visually presented as an orthographic form; word comprehension was also assessed using word-to-picture matching tasks in both auditory and visual forms. Discrimination performance on the all-auditory task was four standard deviations above chance, as measured using d', and was unrelated to the degree of non-fluency in the patients' speech production. Performance on the auditory-visual task, however, was worse than, and not correlated with, the all-auditory task. The auditory-visual task was related to the degree of speech non-fluency. Word comprehension was at ceiling for the auditory version (97% accuracy) and near ceiling for the orthographic version (90% accuracy). We conclude that the motor speech system is not necessary for speech perception as measured both by discrimination and comprehension paradigms, but may play a role in orthographic decoding or in auditory-visual matching of phonological forms.


The antiquity of empathy.
The view of humans as violent war-prone apes is poorly supported by archaeological evidence and only partly supported by the behavior of our closest primate relatives, chimpanzees and bonobos. Whereas the first species is marked by xenophobia, the second is relatively peaceful and highly empathic in both behavior and brain organization. Animal empathy is best regarded as a multilayered phenomenon, built around motor mirroring and shared neural representations at basal levels, that develops into more advanced cognitive perspective-taking in large-brained species. As indicated by both observational and experimental studies on our closest relatives, empathy may be the main motivator of prosocial behavior.


Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial.
We hypothesized that perioperative ketamine administration would modify acute central sensitization following amputation and hence reduce the incidence and severity of persistent post-amputation pain (both phantom limb and stump pain). In a randomized, controlled trial, 45 patients undergoing above- or below-knee amputation received ketamine 0.5 mg x kg(-1) or placebo as a pre-induction bolus followed by an intravenous infusion of ketamine 0.5 mg x kg(-1) x h(-1) or normal saline for 72 hours postoperatively. Both groups received standardized general anaesthesia followed by patient-controlled intravenous morphine. The surface area of allodynia over the stump was mapped at days 3 and 6. Postamputation pain was assessed at days 3 and 6 and at 6 months postoperatively. We found no significant difference between groups in the surface area of stump allodynia or in morphine consumption. There was an unexplained, but significant, increase in the incidence of stump pain in the ketamine group at day 3. At six-month review, the incidence of phantom pain was 47% in the ketamine group and 71% in the control group. This did not reach statistical significance (P=0.28) as the power of the study was based on the search for a large treatment effect. The incidence of stump pain at six months was 47% in the ketamine group and 35% in the control group (P=0.72). There were no significant between-group differences in pain severity throughout the study period. Ketamine at the dose administered did not significantly reduce acute central sensitization or the incidence and severity of post-amputation pain.


Is El Nino changing?
Recent advances in observational and theoretical studies of El Nino have shed light on controversies concerning the possible effect of global warming on this phenomenon over the past few decades and in the future. El Nino is now understood to be one phase of a natural mode of oscillation-La Nina is the complementary phase-that results from unstable interactions between the tropical Pacific Ocean and the atmosphere. Random disturbances maintain this neutrally stable mode, whose properties depend on the background (time-averaged) climate state. Apparent changes in the properties of El Nino could reflect the importance of random disturbances, but they could also be a consequence of decadal variations of the background state. The possibility that global warming is affecting those variations cannot be excluded.


Monosodium Urate Contributes to Retinal Inflammation and Progression of Diabetic Retinopathy.
We have investigated the contributing role of monosodium urate (MSU) to the pathological processes associated with the induction of diabetic retinopathy (DR). In human postmortem retinas and vitreous from donors with DR, we have found a significant increase in MSU levels that correlated with the presence of inflammatory markers and enhanced expression of xanthine oxidase. The same elevation in MSU levels was also detected in serum and vitreous of streptozotocin-induced diabetic rats (STZ-rats) analyzed at 8 weeks of hyperglycemia. Furthermore, treatments of STZ-rats with the hypouricemic drugs allopurinol (50 mg/kg) and benzbromarone (10 mg/kg) given every other day resulted in a significant decrease of retinal and plasma levels of inflammatory cytokines and adhesion factors, a marked reduction of hyperglycemia-induced retinal leukostasis, and restoration of retinal blood-barrier function. These results were associated with effects of the hypouricemic drugs on downregulating diabetes-induced levels of oxidative stress markers as well as expression of components of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome such as NLRP3, Toll-like receptor 4, and interleukin-1β. The outcomes of these studies support a contributing role of MSU in diabetes-induced retinal inflammation and suggest that asymptomatic hyperuricemia should be considered as a risk factor for DR induction and progression.


Support-assisted optical superresolution of low-resolution image sequences: the one-dimensional problem.
We analyze the problem of optical superresolution (OSR) of a one-dimensional (1D) incoherent spatial signal from undersampled data when the support of the signal is known in advance. The present paper corrects and extends our previous work on the calculation of Fisher information (FI) and the associated Cramer-Rao lower bound (CRB) on the minimum error for estimating the signal intensity distribution and its Fourier components at spatial frequencies lying beyond the optical band edge. The faint-signal and bright-signal limits emerge from a unified noise analysis in which we include both additive noise of detection and shot noise of photon counting via an approximate Gaussian statistical distribution. For a large space-bandwidth product, we derive analytical approximations to the exact expressions for FI and CRB in the faint-signal limit and use them to argue why achieving any significant amount o unbiased bandwidth extension in the presence of noise is a uniquely challenging proposition. Unlike previous theoretical work on the subject of support-assisted bandwidth extension, our approach is not restricted to specific forms of the system transfer functions, and provides a unified analysis of both digital and optical superresolution of undersampled data.


