Adenosinergic and cholinergic control mechanisms during hypoxia in the epaulette shark (Hemiscyllium ocellatum), with emphasis on branchial circulation.
Coral reef platforms may become hypoxic at night during low tide. One animal in that habitat, the epaulette shark (Hemiscyllium ocellatum), survives hours of severe hypoxia and at least one hour of anoxia. Here, we examine the branchial effects of severe hypoxia (<0.3 mg oxygen l(-1) for 20 min in anaesthetized epaulette shark), by measuring ventral and dorsal aortic blood pressure (P(VA) and P(DA)), heart rate (fh), and observing gill microcirculation using epi-illumination microscopy. Hypoxia induced a flow of blood in two parallel blood vessels, termed longitudinal vessels, in the outer borders of the free tip of the gill filament. Hypoxia also induced significant falls in fh, P(VA) and P(DA), and a biphasic change in ventilation frequency (increase followed by decrease). Adenosine injection (1 micromol kg(-1)) also initiated blood flow in the longitudinal vessels, in addition to significant drops in P(VA), P(DA) and fh, and a biphasic response in ventilation frequency (decrease followed by increase) indicating that adenosine influences ventilation. Aminophylline (10 mg kg(-1)), an A(1) and A(2) adenosine receptor antagonist, blocked the effects of adenosine injection, and also significantly reduced blood flow in the longitudinal vessels during hypoxia. In the second part of the study, we examined the cholinergic influence on the cardiovascular circulation during severe hypoxia (<0.3 mg l(-1)) using antagonists against muscarinic (atropine 2 mg kg(-1)) and nicotinic (tubocurarine 5 mg kg(-1)) receptors. Injection of acetylcholine (ACh; 1 micromol kg(-1)) into the ventral aorta caused a marked fall in fh, a large increase in P(VA), but small changes in P(DA) (suggesting increased R(gill)). Atropine was able to inhibit the branchial vascular responses to ACh but not the hypoxic bradycardia, suggesting the presence of muscarinic receptors on the heart and gill vasculature, and that the hypoxia induced bradycardia is of non-cholinergic origin. The results suggest that adenosine mediates increases in the arterio-venous circulation in the gill during hypoxia. This may serve to increase blood supply to heart and gill tissue.


Myoelectrically controlled wrist robot for stroke rehabilitation.
Robot-assisted rehabilitation is an advanced new technology in stroke rehabilitation to provide intensive training. Post-stroke motor recovery depends on active rehabilitation by voluntary participation of patient's paretic motor system as early as possible in order to promote reorganization of brain. However, voluntary residual motor efforts to the affected limb have not been involved enough in most robot-assisted rehabilitation for patients after stroke. The objective of this study is to evaluate the feasibility of robot-assisted rehabilitation using myoelectric control on upper limb motor recovery. In the present study, an exoskeleton-type rehabilitation robotic system was designed to provide voluntarily controlled assisted torque to the affected wrist. Voluntary intention was involved by using the residual surface electromyography (EMG) from flexor carpi radialis(FCR) and extensor carpi radialis (ECR)on the affected limb to control the mechanical assistance provided by the robotic system during wrist flexion and extension in a 20-session training. The system also applied constant resistant torque to the affected wrist during the training. Sixteen subjects after stroke had been recruited for evaluating the tracking performance and therapeutical effects of myoelectrically controlled robotic system. With the myoelectrically-controlled assistive torque, stroke survivors could reach a larger range of motion with a significant decrease in the EMG signal from the agonist muscles. The stroke survivors could be trained in the unreached range with their voluntary residual EMG on the paretic side. After 20-session rehabilitation training, there was a non-significant increase in the range of motion and a significant decrease in the root mean square error (RMSE) between the actual wrist angle and target angle. Significant improvements also could be found in muscle strength and clinical scales. These results indicate that robot-aided therapy with voluntary participation of patient's paretic motor system using myoelectric control might have positive effect on upper limb motor recovery.


Resampling Procedures for Making Inference under Nested Case-control Studies.
The nested case-control (NCC) design have been widely adopted as a cost-effective solution in many large cohort studies for risk assessment with expensive markers, such as the emerging biologic and genetic markers. To analyze data from NCC studies, conditional logistic regression (Goldstein and Langholz, 1992; Borgan et al., 1995) and maximum likelihood (Scheike and Juul, 2004; Zeng et al., 2006) based methods have been proposed. However, most of these methods either cannot be easily extended beyond the Cox model (Cox, 1972) or require additional modeling assumptions. More generally applicable approaches based on inverse probability weighting (IPW) have been proposed as useful alternatives (Samuelsen, 1997; Chen, 2001; Samuelsen et al., 2007). However, due to the complex correlation structure induced by repeated finite risk set sampling, interval estimation for such IPW estimators remain challenging especially when the estimation involves non-smooth objective functions or when making simultaneous inferences about functions. Standard resampling procedures such as the bootstrap cannot accommodate the correlation and thus are not directly applicable. In this paper, we propose a resampling procedure that can provide valid estimates for the distribution of a broad class of IPW estimators. Simulation results suggest that the proposed procedures perform well in settings when analytical variance estimator is infeasible to derive or gives less optimal performance. The new procedures are illustrated with data from the Framingham Offspring Study to characterize individual level cardiovascular risks over time based on the Framingham risk score, C-reactive protein (CRP) and a genetic risk score.


Subversion of a lysosomal pathway regulating neutrophil apoptosis by a major bacterial toxin, pyocyanin.
Neutrophils undergo rapid constitutive apoptosis that is accelerated following bacterial ingestion as part of effective immunity, but is also accelerated by bacterial exotoxins as a mechanism of immune evasion. The paradigm of pathogen-driven neutrophil apoptosis is exemplified by the Pseudomonas aeruginosa toxic metabolite, pyocyanin. We previously showed pyocyanin dramatically accelerates neutrophil apoptosis both in vitro and in vivo, impairs host defenses, and favors bacterial persistence. In this study, we investigated the mechanisms of pyocyanin-induced neutrophil apoptosis. Pyocyanin induced early lysosomal dysfunction, shown by altered lysosomal pH, within 15 min of exposure. Lysosomal disruption was followed by mitochondrial membrane permeabilization, caspase activation, and destabilization of Mcl-1. Pharmacological inhibitors of a lysosomal protease, cathepsin D (CTSD), abrogated pyocyanin-induced apoptosis, and translocation of CTSD to the cytosol followed pyocyanin treatment and lysosomal disruption. A stable analog of cAMP (dibutyryl cAMP) impeded the translocation of CTSD and prevented the destabilization of Mcl-1 by pyocyanin. Thus, pyocyanin activated a coordinated series of events dependent upon lysosomal dysfunction and protease release, the first description of a bacterial toxin using a lysosomal cell death pathway. This may be a pathological pathway of cell death to which neutrophils are particularly susceptible, and could be therapeutically targeted to limit neutrophil death and preserve host responses.


Preclinical, pharmacologic, and phase I studies of gemcitabine.
Gemcitabine (2',2'-difluorodeoxycytidine) is a novel nucleoside analogue that exerts its antitumor activity via multiple mechanisms of action. These include (1) incorporation of gemcitabine into replicating DNA, which inhibits DNA replication and cell growth, (2) masked DNA chain termination, and (3) several self-potentiation mechanisms that serve to increase intracellular levels of the active compound. Preclinical experiments in various cell lines and animal models demonstrate a broad range of cytotoxic activity. Pharmacokinetic studies of gemcitabine delivered by its usual schedule (30-minute weekly infusion) reveal a short plasma half-life and a high clearance into central and peripheral compartments (two-compartment model). The drug is excreted almost completely in the urine as the parent compound and primary metabolite (difluorodeoxyuridine). Phase I trials demonstrate that pharmacokinetics are schedule dependent and that, in general, gemcitabine is well tolerated. Dose-limiting toxicities are primarily myelosuppression, with other toxicities being rash, flu-like symptoms, and transient elevations in liver function tests.