Gonadectomy in cats and dogs: a review of risks and benefits.
The necessity, and in particular the timing, of gonadectomy in dogs and cats is still controversial. This is mainly because gonadectomy confers a mixture of benefits and adverse effects that depend upon the age at neutering, sex, species and breed. In this paper, the long-term risks and benefits of gonadectomy, at various ages, in dogs and cats are reviewed using data describing the effects of desexing on the urogenital tract and on other medical conditions, such as orthopaedic diseases, immune-mediated diseases, tumour development and behaviour.


A physician-pharmacist model for the surveillance of blood pressure in the community: a feasibility study.
Hypertension is poorly managed. Hospital-based pharmacists working with physicians have been shown to improve the rate of achievement of "target" blood pressure in selected patients. It is unknown if such schemes can operate in the community and to what extent they would attract volunteers with poorly managed blood pressure. We assessed the feasibility of pharmacists to provide community-based, open-access, blood pressure monitoring. In addition, we describe the blood pressure profile of the group in comparison to that of the 1994 Health Survey of England (HSE). Pharmacists from six pharmacies were trained to deliver the service. Adults living within the postal districts of the pharmacies were invited, through an advertising campaign, to volunteer to have their blood pressure measured. Blood pressure data and information on treatment for hypertension and/or diabetes were collected on 263 registrants. Patients were advised to have their blood pressure managed by the general practitioner immediately (category 1), re-measured within 2-3 months (category 2) or in 12 months time (category 3). The mean (s.d.) blood pressure of patients in categories 1 (n = 16), 2 (n = 117) and 3 (n = 130) was 186(16)/97(29), 151(13)/94(9) and 139(22)/86(13) mm Hg respectively; P < 0.001. Ninety-one patients (35%) were in receipt of antihypertensive therapy. Forty-five percent of the treated group had controlled blood pressure (<160/95 mm Hg) compared with 30% in the HSE dataset. A large proportion of known hypertensive patients with poor blood pressure control who had visited their general practitioner within the previous 6 months were detected by the pharmacist-led service. Pharmacists operating an open-access blood pressure monitoring service may be of value in improving the management of hypertension.


Mid and long term outcomes of dural arteriovenous fistula endovascular management with Onyx. Experience of a single tertiary center.
The natural history of intracranial dural arteriovenous fistulas (DAVFs) with cortical venous drainage is unfavorable, and treatment is recommended in most cases. Early reports have documented excellent initial clinical and radiographic outcomes after Onyx embolization of DAVFs but little evidence is available regarding the long term durability of this technique. We retrospectively reviewed a database of 63 DAVFs in 53 consecutive patients who underwent Onyx embolization of a DAVF between 2001 and 2012 at our institution. Cognard types I and III were seen most commonly. A total of 72 Onyx embolization procedures were successfully completed during the study period, resulting in complete or near complete occlusion by the end of the study period in 58 (92.1%) DAVFs. For DAVFs in which complete or near complete obliteration was attained, stability of obliteration at 6, 12, 24, and 46 months was 100%, 95.4%, 93.8%, and 92.3%, respectively. DAVF recanalization/regrowth was discovered on delayed follow-up angiography in only five instances in which immediate post-embolization angiography revealed complete obliteration. Complications were seen in seven embolization procedures and included cranial nerve palsies (n=3), embolic infarcts (n=2), intraparenchymal hemorrhage (n=1), and unintentional stent deployment (n=1). Early evidence has indicated that endovascular Onyx embolization is safe and effective at achieving an initial angiographic cure. Results of our series suggest that angiographic and clinical outcomes of Onyx embolization remain relatively stable at mid and long term follow-up.


Two-Stage Evaluation of a Telehealth Nutrition Management Service in Support of Diabesity Therapy.
Diabesity, a combination of diabetes mellitus type 2 and obesity, is one of the biggest global health problems. Individual nutrition therapy and physical activity are effective measures in prevention and treatment. Requirements for an integrated diabesity service were specified and evaluated in two stages. The aim of the first stage was to perform a feasibility trial in patients with diabesity, using separate diaries. DiabMemory for diabetes and Nutrinaut for nutrition. Based on the results of the first stage, a prototype of an integrated diabesity solution (KIT-Nutriton, AIT) was developed and evaluated. First stage trial was performed with 10 diabesity patients (2f, med:53 y. (IQR:7), T2DM, BMI > 28 kg/m2) with 3 months follow-up and a significant reduction of BMI. Participants noticed concerns about using two separate diary solutions. Results of the field trial with KIT-Nutrition with 14 healthy subjects (3f, med:26 y (IQR: 20,25)) showed that overall, 77.6% of the intended tasks had been achieved. Results show that the integrated KIT-Nutrition app, providing access to a nutrition database, is feasible and accepted by the users. Before further trials can be made, an extension for regional food terms is recommended.


Guidelenines in the management of obstructing cancer of the left colon: consensus conference of the world society of emergency surgery (WSES) and peritoneum and surgery (PnS) society.
Obstructive left colon carcinoma (OLCC) is a challenging matter in terms of obstruction release as well of oncological issues. Several options are available and no guidelines are established. The paper aims to generate evidenced based recommendations on management of OLCC. The PubMed and Cochrane Library databases were queried for publications focusing on OLCC published prior to April 2010. A extensive retrieval, analyses, and grading of the literature was undertaken. The findings of the research were presented and largely discussed among panellist and audience at the Consensus Conference of the World Society of Emergency Surgery (WSES) and Peritoneum and Surgery (PnS) Society held in Bologna July 2010. Comparisons of techniques are presented and final committee recommendation are enounced. Hartmann's procedure should be preferred to loop colostomy (Grade 2B). Hartmann's procedure offers no survival benefit compared to segmental colonic resection with primary anastomosis (Grade 2C+); Hartmann's procedure should be considered in patients with high surgical risk (Grade 2C). Total colectomy and segmental colectomy with intraoperative colonic irrigation are associated with same mortality/morbidity, however total colectomy is associated with higher rates impaired bowel function (Grade 1A). Segmental resection and primary anastomosis either with manual decompression or intraoperative colonic irrigation are associated with same mortality/morbidity rate (Grade 1A). In palliation stent placement is associated with similar mortality/morbidity rates and shorter hospital stay (Grade 2B). Stents as a bridge to surgery seems associated with lower mortality rate, shorter hospital stay, and a lower colostomy formation rate (Grade 1B). Loop colostomy and staged procedure should be adopted in case of dramatic scenario, when neoadjuvant therapy could be expected. Hartmann's procedure should be performed in case of high risk of anastomotic dehiscence. Subtotal and total colectomy should be attempted when cecal perforation or in case of synchronous colonic neoplasm. Primary resection and anastomosis with manual decompression seems the procedure of choice. Colonic stents represent the best option when skills are available. The literature power is relatively poor and the existing RCT are often not sufficiently robust in design thus, among 6 possible treatment modalities, only 2 reached the Grade A.


Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice.
MicroRNA (miR) are short non-coding RNA sequences of 19-24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the individual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.


Epidural electrocorticography for monitoring of arousal in locked-in state.
Electroencephalography (EEG) often fails to assess both the level (i.e., arousal) and the content (i.e., awareness) of pathologically altered consciousness in patients without motor responsiveness. This might be related to a decline of awareness, to episodes of low arousal and disturbed sleep patterns, and/or to distorting and attenuating effects of the skull and intermediate tissue on the recorded brain signals. Novel approaches are required to overcome these limitations. We introduced epidural electrocorticography (ECoG) for monitoring of cortical physiology in a late-stage amytrophic lateral sclerosis patient in completely locked-in state (CLIS). Despite long-term application for a period of six months, no implant-related complications occurred. Recordings from the left frontal cortex were sufficient to identify three arousal states. Spectral analysis of the intrinsic oscillatory activity enabled us to extract state-dependent dominant frequencies at <4, ~7 and ~20 Hz, representing sleep-like periods, and phases of low and elevated arousal, respectively. In the absence of other biomarkers, ECoG proved to be a reliable tool for monitoring circadian rhythmicity, i.e., avoiding interference with the patient when he was sleeping and exploiting time windows of responsiveness. Moreover, the effects of interventions addressing the patient's arousal, e.g., amantadine medication, could be evaluated objectively on the basis of physiological markers, even in the absence of behavioral parameters. Epidural ECoG constitutes a feasible trade-off between surgical risk and quality of recorded brain signals to gain information on the patient's present level of arousal. This approach enables us to optimize the timing of interactions and medical interventions, all of which should take place when the patient is in a phase of high arousal. Furthermore, avoiding low-responsiveness periods will facilitate measures to implement alternative communication pathways involving brain-computer interfaces (BCI).


Innovative approaches to bipolar disorder and its treatment.
All psychiatric disorders have suffered from a dearth of truly novel pharmacological interventions. In bipolar disorder, lithium remains a mainstay of treatment, six decades since its effects were serendipitously discovered. The lack of progress reflects several factors, including ignorance of the disorder's pathophysiology and the complexities of the clinical phenotype. After reviewing the current status, we discuss some ways forward. First, we highlight the need for a richer characterization of the clinical profile, facilitated by novel devices and new forms of data capture and analysis; such data are already promoting a reevaluation of the phenotype, with an emphasis on mood instability rather than on discrete clinical episodes. Second, experimental medicine can provide early indications of target engagement and therapeutic response, reducing the time, cost, and risk involved in evaluating potential mood stabilizers. Third, genomic data can inform target identification and validation, such as the increasing evidence for involvement of calcium channel genes in bipolar disorder. Finally, new methods and models relevant to bipolar disorder, including stem cells and genetically modified mice, are being used to study key pathways and drug effects. A combination of these approaches has real potential to break the impasse and deliver genuinely new treatments.