Primary prophylaxis for venous thromboembolism in patients undergoing cardiac or thoracic surgery.
Cardiac and thoracic surgery are associated with an increased risk of venous thromboembolism (VTE). The safety and efficacy of primary thromboprophylaxis in patients undergoing these types of surgery is uncertain. To assess the effects of primary thromboprophylaxis on the incidence of symptomatic VTE and major bleeding in patients undergoing cardiac or thoracic surgery. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). The authors searched the reference lists of relevant studies, conference proceedings, and clinical trial registries. Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We identified 12 RCTs and one quasi-RCT (6923 participants), six for cardiac surgery (3359 participants) and seven for thoracic surgery (3564 participants). No study evaluated fondaparinux, the new oral direct thrombin, direct factor Xa inhibitors, or caval filters. All studies had major study design flaws and most lacked a placebo or no treatment control group. We typically graded the quality of the overall body of evidence for the various outcomes and comparisons as low, due to imprecise estimates of effect and risk of bias. We could not pool data because of the different comparisons and the lack of data. In cardiac surgery, 71 symptomatic VTEs occurred in 3040 participants from four studies. In a study of 2551 participants, representing 85% of the review population in cardiac surgery, the combination of unfractionated heparin with pneumatic compression stockings was associated with a 61% reduction of symptomatic VTE compared to unfractionated heparin alone (1.5% versus 4.0%; risk ratio (RR) 0.39; 95% confidence interval (CI) 0.23 to 0.64). Major bleeding was only reported in one study, which found a higher incidence with vitamin K antagonists compared to platelet inhibitors (11.3% versus 1.6%, RR 7.06; 95% CI 1.64 to 30.40). In thoracic surgery, 15 symptomatic VTEs occurred in 2890 participants from six studies. In the largest study evaluating unfractionated heparin versus an inactive control the rates of symptomatic VTE were 0.7% versus 0%, respectively, giving a RR of 6.71 (95% CI 0.40 to 112.65). There was insufficient evidence to determine if there was a difference in the risk of major bleeding from two studies evaluating fixed-dose versus weight-adjusted low molecular weight heparin (2.7% versus 8.1%, RR 0.33; 95% CI 0.07 to 1.60) and unfractionated heparin versus low molecular weight heparin (6% and 4%, RR 1.50; 95% CI 0.26 to 8.60). The evidence regarding the efficacy and safety of thromboprophylaxis in cardiac and thoracic surgery is limited. Data for important outcomes such as pulmonary embolism or major bleeding were often lacking. Given the uncertainties around the benefit-to-risk balance, no conclusions can be drawn and a case-by-case risk evaluation of VTE and bleeding remains preferable.


Dietary Patterns with Healthy and Unhealthy Traits Among Overweight/Obese Hispanic Women with or at High Risk for Type 2 Diabetes.
Hispanic women are at high risk for type 2 diabetes (T2D), with obesity and unhealthy eating being important contributing factors. A cross-sectional design was used in this study to identify dietary patterns and their associations with diabetes risk factors. Participants completed a culturally adapted Food Frequency Questionnaire capturing intake over the prior 3 months. Overweight/obese Hispanic women (n = 191) with or at risk for T2D were recruited from a community clinic into a weight loss intervention. Only baseline data was used for this analysis. Dietary patterns and their association with diabetes risk factors (age, body mass index, abdominal obesity, elevated fasting blood glucose [FBG], and hemoglobin A1c). An exploratory factor analysis of dietary data adjusted for energy intake was used to identify eating patterns, and Pearson correlation coefficient (r) to assess the association of the eating patterns with the diabetes risk factors. Six meaningful patterns with healthful and unhealthful traits emerged: (1) sugar and fat-laden, (2) plant foods and fish, (3) soups and starchy dishes, (4) meats and snacks, (5) beans and grains, and (6) eggs and dairy. Scores for the "sugar and fat-laden" and "meats and snacks" patterns were negatively associated with age (r = - 0.230, p = 0.001 and r = - 0.298, p < 0.001, respectively). Scores for "plant foods and fish" were positively associated with FBG (r = 0.152, p = 0.037). Being younger may be an important risk factor for a diet rich in sugar and fat; this highlights the need to assess dietary patterns among younger Hispanic women to identify traits potentially detrimental for their health.


Role of intracellular cyclic adenosine 3',5'-monophosphate concentration and oocyte-cumulus cells communications on the acquisition of the developmental competence during in vitro maturation of bovine oocyte.
The present study was designed to address the physiological role played by cAMP on gap junction (GJ) mediated communications between oocyte and cumulus cells during in vitro maturation. Cyclic AMP was stimulated by different collection and maturation media known to induce different rates of nuclear maturation and developmental competence as well as different levels of cumulus expansion. Cumulus-oocyte complexes (COCs) were matured for 0, 3, 7, 12, 18, and 24 h in the absence of stimulation or in the presence of serum and gonadotropins (fetal bovine serum+human menopausal gonadotropins [FCS+hMG]) or 0.01 microg/ml of invasive adenylate cyclase (iAC). For each time point, intracellular cAMP concentration ([cAMP]i) was determined either in the whole COC or oocyte after cumulus cell removal. GJ functional status was analyzed by microinjection of Lucifer yellow fluorescent dye in cumulus-enclosed oocytes and by immunohistochemical localization of connexin 43 (Cx43). In the absence of stimulation, [cAMP]i in COC and oocyte was lower than in other groups, and communications declined after 3 h of culture. In the FCS+hMG group, [cAMP]i increased significantly in COC, with a peak between 3 and 7 h that was temporally correlated with the beginning of the cumulus expansion process, which occurred only in this group and with the termination of the communications. COC matured in the presence of iAC showed a moderate increase of [cAMP]i during all of the maturation times as well as a prolongation of oocyte-cumulus cell communications. The immunohistochemical localization of Cx43 confirmed the delay in connexons protein turnover in iAC-treated COCs. Our results show that cumulus expansion and oocyte developmental competence are induced by different levels of cAMP and that its intracellular concentration may affect cell coupling between oocyte and cumulus cells. We hypothesize that the higher developmental competence of COCs matured in the presence of iAC could be achieved through a moderate increase of intracellular cAMP, which in turn determines a prolongation of communications between the two cell types.


Synthesis and biological evaluation of 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-ones as cisplatin sensitizers.
A series of novel 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-one derivatives were synthesized and their anti-cancer as well as cisplatin sensitization activities were evaluated. Among them, compounds 6e and 6h exhibited significant cisplatin sensitization activity against HCT116. Hoechst staining and annexin V-FITC/PI dual-labeling studies demonstrated that the combination of 6e/6h and cisplatin can induce tumour cell apoptosis. Western blot showed that the expression of ATR downstream protein, CHK1, decreased in 6e + cisplatin and 6h + cisplatin groups compared with that in the test compound and cisplatin group. Furthermore, docking of 6e/6h into the ATR structure active site revealed that the N1 and N8 atoms in the naphthyridine ring and the hybrid atom in the oxadiazole ring are involved in hydrogen bonding with Val170, Glu168 and Tyr155. Additionally, the naphthyridine ring is also involved in π-π stacking with Trp169. Accordingly, compounds 6e and 6h can be expected to be potential cisplatin sensitizers that can participate in HCT116 cancer therapy.


Littoral cell angioma in a patient with Crohn's disease.
Littoral cell angioma is a rare vascular tumor of the spleen. The pathogenesis is unknown but the lesion is associated with several malignancies and immunological disorders. The diagnosis requires histopathological examination. The malignant potential of this lesion is unknown, which is why splenectomy is recommend for all cases. Symptomatic cases generally suffer from hypersplenism and pyrexia. A previously healthy 20-year-old female was diagnosed with colonic Crohn's disease; as part of the work-up a magnetic resonance enterography was performed which showed multiple signal changes of the spleen. The patient reported chronic abdominal pain in the left upper quadrant, malaise, and fever. The unknown splenic lesions prompted a laparoscopic splenectomy; pathology revealed a littoral cell angioma. The abdominal pain and malaise remitted but the fever persisted one year despite adequate treatment of the patient's Crohn's disease. Littoral cell angioma is associated with immune-dysregulation including Crohn's disease with several reported cases. Signs and symptoms of hypersplenism and splenic lesions on imaging should raise suspicion of littoral cell angioma in patients with Crohn's disease. Magnetic resonance enterography to assess disease severity in Crohn's disease may provide an opportunity to study the prevalence and natural history of this rare splenic tumor.