Evaluation of PEG-coated iron oxide nanoparticles as blood pool tracers for preclinical magnetic particle imaging.
Superparamagnetic iron oxide (SPIO) nanoparticles with optimized and well-characterized properties are critical for Magnetic Particle Imaging (MPI). MPI is a novel in vivo imaging modality that promises to integrate the speed of X-ray CT, safety of MRI and sensitivity of PET. Since SPIOs are the source of MPI signal, both the core and surface properties must be optimized to enable efficient in vivo imaging with pharmacokinetics tailored for specific imaging applications. Existing SPIOs like Resovist (ferucarbotran) provide a suboptimal MPI signal, and further limit MPI's in vivo utility due to rapid systemic clearance. An SPIO agent with a long blood half-life (t1/2) would be a versatile MPI tracer with widespread applications. Here we show that a long circulating polyethylene glycol (PEG)-coated SPIO tracer, LS-008, provides excellent colloidal stability and a persistent intravascular MPI signal, showing its potential as the first blood pool tracer optimized for MPI. We evaluated variations of PEG coating and found that colloidal stability of tracers improved with the increasing PEG molecular weight (keeping PEG loading constant). Blood circulation in mice, evaluated using Magnetic Particle Spectrometry (MPS), showed that the t1/2 of SPIO tracers varied with both PEG molecular weight and loading. LS-008, coated with 20 kDa PEG at 18.8% loading capacity, provided the most promising long-term colloidal stability with a t1/2 of about 105 minutes in mice. In vivo MPI imaging with LS-008 using a 7 T/m/μ0 3D x-space MPI mouse scanner revealed a prolonged intravascular signal (3-5 hours) post-injection. Our results show the optimized magnetic properties and long systemic retention of LS-008 making it a promising blood pool MPI tracer, with potential to enable MPI imaging in cardio- and cerebrovascular disease models, and solid tumor quantification and imaging via enhanced permeation and retention.


Water safety plans as a tool for drinking water regulatory frameworks in Arctic communities.
Arctic communities often face drinking water supply challenges that are unique to their location. Consequently, conventional drinking water regulatory strategies often do not meet the needs of these communities. A literature review of Arctic jurisdictions was conducted to evaluate the current water management approaches and how these techniques could be applied to the territory of Nunavut in Canada. The countries included are all members of the Arctic Council and other Canadian jurisdictions considered important to the understanding of water management for Northern Canadian communities. The communities in Nunavut face many challenges in delivering safe water to customers due to remoteness, small community size and therefore staffing constraints, lack of guidelines and monitoring procedures specific to Nunavut, and water treatment and distribution systems that are vastly different than those used in southern communities. Water safety plans were explored as an alternative to water quality regulations as recent case studies have demonstrated the utility of this risk management tool, especially in the context of small communities. Iceland and Alberta both currently have regulated water safety plans (WSPs) and were examined to understand shortcomings and benefits if WSPs were to be applied as a possible strategy in Nunavut. Finally, this study discusses specific considerations that are necessary should a WSP approach be applied in Nunavut.


Hyperbaric oxygen therapy for chronic wounds.
Chronic wounds are common and present a health problem with significant effect on quality of life. Various pathologies may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing. To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb. For this first update we searched the Cochrane Wounds Group Specialised Register (searched 12 January 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4); Ovid MEDLINE (1950 to January Week 1 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, 11 July 2012); Ovid EMBASE (1980 to 2012 Week 01); and EBSCO CINAHL (1982 to 6 January 2012). Randomised controlled trials (RCTs) comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy). Three review authors independently evaluated the risk of bias of the relevant trials using the Cochrane methodology and extracted the data from the included trials. We resolved any disagreement by discussion. We included nine trials (471 participants). Eight trials (455 participants) enrolled people with a diabetic foot ulcer: pooled data of three trials with 140 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 5.20, 95% confidence interval (CI) 1.25 to 21.66; P = 0.02) with HBOT at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers. In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias.


Chemical and Morphological Studies of Bacterial Spore Formation : I. The Formation of Spores in Bacillus cereus.
Experimental conditions were developed whereby a culture of Bacillus cereus formed spores with reasonable synchrony following a growth cycle of some 8 hours. The cytology of this metamorphosis was studied by dark phase contrast, bright-field microscopy and electron microscopy of thin sections. Particular attention has been paid to the changes in chromatin patterns and these have been correlated with quantitative chemical estimations of the nucleic acids. The cell commencing sporulation contains two compact chromatin bodies and twice the spore amount of deoxyribonucleic acid. Following fusion of the two chromatin bodies, one-half of this chromatin becomes located at a cell end. A transverse septum growing inwards from, and remaining attached to, the inner surface of the cell wall separates this end-piece of chromatin and some associated cytoplasm from the rest of the cell to form the primordial spore. Although the synthesis of deoxyribonucleic acid ceases during the segregation process, it recommences in this organism and continues at a linear rate as the spore develops. Tracer studies with radioactive phosphorus indicated that this further synthesis is confined to the non-spore portion of the sporangium. Although the net synthesis of ribonucleic acid ceased prior to the onset of sporogenesis, some evidence of a turnover of this fraction during the sporulation process was found.


Neutrophil interaction with inflamed postcapillary venule endothelium alters annexin 1 expression.
Annexin 1 (ANX-A1) exerts antimigratory actions in several models of acute and chronic inflammation. This is related to its ability to mimic the effect of endogenous ANX-A1 that is externalized on neutrophil adhesion to the postcapillary endothelium. In the present study we monitored ANX-A1 expression and localization in intravascular and emigrated neutrophils, using a classical model of rat peritonitis. For this purpose, a pair of antibodies raised against the ANX-A1 N-terminus (ie, able to recognize intact ANX-A1) or the whole protein (ie, able to interact with all ANX-A1 isoforms) was used by immunofluorescence and immunocytochemistry analyses. The majority ( approximately 50%) of ANX-A1 on the plasma membrane of intravascular neutrophils was intact. Extravasation into the subendothelial matrix caused loss of this pool of intact protein (to approximately 6%), concomitant with an increase in total amount of the protein; only approximately 25% of the total protein was now recognized by the antibody raised against the N-terminus (ie, it was intact). In the cytoplasm of these cells, ANX-A1 was predominantly associated with large vacuoles, possibly endosomes. In situ hybridization confirmed de novo synthesis of ANX-A1 in the extravasated cells. In conclusion, biochemical pathways leading to the externalization, proteolysis, and synthesis of ANX-A1 are activated during the process of neutrophil extravasation.