[Current debates on humanization and health: who are we?].
Bearing in mind that the Brazilian Unified Health System (SUS) is a social process in construction, and as health professionals are important individuals in this process, the role of permanent education as an important instrument to ensure humanized care is highlighted. The scope of this paper is to discuss the experience of the training course for health professionals of a public health outpatient unit, based on the prospect of humanized treatment, seeking the implementation of a sanitary model committed to the formal values contained in the SUS ideals. The teaching-learning methodology used is based on problem-solving, derived from the processing of a problem situation taken from the experience of teachers. The professionals identified that the standard established in the way of thinking and acting in health is unsatisfactory to meet the challenges faced in the sector. The strategies used contributed to systematize the content through reflection on the theoretical benchmarks submitted, by eliciting reflective and critical thought, which are fundamental aspects for broadening and increasing the process of empowerment of professionals. The course stimulated group action, placing the discussion on the humanization of health actions on the agenda.


Association study of mitochondrial DNA polymorphisms with type 2 diabetes in Tunisian population.
Mitochondrial DNA (mtDNA) variation may play an important role in the pathogenesis of type 2 diabetes (T2Ds). In this study, we aimed to explore whether mtDNA variants contribute to the susceptibility to T2Ds in a Tunisian population. The hypervariable region 1 (HVS1) of the mtDNA of 64 T2Ds patients and 77 healthy controls was amplified and sequenced. Statistical analysis was performed using the STATA program. Analysis of the total screened variants (N = 88) from the HVS1 region showed no significant difference in the distribution of all polymorphisms between T2Ds and controls, except for the variant G16390A which was more frequent in T2Ds (15.9%) than in controls (5.4%) (p = 0.04). The association of G16390A was not detected after multivariate regression analysis. Similarly, analysis of the distribution of mitochondrial haplogroups within our dataset showed 18 distinct major haplogroups with no significant difference between T2Ds and controls. Except, the weakly association found for the G16390A variant, our results showed that none of the tested polymorphisms from the HVS1 region have a major role in T2Ds pathogenesis in the studied Tunisian population even when taking into account the population stratification.


Nonlethal conditioning for the induction of allogeneic chimerism and tolerance to islet allografts.
We reported that tolerance to skin grafts can be achieved by chimerism induction by way of nonlethal conditioning. In the present study, we evaluated the outcome of islet allografts implanted either simultaneously or after donor bone marrow cell (BMC) infusion when nonlethal conditioning was used. B10 (H-2b) mice were conditioned with antilymphocyte serum (ALS), 100 cGy total body irradiation (TBI), and given 30 x 10(6) allogeneic (B10.BR, H-2k) BMC on day 0. On day 2, cyclophosphamide was given intraperitoneally (IP), followed by a second BMC infusion on day 3. After chimeras were typed for allogeneic BMC engraftment on day 28, animals were rendered diabetic chemically and transplanted under the kidney capsule with islet allografts genetically matched or disparate to the BM. Donor-specific islet grafts were accepted (median survival time [MST] > 180 days, n=6), whereas all major histocompatibility complex (MHC)-disparate third-party BALB/c (H-2d) islet grafts were rejected (MST=13.8 days, n=4). When B10.BR BMC and islets were given simultaneously, graft acceptance (MST >140 days, n=4) was observed. Surprisingly, when MHC-disparate third-party islets (BALB/c) were given together with B10.BR BMC, long-term survival was also observed (MST >100 days, n=3). These findings suggested that conditioning alone at the time of islet implant might induce long-term engraftment without further treatment. However, only chimeric animals accepted a second-set donor-specific graft, whereas all other groups rejected it. Our data indicates that stable allogeneic chimerism and islet indefinite survival can be achieved by the use of a nonmyeloablative protocol. The results of the conditioning-only experiments are consistent with the possibility of graft accommodation.


Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H.
The objective of this study was to explore the role of classical, lectin, and alternative pathways of complement activation in laser-induced choroidal neovascularization (CNV). The classical and alternative pathways were blocked in C57BL/6 mice by small interfering RNAs (siRNA) directed against C1q and factor B, respectively. C4(-/-) mice developed CNV similar to their wild-type controls and inhibition of C1q by siRNA had no effect on the development of CNV. In contrast, CNV was significantly inhibited (p < 0.001) in C5(-/-) mice and C57BL/6 mice treated with factor B siRNA. Inhibition of the alternative pathway by factor B siRNA resulted in decreased levels of membrane attack complex and angiogenic factors-vascular endothelial growth factor and TGF-beta2. Furthermore, factor B was up-regulated in complement sufficient C57BL/6 mice at day 1 postlaser and remained elevated at day 7. Significantly reduced levels of factor H were observed at day 3 in these animals. In conclusion, our results demonstrate that activation of the factor B-dependent alternative pathway, but not the classical or lectin pathways, was essential for the development of CNV in mouse model of laser-induced CNV. Thus, specific blockade of the alternative pathway may represent a therapeutically relevant strategy for the inhibition of CNV.


Organizational considerations for the implementation of a computerized physician order entry.
Several studies stressed that the introduction of CPOE applications deteriorates the doctor-nurse communication. But there are many factors that might influence communication behaviors, as for example the way these communications are organized. The present study aims at showing that the impact of a CPOE system on the cooperative activities can be controlled given that a good understanding of the cooperative workflows support the implementation. By analyzing the doctors-nurses communications during the medication use process, the study demonstrates that the technical system has no impact on the cooperative activities within a given organization. CPOE does not induce differences in the dialogs' durations and contents.


[Modern trends in the arteriography of the lower leg arteries (author's transl)].
The anatomical situation in arteries of the lower leg and foot can be demonstrated in an optimal manner with orthograde catheter-technique, biplane seriography, magnification and the use of the Medichrome-film. Angiography would be carried out in local anaesthesia after injection from Priscolin and an oral trunk of alcohol. This technique in 580 legs had no complications. All arteries behind arterial occlusions can be demonstrated before and after vascular surgery and other therapeutic procedures.


Immune CD8+ T lymphocytes lyse Listeria monocytogenes-infected hepatocytes by a classical MHC class I-restricted mechanism.
Hepatocytes constitute the principal site of listerial replication in the livers of mice infected i.v. CD8+ T lymphocytes play a predominant role in the host defenses to Listeria monocytogenes. In vitro experiments by others undertaken to delineate the functions of CD8+ T lymphocytes have focused primarily on their interaction with Listeria-infected macrophages. Such experiments do not address directly the role of CD8+ T lymphocytes in eliminating the bulk of Listeria replicating within the liver. Here, we report that immune CD8+ T cells at an E:T cell ratio > or = 10:1 lysed Listeria-infected hepatocytes as judged by the following two criteria. Aspartate aminotransferase activity in the culture supernatants, indicative of hepatocyte damage, increased significantly. Conversely, infected hepatocytes cocultured with immune CD8+ T cells exhibited a marked reduction in viable intracellular Listeria assessed by CFUs. Neither immune CD4+ T cells nor nonimmune CD8+ T cells caused a similar increase in aspartate aminotransferase activity released or a decrease in intracellular bacteria. Immune CD8+ T cell-mediated lysis of infected hepatocytes was restricted by classical MHC class I (H-2Kb) molecules and was inhibited by the presence of either brefeldin A or mAb specific for CD8. These results suggest that the predominant role of CD8+ T lymphocytes in host resistance to listerial infections of the liver may be due to their capacity to lyse infected hepatocytes.


Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release.
Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca(2+))- and zinc (Zn(2+))-permeable ion channels that sense noxious substances. Despite the biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance. In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-α and interleukin-1α) induced TRPA1 gene expression via nuclear factor-κB signaling and downstream activation of the transcription factor hypoxia-inducible factor-1α (HIF1α). HIF1α unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn(2+), suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1α mechanism that links inflammatory mediators to ion channel expression.


Informed Consent in Biomedical Research: Scopes and Challenges.
Medical science is evolving constantly and this evolution cannot happen without biomedical research involving human participant. Owing to a tumultuous history, importance of ethical research cannot be over emphasized in today's world and the concept of informed consent becomes the guardian of ethics, not only to improve the bonding between the participant and researcher aiding a wholehearted involvement but also ensuring safety for the participants from research related injury/loss. Subject information sheet (SIF) and Informed consent form (ICF) are the fundamental elements of informed consent document. Process of obtaining them from illiterate and vulnerable populations involves the legally authorized representative (LAR) and impartial witness. Audiovisual recording becomes important in case of clinical trials. Process of obtaining informed consent becomes challenging for vulnerable populations as well as during pandemic situations. A comprehensive informed consent is essential for a credible and ethical research.