Above- and below-ground terpenoid aldehyde induction in cotton, Gossypium herbaceum, following root and leaf injury.
Studies on induced defenses have predominantly focused on foliar induction by above-ground herbivores and pathogens. However, roots are attacked by as many if not more phytophages than shoots, so in reality plants are exposed to above- and below-ground attack. Here, we report effects of foliar and/or root damage on terpenoid aldehyde accumulation in cotton (Gossypium herbaceum). Using HPLC, we analyzed concentrations of individual terpenoid aldehydes in foliage and root tissue. In undamaged plants, terpenoid aldehydes were concentrated in young immature main leaves. Concentrations in side leaves, branching from the main leaves, did not differ among leaf position. Above-ground feeding by Spodopterta exigua larvae on a mature leaf enhanced terpenoid concentrations in immature leaves but not in the damaged leaf. In particular, concentrations of hemigossypolone and the heliocides 1 and 4 were enhanced following herbivory. Root herbivory by wireworms (Agriotes lineatus) also resulted in an increase in terpenoid levels in the foliage. In contrast with foliar herbivory, both immature and mature leaves were induced. However, the level of induction after root herbivory was much lower compared to foliar herbivory. Plants exposed to root herbivory also had significantly higher levels of terpenoid aldehydes in root tissue, while no such effect was found following foliar herbivory. Plants exposed to both root and foliar herbivory appeared to induce primarily above-ground at the cost of below-ground defense. The implications for above- and below-ground Mutitrophic interactions are discussed.


Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart.
There is substantial interest in the development of drugs that limit the extent of ischemia-induced cardiac damage caused by myocardial infarction or by certain surgical procedures. Here, using an unbiased proteomic search, we identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as an enzyme whose activation correlates with reduced ischemic heart damage in rodent models. A high-throughput screen yielded a small-molecule activator of ALDH2 (Alda-1) that, when administered to rats before an ischemic event, reduced infarct size by 60%, most likely through its inhibitory effect on the formation of cytotoxic aldehydes. In vitro, Alda-1 was a particularly effective activator of ALDH2*2, an inactive mutant form of the enzyme that is found in 40% of East Asian populations. Thus, pharmacologic enhancement of ALDH2 activity may be useful for patients with wild-type or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery.


Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth.
Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.


Pilot investigation of the relationship between hippocampal volume and pattern separation deficits in multiple sclerosis.
Memory impairment and hippocampal atrophy are common in multiple sclerosis (MS). In the present pilot study, we investigate whether the mnemonic process of pattern separation is impaired and a predictor of hippocampal volume in relapsing remitting MS. MS participants and healthy controls completed the Mnemonic Similarities Task (MST) along with traditional neurocognitive assessments of memory. 3T structural magnetic resonance imaging was used to estimate whole hippocampal volumes (main aim) and hippocampal subfield volumes (exploratory aim). Results revealed that pattern separation performance was worse for MS participants compared to healthy controls (Cohen's d = 0.96). For MS participants, hippocampal volume was more strongly related to pattern separation performance (r = 0.83) than a traditional neurocognitive measure of visual memory (r = 0.65); hippocampal volume was not related to a traditional neurocognitive measure of verbal memory in this sample. No brain-behavior correlations were significant in the healthy control group. Results of the exploratory analysis revealed relationships between pattern separation performance and subiculum, molecular layer, and CA1 hippocampal subfield volumes for MS participants only. Pattern separation assessed using the MST may be a sensitive cognitive-biomarker of memory dysfunction and changes in hippocampal volume in relapsing-remitting MS.


Nontargeted Identification of Reactive Metabolite Protein Adducts.
Metabolic bioactivation of many different chemicals results in the formation of highly reactive compounds (chemically reactive metabolites, CRMs) that can lead to toxicity via binding to macromolecular targets (e.g., proteins or DNA). There is a need to develop robust, rapid, and nontargeted analytical techniques to determine the identity of the protein targets of CRMs and their sites of modification. Here, we introduce a nontargeted methodology capable of determining both the identity of a CRM formed from an administered compound as well as the protein targets modified by the reactive metabolite in a single experiment without prior information. Acetaminophen (N-acetyl-p-aminophenol, APAP) and 13C6-APAP were incubated with rat liver microsomes, which are known to bioactivate APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). Global tryptic digestion followed by liquid chromatographic/mass spectrometric (LC/MS) analysis was used to locate "twin" ion peaks of peptides adducted by NAPQI and for shotgun proteomics via tandem mass spectrometry (MS/MS). By the development of blended data analytics software called Xenophile, the identity of the amino acid residue that was adducted can be established, which eliminates the need for specific parametrization of protein database search algorithms. This combination of experimental design and data analysis software allows the identity of a CRM, the protein target, and the amino acid residues that are modified to be rapidly established directly from experimental data. Xenophile is freely available from https://github.com/mgleeming/Xenophile .


Characterization of a locus determining the mucoid status of Pseudomonas aeruginosa: AlgU shows sequence similarities with a Bacillus sigma factor.
Overproduction of the exopolysaccharide alginate by Pseudomonas aeruginosa results in mucoid colony morphology and is an important virulence determinant expressed by this organism in cystic fibrosis. Mucoidy is transcriptionally regulated by signal transduction systems and histone-like elements. One point of convergence of regulatory elements controlling mucoidy is the algD promoter. A newly described genetic locus required for algD transcription was characterized in this study. This DNA region, cloned from a nonmucoid PAO strain, was initially isolated on the basis of its ability to suppress mucoidy when present on a plasmid. The suppressing activity was observed in several mucoid PAO derivatives, including strain PAO568, in which the mapped muc-2 mutation is responsible for its mucoid phenotype, and in close to 40% of cystic fibrosis strains tested. Protein expression studies detected two polypeptides with apparent molecular masses of 27.5 and 20 kDa encoded by the region required for the suppression activity. The gene encoding the polypeptide with an apparent molecular mass of 27.5 kDa, termed algU, was further characterized. A functional chromosomal copy of algU was found to be necessary for the expression of mucoidy. Insertional inactivation of algU on the chromosome of the mucoid strain PAO568 abrogated alginate production and algD transcription. DNA sequence analysis revealed sequence similarity of the predicted algU gene product with sigma H (Spo0H), a sigma factor involved in the control of sporulation and competence in Bacillus spp. Physical mapping revealed that algU resided on the same SpeI fragment (F) as did the pruAB locus, known to be tightly linked with genetic determinants (muc) which can confer mucoidy in genetic crosses. When the chromosomal algU copy was tagged with a Tcr cassette (algU::Tcr), a tight genetic linkage of algU with pruAB was demonstrated by F116L-mediated generalized transduction. Moreover, algU::Tcr derivatives of PAO568 (originally carrying the muc-2 marker) lost the ability to transfer mucoidy in genetic crosses. These results suggest that algU, a regulator of algD transcription showing sequence similarity to an alternative sigma factor, and the genes immediately downstream of algU may be associated with a locus participating in the differentiation into the mucoid phenotype.


Antiviral mouthwashes: possible benefit for COVID-19 with evidence-based approach.
The outbreak, and pandemic of COVID-19 causing widespread concerns in all health systems of countries. Virus-carrying aerosols can penetrate the healthy human body and lungs, resulting in rapid transmission. For the first time, in this evidence-based article, the effects of different types of mouthwashes to reduce the viral load were investigated. Also, another aim of this essay is a reduction in viral load in patients with COVID-19 and prevention developing ventilator-associated pneumonia in critically ill patients. Related databases were comprehensively searched for relevant studies. The present study was performed according to the preferred cases for standard systematic reviews (PRISMA). Five original studies in which the subject matter was directly evaluated were included. Different types of mouthwashes and viruses were investigated in this study. The antiviral mouthwashes play a certainly important role in reducing the viral load of the salivary virus. In the present study, this importance could be proved in two different aspects, that is, the use of mouthwash before dental procedures to reduce the risk of transmission of the virus to the dental team and the use of this mouthwash in COVID-19 patients to help improve systemic problems associated with oral microbial flora.


HBV vaccination and PMTCT as elimination tools in the presence of HIV: insights from a clinical cohort and dynamic model.
Sustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Deployment of a robust prophylactic vaccine and enhanced interventions for prevention of mother to child transmission (PMTCT) are cornerstones of elimination strategy. However, in light of the estimated global burden of 290 million cases, enhanced efforts are required to underpin optimisation of public health strategy. Robust analysis of population epidemiology is particularly crucial for populations in Africa made vulnerable by HIV co-infection, poverty, stigma and poor access to prevention, diagnosis and treatment. We here set out to evaluate the current and future role of HBV vaccination and PMTCT as tools for elimination. We first investigated the current impact of paediatric vaccination in a cohort of children with and without HIV infection in Kimberley, South Africa. Second, we used these data to inform a new parsimonious model to simulate the ongoing impact of preventive interventions. By applying these two approaches in parallel, we are able to determine both the current impact of interventions, and the future projected outcome of ongoing preventive strategies over time. Existing efforts have been successful in reducing paediatric prevalence of HBV infection in this setting to < 1%, demonstrating the success of the existing vaccine campaign. Our model predicts that, if consistently deployed, combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, such that a major public health impact is possible even without achieving elimination. However, the prevalence of HBV e-antigen (HBeAg)-positive carriers will decline more slowly, representing a persistent population reservoir. We show that HIV co-infection significantly reduces titres of vaccine-mediated antibody, but has a relatively minor role in influencing the projected time to elimination. Our model can also be applied to other settings in order to predict impact and time to elimination based on specific interventions. Through extensive deployment of preventive strategies for HBV, significant positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be substantially longer than that proposed by current goals.


Cationic Liposomes Modified with Polyallylamine as a Gene Carrier: Preparation, Characterization and Transfection Efficiency Evaluation.
Purpose: Cationic polymers and cationic liposomes have shown to be effective non-viral gene delivery vectors. In this study, we tried to improve the transfection efficiency by employing the advantages of both. Methods: For this purpose, modified polyallylamines (PAAs) were synthesized. These modifications were done through the reaction of PAA (15 KDa) with acrylate and 6-bromoalkanoic acid derivatives. Liposomes comprising of these cationic polymers and cationic lipid were prepared and extruded through polycarbonate filters to obtain desired size. Liposome-DNA nanocomplexes were prepared in three carrier to plasmid (C/P) ratios. Size, zeta potential and DNA condensation ability of each complex were characterized separately and finally transfection efficiency and cytotoxicity of prepared vectors were evaluated in Neuro2A cell line. Results: The results showed that mean particle size of all these nanocomplexes was lower than 266 nm with surface charge of 22.0 to 33.9 mV. Almost the same condensation pattern was observed in all vectors and complete condensation was occurred at C/P ratio of 1.5. The lipoplexes containing modified PAA 15 kDa with 10% hexyl acrylate showed the highest transfection efficacy and lowest cytotoxicity in C/P ratio of 0.5. Conclusion: In some cases nanocomplexes consisting of cationic liposome and modified PAA showed better transfection activity and lower cytotoxicity compared to PAA.