Anti-nuclear envelope antibodies: Clinical associations.
Characterization of the clinical associations and clinical implications of antibodies reacting with antigens of the nuclear envelope. Description of an illustrative case and a MEDLINE search-assisted literature review of relevant cases. With indirect immunofluorescence, autoantibodies directed against various antigens of the nuclear envelope stain the nucleus in a ring-like (rim) pattern. Autoantibodies against 5 antigenic components of the nuclear envelope have been described: anti-gp210, p62, lamina, lamina-associated polypeptides, and lamin B receptor. Antibodies to antigens of the nuclear pore complex, such as gp210 and p62, are highly specific (> 95%) for primary biliary cirrhosis and may aid in the serologic diagnosis of this condition, especially in cases in which antimitochondrial antibodies are not detectable. In contrast, antilamin antibodies are not disease-specific but seem to be associated with lupus anticoagulant or anticardiolipin antibodies, antiphospholipid syndrome, thrombocytopenia, autoimmune liver diseases, and arthralgia. High-titered antilamin antibodies help to define a subset of lupus patients with antiphospholipid antibodies who are at a lower risk of developing thrombotic events. In addition, preliminary data suggest that the presence of antilamin antibodies may be helpful in the diagnosis of chronic fatigue syndrome. Each of the antibodies reacting with nuclear membrane antigens has its own spectrum of disease associations. Determination of anti-nuclear envelope antibody pattern by indirect immunofluorescence, with subsequent determination of the specific antibody, carries important diagnostic and prognostic implications in various autoimmune conditions.


Traditional versus up-front [18F] fluorodeoxyglucose-positron emission tomography staging of non-small-cell lung cancer: a Dutch cooperative randomized study.
We investigated whether application of positron emission tomography (PET) immediately after first presentation might simplify staging while maintaining accuracy, as compared with traditional strategy in routine clinical setting. At first presentation, patients with a provisional diagnosis of lung cancer without overt dissemination were randomly assigned to traditional work-up (TWU) according to international guidelines or early PET followed by histologic/cytologic verification of lesions, or imaging and follow-up. Patients with [18F] fluorodeoxyglucose (18FDG) -avid, noncentral tumors without suspicion of mediastinal or distant metastases on PET proceeded directly to thoracotomy. Follow-up in presumed benign lesions was at least 12 months. In patients treated with surgery or neoadjuvant therapy, the quality of staging was measured by comparing the clinical stage to the final stage (combination of peroperative staging and 6 months of follow-up). To investigate test substitution, we analyzed the number of (non)invasive tests to achieve clinical TNM staging, and its associated costs. Between 1999 and 2001, 465 patients (233 TWU, 232 PET) were enrolled at 22 hospitals. The mean (standard deviation) number of procedures to finalize staging was equal in the TWU arm and the PET arm: 7.9 (2.0) v 7.9 (1.9), P = .90, respectively. Mediastinoscopies occurred significantly less often in the PET arm. Agreement between clinical and final stage was good in both arms (kappa = .85 v .78; P = .07). Costs did not differ significantly. Up-front 18FDG-PET in patients with (suspected) lung cancer does not reduce the overall number of diagnostic test, but it maintains quality of TNM staging with the use of less invasive surgery.


[Increase in lipophilicity of enalaprilat by complexation with copper(II) or zinc(II) Ions].
Enalaprilat (H2L), which is the active metabolite of the pro-drug enalapril, is an angiotensin-converting enzyme inhibitor. Some side effects such as neurodegeneration and taste disorder can be related to copper or zinc deficiency, which would be caused by the metal complex formation of dianionic elalaprilat (L(2-)). For a better understanding of this phenomenon, we investigated the solution species of enalaprilat in the presence of copper(II) or zinc(II) ions by pH titration analysis with I=0.10 M (NaCl) at 25℃. The 1:1 complex formation constants (KML=[ML]/[M(2+)][L(2-)] M(-1)) of 10(7.4) for CuL and 10(4.4) for ZnL complexes were evaluated, indicating the presence of those complexes at a physiological pH. Furthermore, partition experiments with a two-phase system of 1-butanol/water at 25℃ disclosed that copper(II) and zinc(II) complexes of enalaprilat were partially extracted into the organic layer. In the absence of those metal ions, enalaprilat was not soluble in the 1-butanol phase. The increase in lipophilicity of enalaprilat by metal complexation suggests that the long-term administration of enalapril could be a possible risk factor for the disrupted distribution of those metal ions in biological systems.


Perfusion magnetic resonance abnormalities in patients with sickle cell disease.
Neurological complications are common in sickle cell disease (SCD). However, it is often difficult to relate the clinical presentation to conventional neuroimaging, because subclinical infarction is common and stroke has been described in the absence of large-vessel disease. We studied 48 patients with SCD aged 4-34 (median 13) years with T2-weighted, diffusion and perfusion magnetic resonance imaging (MRI) and with MR angiography. Forty-four underwent transcranial Doppler (TCD). Abnormalities on perfusion imaging were seen in 25 cases, 24 of whom had been symptomatic. The remaining patient had evidence of executive dysfunction and reduced perfusion in the frontal lobes. The perfusion abnormality was larger than the area of infarction in 9 patients and was seen in an arterial distribution with no infarction in a further 9. In 3 patients with transient ischemic attacks, perfusion abnormalities were demonstrated in the absence of any other neuroimaging abnormalities, and perfusion changes were seen in 3 others despite normal MR angiography and TCD. Perfusion abnormalities are associated with neurological symptoms in patients with SCD, whether or not MRI, MR angiography, and TCD are abnormal. It is likely that this technique will guide management in individual patients.


Multi-stage domain-specific pretraining for improved detection and localization of Barrett's neoplasia: A comprehensive clinically validated study.
Patients suffering from Barrett's Esophagus (BE) are at an increased risk of developing esophageal adenocarcinoma and early detection is crucial for a good prognosis. To aid the endoscopists with the early detection for this preliminary stage of esophageal cancer, this work concentrates on the development and extensive evaluation of a state-of-the-art computer-aided classification and localization algorithm for dysplastic lesions in BE. To this end, we have employed a large-scale endoscopic data set, consisting of 494,355 images, in combination with a novel semi-supervised learning algorithm to pretrain several instances of the proposed neural network architecture. Next, several Barrett-specific data sets that are increasingly closer to the target domain with significantly more data compared to other related work, were used in a multi-stage transfer learning strategy. Additionally, the algorithm was evaluated on two prospectively gathered external test sets and compared against 53 medical professionals. Finally, the model was also evaluated in a live setting without interfering with the current biopsy protocol. Results from the performed experiments show that the proposed model improves on the state-of-the-art on all measured metrics. More specifically, compared to the best performing state-of-the-art model, the specificity is improved by more than 20% points while simultaneously preserving high sensitivity and reducing the false positive rate substantially. Our algorithm yields similar scores on the localization metrics, where the intersection of all experts is correctly indicated in approximately 92% of the cases. Furthermore, the live pilot study shows great performance in a clinical setting with a patient level accuracy, sensitivity, and specificity of 90%. Finally, the proposed algorithm outperforms each individual medical expert by at least 5% and the average assessor by more than 10% over all assessor groups with respect to accuracy.


TRP channels in Drosophila photoreceptor cells.
TRP cation channels are conserved throughout animal phylogeny and include many members that function in sensory physiology. The founding TRP is required for Drosophila phototransduction and has served as a paradigm for unravelling the roles and macromolecular organizations of TRP channels in native tissues. Two other TRPC channels, TRPL and TRPgamma, are expressed in photoreceptor cells and form heteromultimers with TRP and with each other. TRP is a member of a supramolecular signalling complex, the signalplex, which includes the PDZ scaffold protein, INAD, and two other core members that remain bound and depend on INAD for localization. Other INAD binding proteins are proposed to interact dynamically with INAD, one of which, TRPL, undergoes light-dependent translocation in photoreceptor cells. Surprisingly, TRP has non-channel functions, including an anchoring role necessary for retaining INAD in the rhabdomeres. Loss of TRP function or constitutive TRP activity results in retinal degeneration, which can be suppressed by disruption or overexpression of the Na+/Ca2+ exchanger, CalX, respectively. Given that hypoxia-induced constitutive activity of some mammalian TRPs leads to neuronal cell death, interventions that increase Na+/Ca2+ exchanger or decrease TRP function have the potential to reduce the severity of cell death due to ischaemia.