Teaching brain-machine interfaces as an alternative paradigm to neuroprosthetics control.
Brain-machine interfaces (BMI) usually decode movement parameters from cortical activity to control neuroprostheses. This requires subjects to learn to modulate their brain activity to convey all necessary information, thus imposing natural limits on the complexity of tasks that can be performed. Here we demonstrate an alternative and complementary BMI paradigm that overcomes that limitation by decoding cognitive brain signals associated with monitoring processes relevant for achieving goals. In our approach the neuroprosthesis executes actions that the subject evaluates as erroneous or correct, and exploits the brain correlates of this assessment to learn suitable motor behaviours. Results show that, after a short user's training period, this teaching BMI paradigm operated three different neuroprostheses and generalized across several targets. Our results further support that these error-related signals reflect a task-independent monitoring mechanism in the brain, making this teaching paradigm scalable. We anticipate this BMI approach to become a key component of any neuroprosthesis that mimics natural motor control as it enables continuous adaptation in the absence of explicit information about goals. Furthermore, our paradigm can seamlessly incorporate other cognitive signals and conventional neuroprosthetic approaches, invasive or non-invasive, to enlarge the range and complexity of tasks that can be accomplished.


Polo-like kinase and survivin are esophageal tumor-specific promoters.
For developing successful cancer gene therapy strategies, tumor-specific gene delivery is essential. In this study, we used esophageal cancer (EC) cells to identify and evaluate esophageal tumor-specific gene promoters. Four genes (polo-like kinase-1/PLK, survivin/BIRC5, karyopherin alpha 2/KPNA2, and pituitary tumor transforming gene protein 1/PTTG1) were identified by a microarray analysis as highly expressed in EC cell lines vs. five normal organ tissues (liver, lung, kidney, brain, and heart). By quantitative RT-PCR, the average mRNA expression levels of these four genes in 20 primary ECs were 2.7-fold (PLK), 6.1-fold (survivin), 2.6-fold (KPNA2), and 2.4-fold (PTTG1) higher than that of each gene in 24 different normal organs. By dual luciferase assay, the promoter activity of PLK and survivin in EC cell lines was 18.9-fold and 28.5-fold higher, respectively, than in normal lung and renal cells. The promoters of PLK and survivin could be useful tools for developing EC-specific gene therapy vectors.


Characterization of a soluble protein of Coccidiodes immitis with activity as an immunodiffusion-complement fixation antigen.
A 48-kilodalton (kDa) electrophoretically distinct antigen from Coccidioides immitis mycelial- and spherule-endospore-phase filtrates was previously associated by immunoblotting with the immunodiffusion band that corresponds to complement-fixing activity (ID-CF). To characterize this antigen and its precursor, both mycelial- and spherule-endospore-phase filtrates were fractionated by size exclusion chromatography, lectin affinity chromatography, and nondenaturing electrophoresis. By size exclusion chromatography, most of the protein and carbohydrate of the crude filtrates eluted in a peak of average molecular size less than 30 kDa, although other components were detected. ID-CF activity was associated with the component at a relative mobility of 110 kDa. Fractions containing the ID band that corresponded to tube precipitin activity occurred from 200 to 40 kDa. The appearance of the 48-kDa band in denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (PAGE) specifically coincided with the fractions containing ID-CF activity. Nondenaturing PAGE of filtrates showed silver-stainable and immunoblot-reactive bands in the region of 110 kDa. Prior treatment with pronase destroyed this electrophoretically separable antigen, whereas periodate had no effect. Trypsin did not affect the 110-kDa band in unheated or unreduced antigen. Mycelial filtrates were chromatographed on lentil lectin or concanavalin A-Sepharose 4B to deplete them of glucose- or mannose-containing carbohydrate. The effluent fraction contained ID-CF activity and, upon denaturing electrophoresis, the 48-kDa antigen. The 110-kDa protein represents the ID-CF antigen which is heat labile and denatured to a 48-kDa band by sodium dodecyl sulfate-PAGE.


Probiotics in Human Immunodeficiency Virus Infection: A Systematic Review and Evidence Synthesis of Benefits and Risks.
People living with human immunodeficiency virus frequently use dietary supplements, including probiotics, but concern exists about ingesting live organisms. We performed a systematic review of the benefits of probiotics and a meta-analysis of sepsis risk. We undertook a protocol-driven, comprehensive review to identify all relevant studies, assess their quality, and summarize the evidence. Of 2068 references, 27 were analyzed. The data suggest possible benefits for CD4 count, recurrence or management of bacterial vaginosis, and diarrhea management. We examined randomized, controlled studies explicitly assessing sepsis in any patient population, and we found zero cases of supplement-associated bacteremia or fungemia in 39 randomized controlled trials comprising 9402 subjects. The estimated number needed to harm is 7369 in Bayesian approach (95% credible interval: 1689, ∞), which should reassure clinicians. No or mild adverse effects were reported. Longer duration studies investigating different individual and mixed strains for plausible indications are needed to establish best practices.


Biological properties of an influenza A virus-specific killer T cell clone. Inhibition of virus replication in vivo and induction of delayed-type hypersensitivity reactions.
We tested two biological properties of a continuously growing mouse cytotoxic T cell line, L4, which is specific for influenza A virus and has been cloned and recloned many times. We previously reported that L4 cells are H-2 restricted and cross-reactive for all type A influenza viruses, whereas they do not recognize type B influenza viruses. They bear Thy-1 and Lyt-2 markers. In the present study, we show that L4 cytotoxic T cells protect mice against a lethal influenza infection on transfer to syngeneic recipients, and reduce virus titers in the lungs of mice challenged with a heterologous type A influenza virus. This provides further support for the active role of cytotoxic T cells in limiting virus replication in influenza infection. We could also demonstrate that the cloned cytotoxic T cells induce a delayed-type hypersensitivity skin reaction in the footpads of mice challenged with live or inactivated influenza virus. This reaction can be observed at 24 h, but has declined by 48 h. A clone of cells derived from L4 that has lost its cytotoxic potential and its ability to recognize infected cells did not induce a delayed-type hypersensitivity reaction in the presence of virus. Thus, cytotoxic T cells actively killing influenza virus-infected cells are able to induce a delayed-type hypersensitivity skin reaction to homologous and heterologous type A influenza viruses.


The physiology of substance P in the rabbit retina.
The neuropeptide substance P (SP) has been localized to amacrine and ganglion cells in the rabbit retina. We have examined the effects of SP and related peptides on rabbit retinal neurons using bath application and intra- and extra-cellular electrophysiological methods in an in vitro retina eyecup preparation. Substance P, at concentrations as low as 25 nM, moderately excited most brisk ganglion cells. SP excited some ganglion cells directly during cobalt block of synaptic transmission. Intracellular recordings from amacrine cells demonstrated that some, but not all, were depolarized by SP; pharmacological evidence suggested GABAergic amacrines were probably among those sensitive to SP. SP did not affect horizontal cells or the ERG, suggesting that the effects of this peptide are confined to the inner retina. The effects of SP were strongly potentiated by peptidase inhibitors, raising the possibility that endogenously released SP may act quite locally in the rabbit retina. The relative potencies of SP and the related peptides substance K and eledoisin on different cells suggest that more than one tachykinin receptor subtype is present in the rabbit retina. The responses of ganglion cells to SP desensitized with repeated or prolonged applications. Comparison of a cell's light responses before and after the receptors were desensitized revealed no qualitative changes in receptive field characteristics, but quantitative changes in excitability were apparent. SP antagonist analogs, although not potent, specifically blocked the effects of SP on some ganglion cells. The effects of these antagonists on light responses reinforced the inferences from desensitization paradigms regarding the role of endogenous SP.(ABSTRACT TRUNCATED AT 250 WORDS)


Graphene nanoribbons from unzipped carbon nanotubes: atomic structures, Raman spectroscopy, and electrical properties.
We investigated the atomic structures, Raman spectroscopic and electrical transport properties of individual graphene nanoribbons (GNRs, widths ~10-30 nm) derived from sonochemical unzipping of multiwalled carbon nanotubes (MWNTs). Aberration-corrected transmission electron microscopy (TEM) revealed a high percentage of two-layer (2 L) GNRs and some single-layer ribbons. The layer-layer stacking angles ranged from 0° to 30° including average chiral angles near 30° (armchair orientation) or 0° (zigzag orientation). A large fraction of GNRs with bent and smooth edges was observed, while the rest showed flat and less smooth edges (roughness ≤1 nm). Polarized Raman spectroscopy probed individual GNRs to reveal D/G ratios and ratios of D band intensities at parallel and perpendicular laser excitation polarization (D(∥)/D(⊥)). The observed spectroscopic trends were used to infer the average chiral angles and edge smoothness of GNRs. Electrical transport and Raman measurements were carried out for individual ribbons to correlate spectroscopic and electrical properties of GNRs.


Method of assessing the reproducibility of blood flow measurement: factors influencing the performance of thermodilution cardiac output computers.
Measurements of blood flow by three different makes of thermodilution cardiac output computer in an artificial circulation were analysed by linear regression against absolute flow measured by timed blood volume collection. For each computer the horizontal distance between the 95% confidence limits for a single prediction was calculated at a standard flow rate of 5 litres per minute. This measurement represents the range of flow rates that could give rise to an identical measurement and provides a summary of the reproducibility of the computer's results and its ability to detect a change of flow rate. This measurement was used to evaluate the effect on each computer's performance of pulsatile or continuous flow, injectate volume, and injectate temperature. With continuous flow the optimum results were 1.8, 0.85, and 0.85 litres per minute and with pulsatile flow they were 1.3, 1.05, and 1.65 litres per minute. There was generally a deterioration in performance when pulsatile flow was evaluated. Under the conditions of the experiment optimum performance in both flow modes was obtained with 5 ml of ice cold injectate, but these findings cannot necessarily be extrapolated to the clinical situation. With pulsatile flow the overall range of blood flows that could give rise to identical measurements were for each computer 2.0, 1.5, and 3.1 litres per minute, corresponding to 40, 30, and 62% changes of the standard flow rate of 5 litres per minute.