Evaluation of radiation risk and work practices during cerebral interventions.
This study was intended to evaluate radiation risk to patients during cerebral interventions and the contribution to this risk from work practices. Thirty nine patients undergoing cerebral interventions in a digital subtraction angiography suite were included in this study. Patients who underwent cerebral interventions were categorised into two groups according to the number of cerebral interventions performed on them, and their effective doses were calculated. The effective dose for patients undergoing a single cerebral intervention (group A) varied from 1.55 to 15.9 mSv and for multiple cerebral interventions (group B) varied from 16.52 to 43.52 mSv. Two patients who underwent multiple cerebral interventions (group B) had alopecia of the irradiated scalp.


Aspergillus luchuensis fatty acid oxygenase ppoC is necessary for 1-octen-3-ol biosynthesis in rice koji.
Awamori is a distilled spirit produced in Okinawa Prefecture, in southern Japan. Awamori contains the volatile organic compound 1-octen-3-ol, an important flavor component. Here, using solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GCMS), we demonstrate that the black koji mold Aspergillus luchuensis produces 1-octen-3-ol in rice koji. To examine the role of the fatty acid oxygenase genes ppoA and ppoC in 1-octen-3-ol biosynthesis by A. luchuensis, we constructed ppoA and ppoC disruptants, ΔppoA and ΔppoC, respectively, via protoplast-PEG transformation. No clear differences in growth and conidiation were observed between the transformants and the parent strain. Volatile compounds in rice koji prepared using these gene disruptants were analyzed by SPME-GCMS. The amount of 1-octen-3-ol contained in koji produced by the ΔppoA strain was the same as that produced by the parental strain. In contrast, although the ΔppoC strain grew on the rice koji, 1-octen-3-ol was not detected. These results indicate that ppoC is involved in 1-octen-3-ol biosynthesis in A. luchuensis.


Calcium modulates the generation of inositol 1,3,4-trisphosphate in human platelets by the activation of inositol 1,4,5-trisphosphate 3-kinase.
We observed that more total inositol trisphosphate (InsP3) was formed when human platelets were stimulated with agonists (15-hydroxy-9,11-azo-prosta-5,13-dienoic acid or thrombin) in the presence of extracellular Ca2+ than in its absence. Analysis of the InsP3 by h.p.l.c. indicated that the increased InsP3 formed in the presence of extracellular Ca2+ was primarily the 1,3,4-trisphosphate [Ins(1,3,4)P3]. In addition, more inositol 1,3,4,5-tetrakisphosphate (InsP4) was formed in the presence of extracellular Ca2+. Experiments conducted with electrically permeabilized platelets demonstrated that conversion of [3H]Ins(1,4,5)P3 to [3H]InsP4 in platelets was Ca2+-dependent, with half-maximal conversion observed at approx. 2.5 microM-Ca2+. By contrast, dephosphorylation of [3H]InsP4 to [3H]Ins(1,3,4)P3 was not activated by Ca2+. A partially purified preparation of Ins(1,4,5)P3 3-kinase from human platelets was found to be insensitive to Ca2+, but addition of calmodulin restored Ca2+-sensitivity to the kinase, increasing its activity about 5-fold. These results show that in human platelets the metabolism of Ins(1,4,5)P3 is regulated by Ca2+-calmodulin, and suggest that the metabolites of Ins(1,4,5)P3 may also have important second-messenger functions in platelets, and are consistent with the hypothesis that the activation of phospholipase C is not dependent on extracellular Ca2+.


Pathogenesis of the acquired immune deficiency syndrome (AIDS).
The pathogenesis of the acquired immune deficiency syndrome (AIDS) is still unknown. However, it appears to develop in the milieu of prolonged immunodeficiency. Recently, the disease has reached almost epidemic proportions among homosexuals. Patients with AIDS present primarily with disseminated Kaposi's sarcoma and/or a host of opportunistic infections. A hypothesis is submitted incriminating induced tolerance leading to multiple viral infections and reinfections with cytomegalovirus and others, with or without additional immunosuppression by drugs and chemicals, as the cause of prolonged immunosuppression necessary for the development of AIDS. These viruses, behaving as both tumor inducers and promotors in turn, could result in tumors like Kaposi's sarcoma.


A Pragmatic Mapping of Perceptions and Use of Digital Information Systems in Primary Care in Sweden: Survey Study.
Electronic health records and IT infrastructure in primary care allow for digital documentation and access to information, which can be used to guide evidence-based care and monitor patient safety and quality of care. Quality indicators specified by regulatory authorities can be automatically computed and presented to primary care staff. However, the implementation of digital information systems (DIS) in health care can be challenging, and understanding factors such as relative advantage, compatibility, complexity, trialability, and observability is needed to improve the success and rate of adoption and diffusion. This study aims to explore how DIS are used and perceived by health care professionals in primary care. This study used quantitative assessment to gather survey data on the use and potential of DIS in health care in Sweden from the perspectives of primary care personnel in various roles. The digital questionnaire was designed to be short and contained 3 sections covering respondent characteristics, current use of platforms, and perceptions of decision support tools. Data were analyzed using descriptive statistics, nonparametric hypothesis testing, ordinal coefficient α, and confirmatory factor analysis. The study collected responses from participants across 10 regions of Sweden, comprising 31.9% (n=22) from private clinics and 68.1% (n=47) from public clinics. Participants included administrators (18/69, 26.1%), a medical strategist (1/69, 1.4%), and physicians (50/69, 72.5%). Usage frequency varied as follows: 11.6% (n=8) used DIS weekly, 24.6% (n=17) monthly, 27.5% (n=19) a few times a year, 26.1% (n=18) very rarely, and 10.1% (n=7) lacked access. Administrators used DIS more frequently than physicians (P=.005). DIS use centered on quality improvement and identifying high-risk patients, with differences by role. Physicians were more inclined to use DIS out of curiosity (P=.01). Participants desired DIS for patient follow-up, lifestyle guidance, treatment suggestions, reminders, and shared decision-making. Administrators favored predictive analysis (P<.001), while physicians resisted immediate patient identification (P=.03). The 5 innovation attributes showed high internal consistency (α>.7). These factors explained 78.5% of questionnaire variance, relating to complexity, competitive advantage, compatibility, trialability, and observability. Factors 2, 3, and 4 predicted intention to use DIS, with factor 2 alone achieving the best accuracy (root-mean-square=0.513). Administrators and physicians exhibited role-based DIS use patterns highlighting the need for tailored approaches to promote DIS adoption. The study reveals a link between positive perceptions and intention to use DIS, emphasizing the significance of considering all factors for successful health care integration. The results suggest various directions for future studies. These include refining the trialability and observability questions for increased reliability and validity, investigating a larger sample with more specific target groups to improve generalization, and exploring the relevance of different groups' perspectives and needs in relation to decisions about and use of DIS.


[Effects of vagotomy on the secretion of secretin].
The effect of truncal and proximal gastric vagotomies on the secretin secretion was investigated on 28 dogs. Truncal vagotomy was applied 15, and proximal gastric vagotomy on the rest of them. The secretin secretion was stimulated giving HCl of 0, 1 N into duodenum. The level of secretin in portal plasma was measured with RIA at 3, 5, 10, 15, 30 and 45th minutes just before and after stimulation. It was found out that various responses were given to the stimulation when the results were obtained before vagotomy, just after it and one month later. After truncal vagotomy the response of taken out duodenal acidification decreased significatively. A clear increase was noticed in the response one month later, but this increase didn't reach to the level seen just before truncal vagotomy. The responses in proximal gastric vagotomized group were not effected by the operation in early stage, one month later a decrease was seen in the response, the later stages.


Signaling through IL-17C/IL-17RE is dispensable for immunity to systemic, oral and cutaneous candidiasis.
Candida albicans is a commensal fungal microbe of the human orogastrointestinal tract and skin. C. albicans causes multiple forms of disease in immunocompromised patients, including oral, vaginal, dermal and disseminated candidiasis. The cytokine IL-17 (IL-17A) and its receptor subunits, IL-17RA and IL-17RC, are required for protection to most forms of candidiasis. The importance of the IL-17R pathway has been observed not only in knockout mouse models, but also in humans with rare genetic mutations that impact generation of Th17 cells or the IL-17 signaling pathway, including Hyper-IgE Syndrome (STAT3 or TYK2 mutations) or IL17RA or ACT1 gene deficiency. The IL-17 family of cytokines is a distinct subclass of cytokines with unique structural and signaling properties. IL-17A is the best-characterized member of the IL-17 family to date, but far less is known about other IL-17-related cytokines. In this study, we sought to determine the role of a related IL-17 cytokine, IL-17C, in protection against oral, dermal and disseminated forms of C. albicans infection. IL-17C signals through a heterodimeric receptor composed of the IL-17RA and IL-17RE subunits. We observed that IL-17C mRNA was induced following oral C. albicans infection. However, mice lacking IL-17C or IL-17RE cleared C. albicans infections in the oral mucosa, skin and bloodstream at rates similar to WT littermate controls. Moreover, these mice demonstrated similar gene transcription profiles and recovery kinetics as WT animals. These findings indicate that IL-17C and IL-17RE are dispensable for immunity to the forms of candidiasis evaluated, and illustrate a surprisingly limited specificity of the IL-17 family of cytokines with respect to systemic, oral and cutaneous Candida infections.


Complement Titres of Naturally and Artificially Raised Piglets II. Comparison with the Results of Electrophoretic Examinations.
Serial serum samples from piglets in one naturally-raised and three artificially-raised litters, 19 animals, were examined by cellulose acetate electrophoresis. The electropherograms of all day-old suckling and colostrum deprived piglets showed five definite bands, the first, third, fourth and fifth corresponding in position to the albumin, alpha-, beta- and gamma-globulin regions for adult pig serum. The second, well-defined band was located between the albumin and main alpha-globulin bands. This component, considered to be alpha(1)-globulin or fetuin, was no longer visible as a distinct band in the electrophoretic pattern for sera of three-week old suckling piglets or of five-week old artificially-raised piglets. No consistent relationship was observed between the rate of increase in haemolytic complement titre and the proportional changes in the various categories of serum globulins.


Jejunal tubulovillous adenocarcinoma in adenoma presenting with entero-enteric intussusception.
A 73-year-old male was admitted to our institution with complaints of nausea, vomiting, and abdominal distension. Plain abdominal computed tomography (CT) suggested intussusception in the jejunum. Enhanced abdominal CT revealed the 'target-like' sign and ultrasonography revealed the 'multiple concentric ring' sign; therefore, a diagnosis of entero-enteric intussusception was made. The small intestinal obstruction and cause of the intussusception were not evident. The patient was treated conservatively with fasting and transfusion therapy to prevent intestinal obstruction. However, with no spontaneous resolution of intussusception, surgical treatment was decided. The operative findings revealed a jejunal tumor about 30 cm from the Treiz ligament, and the jejunum including the tumor with a 5 cm margin were partially resected. The resected tumor was a 35 × 50 mm soft mass spreading laterally with nodules. The pathological examinations revealed tubulovillous adenocarcinoma in the adenoma. Intussusception is rare in adults compared to children. About 45 % of cases of intussusception in adults are due to small intestinal tumors such as malignant lymphoma or lipoma, but a tubulovillous adenocarcinoma with adenoma is a rare cause of intussusception. We present a rare case of jejunal tubulovillous adenocarcinoma in adenoma presenting with entero-enteric intussusception.


Congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition characterized by an insufficient production of cortisol and mineraloactive hormones with a consequent hyperstimulation of hypothalamo-pituitary-adrenal feedback and an increase of androgens. Although the lack of different enzymes in adrenal steroidogenesis can be responsible for different forms of the disease, the deficiency of 21-hydroxylase is the more frequent defect. It is caused by mutations in CYP21 gene located on the short arm of chromosome 6 and it causes a heterogeneous phenotype characterized by a classical form (genitalia virilization in female, early onset acute adrenal insufficiency with salt wasting, precocious pseudopuberty, signs of hyperandrogenism), or by a simple virilizing form (presence of signs of hyperandrogenism without salt-loosing crises) or by a non-classic form evidenced only by mild to moderate signs of hyperandrogenism. The diagnosis can be made by 17-hydroxyprogesterone measurement in basal and after ACTH stimulation test. Glucocorticoid and mineraloactive therapy have been proved to reduce the risk of adrenal crisis reducing the levels of androgens and controlling the symptoms of the disease.


Metabolomics Profiles of Smokers from Two Ethnic Groups with Differing Lung Cancer Risk.
African American (AA) smokers are at a higher risk of developing lung cancer compared to whites. The variations in the metabolism of nicotine and tobacco-derived carcinogens in these groups were reported previously with the levels of nicotine metabolites and carcinogen-derived metabolites measured using targeted approaches. While useful, these targeted strategies are not able to detect global metabolic changes for use in predicting the detrimental effects of tobacco use and ultimately lung cancer susceptibility among smokers. To address this limitation, we have performed global untargeted metabolomics profiling in urine of AA and white smokers to characterize the pattern of metabolites, identify differentially regulated pathways, and correlate these profiles with the observed variations in lung cancer risk between these two populations. Urine samples from AA (n = 30) and white (n = 30) smokers were used for metabolomics analysis acquired in both positive and negative electrospray ionization modes. LC-MS data were uploaded onto the cloud-based XCMS online (http://xcmsonline.scripps.edu) platform for retention time correction, alignment, feature detection, annotation, statistical analysis, data visualization, and automated systems biology pathway analysis. The latter identified global differences in the metabolic pathways in the two groups including the metabolism of carbohydrates, amino acids, nucleotides, fatty acids, and nicotine. Significant differences in the nicotine degradation pathway (cotinine glucuronidation) in the two groups were observed and confirmed using a targeted LC-MS/MS approach. These results are consistent with previous studies demonstrating AA smokers with lower glucuronidation capacity compared to whites. Furthermore, the d-glucuronate degradation pathway was found to be significantly different between the two populations, with lower amounts of the putative metabolites detected in AA compared to whites. We hypothesize that the differential regulation of the d-glucuronate degradation pathway is a consequence of the variations in the glucuronidation capacity observed in the two groups. Other pathways including the metabolism of amino acids, nucleic acids, and fatty acids were also identified, however, the biological relevance and implications of these differences across ethnic groups need further investigation. Overall, the applied metabolomics approach revealed global differences in the metabolic networks and endogenous metabolites in AA and whites, which could be used and validated as a new potential panel of biomarkers that could be used to predict lung cancer susceptibility among smokers in population-based studies.


An account of the first hours of the Covid-19 epidemic at the Nephrology Unit in Lodi (Lombardy).
Marco Farina and colleagues give us their account of the first days of the Covid-19 epidemic in the Nephrology Unit of the Ospedale Maggiore in Lodi. From the news trickling through from Codogno on the 20th of February to the hospitalization, the following day, of the first dialytic patient with signs of pneumonia, who later tested positive to the virus. They tell us of how the hospital has been completely restructured in the wake of the epidemic, at remarkable speed and providing an example for others to follow, and the great sense self-sacrifice displayed by all medical personnel. After an overview of the clinical conditions of the 7 patients positive to the virus hospitalised in the following few days, they describe in some detail how symptomatic Covid+ patients are currently managed at the Ospedale Maggiore in Lodi.


Intake of sugar-sweetened beverages and weight gain: a systematic review.
Consumption of sugar-sweetened beverages (SSBs), particularly carbonated soft drinks, may be a key contributor to the epidemic of overweight and obesity, by virtue of these beverages' high added sugar content, low satiety, and incomplete compensation for total energy. Whether an association exists between SSB intake and weight gain is unclear. We searched English-language MEDLINE publications from 1966 through May 2005 for cross-sectional, prospective cohort, and experimental studies of the relation between SSBs and the risk of weight gain (ie, overweight, obesity, or both). Thirty publications (15 cross-sectional, 10 prospective, and 5 experimental) were selected on the basis of relevance and quality of design and methods. Findings from large cross-sectional studies, in conjunction with those from well-powered prospective cohort studies with long periods of follow-up, show a positive association between greater intakes of SSBs and weight gain and obesity in both children and adults. Findings from short-term feeding trials in adults also support an induction of positive energy balance and weight gain by intake of sugar-sweetened sodas, but these trials are few. A school-based intervention found significantly less soft-drink consumption and prevalence of obese and overweight children in the intervention group than in control subjects after 12 mo, and a recent 25-week randomized controlled trial in adolescents found further evidence linking SSB intake to body weight. The weight of epidemiologic and experimental evidence indicates that a greater consumption of SSBs is associated with weight gain and obesity. Although more research is needed, sufficient evidence exists for public health strategies to discourage consumption of sugary drinks as part of a healthy lifestyle.


[Impact of introduction of the WHO tuberculosis-controlling recommendations adapted to the Russian conditions on the Russian statistical tuberculosis data].
The authors share their experience in introducing the WHO tuberculosis-controlling recommendations adapted to the Russian conditions into the Republic of Mariy El, in the Ivanovo, Oryol, and Tomsk Regions. All the areas are marked by high rates of diagnosis of MBT in the clinical diagnostic laboratories of the general medical network, by the increased rates of detection of patients of tuberculosis who isolate Mycobacterium tuberculosis, by the enhanced efficiency of treatment of patients with tuberculosis, as shown by the Russian statistical data, by the lower rates of growth of the contingents of patients with tuberculosis or by their reduction.


Persistent spontaneous synovial drainage from digital flexor sheath in proliferative tenosynovitis: Two case reports and a review of the literature.
Proliferative flexor tenosynovitis of the hand is an inflammatory process involving the synovial sheaths surrounding the tendons. It is most commonly caused by infection, but may also be caused by overuse, diabetes and rheumatic conditions such as rheumatoid arthritis and crystal arthropathies. The present report describes two patients with severe proliferative tenosynovitis, who developed a fistula between the tendon sheath and skin after instrumentation, resulting in persistent synovial drainage. After failing conservative management, both patients were managed with extensive flexor tenosynovectomy to prevent inoculation of bacteria into the flexor sheath. The presentation, management and outcome of each case is described in addition to a discussion of the literature on tenosynovial fistulas.


High-tech cardiac home care. An emerging delivery system.
The high cost of cardiac care and the increasing number of cardiac patients make high-tech care at home an increasingly attractive option for patients and caregivers. The latest advances in medicine and technology are transforming cardiac home care into more accessible, sophisticated care with fewer trips to and from the hospital.


Co-expression network analysis of lncRNAs and mRNAs in rat liver tissue reveals the complex interactions in response to pathogenic cytotoxicity.
Liver is one of the most vital organs to maintain homeostasis because of its peculiar detoxification functionalities to detoxify chemicals and metabolize drugs and toxins. Due to its crucial functions, the liver is also prone to various diseases, i.e., hepatitis, cirrhosis and hepatoma, etc. Additionally, long non-coding RNAs (lncRNAs) has emerged as key regulators which are found to play important roles in transcription, splicing, translation, replication, chromatin shaping and post translational modification of proteins in living cells. However, the underlying mechanisms of biological processes mediated by lncRNA remain unclear. Here, with the aim of disclosing potential lncRNAs implicated in the biological processes in liver in response to cytotoxicity, we performed a co-expression network analysis based on the transcriptome data of the damaged liver tissue of Rattus norvegicus induced by three cytotoxic compounds (carbon tetrachloride, chloroform and thioacetamide). Our analysis unveils that many biological processes and pathways were collectively affected by the three cytotoxic compounds, including drug metabolism, oxidation-reduction process, oxidative stress, glucuronidation, liver development and flavonoid biosynthetic process, etc. Also, our network analysis has identified several highly conserved lncRNA-mRNA interactions participating in those correlated processes and pathways, implying their potential roles in response to the induced cytotoxicity in liver. Our study provides new insights into lncRNA-mRNA regulatory mechanisms in response to pathogenic cytotoxic damaging in liver and facilitates the development of lncRNA-oriented therapies for hepatic diseases in the future.


Parental experience of a risky environment leads to improved offspring growth rate.
Parasites (or diseases) are a major selective force for the evolution of life history traits and parasite-host evolution. Mothers can show a variety of responses to parasites during pregnancy, with different consequences for them or their offspring. However, whether information in the maternal environment before pregnancy can cause a change in the phenotype of the offspring is unknown. To avoid the confounding effect of pathogens and to reduce the risk of a direct effect of maternal immune system activation, we injected female laboratory mice with lipopolysaccharides (LPS) before they mated. In order to provide constant information on the potential infectious risk of the environment, females were mated with males that were also exposed to LPS before mating. Offspring from immune-challenged parents were larger and grew at a faster rate than offspring from control parents (injected with PBS). Additionally, offspring from immune-challenged parents that suffered the most from inflammation grew at a faster rate than offspring from low suffering parents. Producing heavier offspring that will reach sexual maturity earlier is likely to have fitness benefits for parents and offspring through improved reproductive success.


Waldenstróm's macroglobulinemia with peripheral neuropathy--the role of IgM M-protein in autoimmune mechanism.
A total of 11 cases of Waldenstróm's Macroglobulinemia (WM) have been investigated to study the association of the disease with neuropathy. A 53-year-old female patient (Wu) had a pronounced peripheral neuropathy, in which the role of IgM M-protein could be observed. Sections of Wu's biopsied sural nerve were subjected to light and electron microscopy and direct immunofluorescence (IF). Myelin degeneration with axonal change was found, while fluorescence reaction occurred in epineurium only. Sections of a healthy dog's sciatic nerve were submitted to purified IgM M-proteins from Wu and another WM patient (Kon) without neuropathy, respectively. Indirect IF showed a deposit of fluorescence on the myelin sheath by Wu's, but not by Kon's, M-proteins. It is proposed that an autoimmune mechanism underlies the peripheral neuropathy in the WM patient.


Risk factors for readmission of orthopaedic surgical patients.
Reducing hospital readmissions has become a priority in the development of policies aimed at patient safety and cost reduction. Evaluating the incidence of rehospitalization of orthopaedic surgical patients could help to identify targets for more efficient perioperative care. We addressed two questions: What is the incidence of thirty-day readmission for orthopaedic patients at an academic hospital? Can any risk factors for readmission be identified among rehospitalized patients? This is a retrospective cohort study examining 3264 orthopaedic surgical admissions during two fiscal years from the hospital's quality-improvement database. Cases of patients with unplanned readmission within thirty days were subjected to univariate and multivariate analysis to determine the odds ratio (OR) for readmission. Further descriptive analysis was performed with use of electronic medical record data from the cohort of readmitted patients. The estimated cumulative incidence of unplanned thirty-day readmissions was 4.2% (i.e., 138 of the 3261 patients who were eligible for the study). Multivariate analysis indicated that marital status of "widowed" significantly increased the risk of readmission (OR, 1.846; 95% confidence interval [CI], 1.070 to 3.184; p = 0.03). Race significantly increased the odds of readmission in patients identified as African-American (OR, 2.178; 95% CI, 1.077 to 4.408; p = 0.03), or American Indian or Alaskan Native race (OR, 3.550; 95% CI, 1.429 to 8.815; p = 0.006). The risk of readmission was significant at p < 0.10 (OR 1.547; 95% CI, 0.941 to 2.545; p = 0.09) for patients with Medicaid insurance. Any intensive care unit stay gave the highest OR of readmission (OR, 2.356; 95% CI, 1.361 to 4.079; p = 0.002) for all demographic groups. Mean length of hospital stay was significantly longer, 5.9 days in the unplanned readmission group compared with 3.6 days for non-readmitted patients (OR, 1.038; 95% CI, 1.014 to 1.062; p = 0.002). Chart review of readmitted patients showed that 102 readmissions (73.9%) were classified as surgical; of these, thirty-five readmission events (34.3%) were for infection at the surgical site. Longer length of hospital stay or admission to the intensive care unit significantly increased the likelihood of thirty-day readmission, regardless of demographics or discharge disposition. Marital status, Medicaid insurance status, and race may indicate how a patient's social and economic resources can impact his or her risk of being readmitted to the hospital. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


[Anthropometric indices as the indicators of arterial hypertension risk in a group of elderly women of the city of Belgorod.]
A comparative study of three anthropometric indices as generalized characteristics of the morphological status of elderly women of Belgorod (sample size 50) in the connection with blood pressure (BP) was conducted. The age of the participants ranges from 50 to 79, with the average age of 61. In modern scientific literature, the problem of choosing among anthropometric indices the most reliable predictor of metabolic disorders and related diseases, including high BP, is widely discussed. The paper considers three most widely used anthropometric indices - body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WtHR). BMI and WtHR better reflect morphological specificity of the sample, with a tendency to increased body mass and girths. The highest and most reliable associations with BP are identified for BMI. The results of the study confirm the high predictive value of BMI as an indicator of the risk of arterial hypertension and associated metabolic disorders.


Long-chain polyunsaturated fatty acid supplementation in preterm infants.
This section is under preparation and will be included in the next issue. The n-3 and n-6 essential fatty acids alpha linolenic acid and linoleic acid are the precursors of the n-3 and n-6 longchain polyunsaturated fatty acids (LCPUFA). Controversy exists over whether LCPUFA are essential nutrients for preterm infants who may not be able to synthesise sufficient amounts of LCPUFA to satisfy the needs of the developing brain and retina. The aim of this review is to assess whether supplementation of infant formula with LCPUFA is safe and of benefit to preterm infants. Trials were identified by MEDLINE and by checking reference lists of relevant articles and conference proceedings. All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. Eight randomised trials were identified. Five were assessed as being of high quality and one is awaiting assessment. Problems with the remaining two included a change in assessment methodology mid-study (Memphis 1996) and assessment methodology that deviated from generally accepted international standards (Bologna 1996). Studies from Dallas (Uauy et al 1990, Birch et al 1992, Hoffman & Uauy 1992, Uauy et al 1994) and Memphis (Carlson et al 1991, Carlson et al 1992, Carlson et al 1993, Werkman & Carlson 1996) suggest that early visual development is better in formula-fed infants who receive a LCPUFA supplement compared with those fed standard formula. However, the effects were not long-term, with no differences detected between groups after 4 months of age. The Bologna group (Fadelli et al 1996) reported some differences in the visual evoked potential at 3 months post-term but their methodology was questionable making interpretation of the data difficult. In the largest study (the Mead Johnson study, Hansen et al 1997), no difference in visual acuity was demonstrated between LCPUFA supplemented and control infants at 2 and 4 months post-term. The Memphis studies used the Fagan Infantest (Fagan 1970) to measure infant development and demonstrated lower novelty preferences (possibly predictive of lower intelligence) in preterm infants supplemented with LCPUFA. However, the supplemented infants had more looks at the novel stimulus and each look was of shorter duration which may represent more rapid visual information processing. Normalised weight (expressed as SD from the mean for age) was lower in preterm infants who were fed supplemented formula in the Memphis studies. No difference in growth between supplemented and control infants was documented in the Dallas, Bologna, Alberta (Clandinin et al 1997) and Wyeth (Vanderhoof et al 1997) studies while the Mead Johnson study documented higher weights in supplemented infants compared with controls at two months post-term. The Dallas study documented little effect of LCPUFA supplements on bleeding time and membrane fragility. No long-term benefit has been demonstrated for preterm infants receiving formula supplemented with LCPUFA. There is some evidence that n-3 LCPUFA supplementation of formula increases the early rate of visual maturation in preterm infants. Supplementation of formula with n-3 and n-6 LCPUFA does not impair the growth of preterm infants.


Design and experimental demonstration of pointing correction module for a Fizeau imaging interferometer.
To increase the spatial resolution while circumventing the problems of increased mass and volume of monolithic telescopes, a Fizeau imaging interferometer testbed (FIIT) with three individual subtelescopes was designed and constructed for high resolution astronomical observation. FIIT is intended to be mounted on a distributed small-satellite constellation with a formation fly configuration; thus the extremely stable pointing of the subtelescopes is the prerequisite for phased imaging, which is because the satellite suffers from some extent of detrimental jitters and drifts needs to be corrected by FIIT itself. FIIT makes use of a shared tip/tilt detection module with a cross-correlation algorithm, three fast-steering mirrors, and closed-loop control technology for pointing correction of three subtelescopes, which can make sure the images are coaligned for a long period of time used to image some faint astronomical objects. This study gives a detailed description of the detection algorithm of image shifts, the hardware design, and data processing flow, followed by closed-loop experiments of a wide-band white light point source. The results of residual errors on the detection camera and the beam-combining camera demonstrate the performance of the pointing correction function, which is a significant milestone for FIIT.


[Sarcoidosis as seen by a patient: results of questionnaire survey].
Two hundred patients with sarcoidosis were interviewed by a questionnaire in the global Internet. For comparison, the same questionnaire was used in the interviews of 60 patients in Kazan. Among international responders, patients from the USA were prevalent. The age of 30-39 years was predominant in both groups, females were three fourths. Predominance of these or those social groups was not established. At the same time, analysis of professions revealed a large number of medical workers in both Kazan (11.7%) and abroad (17%). In global practice the diagnosis of sarcoidosis is much more frequently histologically verified though in Russia the likely diagnosis of sarcoidosis is much earlier established during the patient's visit to a doctor. The basic drugs for its therapy are glucocorticoids. Inhaled steroids are used relatively rarely. Only Russia is marked by the use of antituberculous agents. The authors note that the Internet may be a field for research activities in medical science.


The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase.
Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.


On the accumulation of deleterious mutations during range expansions.
We investigate the effect of spatial range expansions on the evolution of fitness when beneficial and deleterious mutations cosegregate. We perform individual-based simulations of 1D and 2D range expansions and complement them with analytical approximations for the evolution of mean fitness at the edge of the expansion. We find that deleterious mutations accumulate steadily on the wave front during range expansions, thus creating an expansion load. Reduced fitness due to the expansion load is not restricted to the wave front, but occurs over a large proportion of newly colonized habitats. The expansion load can persist and represent a major fraction of the total mutation load for thousands of generations after the expansion. The phenomenon of expansion load may explain growing evidence that populations that have recently expanded, including humans, show an excess of deleterious mutations. To test the predictions of our model, we analyse functional genetic diversity in humans and find patterns that are consistent with our model.


[Screening of tetrahydrobiopterin deficiency among hyperphenylalaninemic patients].
Tetrahydrobiopterin deficiency in hyperphenylalaninemic babies has to be rapidly recognized since the disease requires a specific follow-up. Based on specimen collection on filter paper, a simple strategy for the screening of this condition has been used since 1987. Urine pteridine measurement can detect 6-pyruvoyl-tetrahydropterin synthase, GTPcyclohydrolase I and pterin-4a-carbinolamine dehydratase deficiencies and direct enzyme measurement in dried blood sample detects dihydropteridine-reductase deficiency. A total of 1,814 hyperphenylalaninemic patients have been studied and 34 tetrahydrobiopterin deficiencies have been detected. The strategy must commend itself by its convenience and simplicity, and can be use on all babies with hyperphenylalaninemia screened in the neonatal period, whatever their blood phenylalanine level.


Spinal allografts of adrenal medulla block nociceptive facilitation in the dorsal horn.
Transplantation of chromaffin cells into the lumbar subarachnoid space has been found to produce analgesia, most conspicuously against chronic neuropathic pain. To ascertain the neurophysiological mechanism, we recorded electrical activity from wide-dynamic-range dorsal horn neurons in vivo, measuring the short-lasting homosynaptic facilitatory effect known as windup, which is induced by repetitive C-fiber input. Rats were given adrenal medulla allografts, or, as controls, striated-muscle allografts. The adrenal-transplanted rats showed analgesia 3--4 wk after transplantation, measured as a reduction in flinching reflexes 30--55 min after subcutaneous formalin injection. Recordings were made under halothane anesthesia, 3--7 days following the behavioral testing. The average C-fiber response and subsequent afterdischarge were facilitated severalfold in control rats by 1-Hz cutaneous electrical stimulation. Such facilitation was essentially absent in adrenal-transplanted animals and also in the A-fiber response of both preparations. Extirpation of transplanted tissue several hours prior to recording did not significantly affect this difference. In conclusion, the adrenal transplants block short-term spinal nociceptive facilitation, probably by stimulating some persistent cellular process that may be an important determinant, but not the only one, of their analgesic effect.


HIV-1 Induced CNS Dysfunction: Current Overview and Research Priorities.
Over the past three decades, the clinical presentation of HIV infection of the Central Nervous System (CNS) has evolved. Prior to wide spread use of effective antiretroviral therapy (ART), more than a third of infected individuals exhibited a range of neurocognitive and motor deficits that frequently progressed to severe dementia and paralysis. However, the use of ART has significantly decreased the prevalence of severe forms of HIV-1 associated neurocognitive disorders (HAND). Studies of neurocognitive dysfunction have reported variable prevalence, ranging from 21% to 77.6%, defined primarily by mild to moderate neurocognitive impairment. HIV-associated chronic inflammation and associated neurotoxicity of long term ART, as well as the aging of the HIV-infected population, likely influence the pathogenesis of HAND. Despite significant research efforts directed towards a better understanding of the mechanisms underlying HIV neuropathogenesis, definitive causal pathophysiology of HAND and thus effective prevention or treatment remain elusive. Furthermore, HIV therapeutic research now includes efforts to effect a cure, by eliminating or silencing HIV within infected cells, which must include efforts to target the latently infected cells within the CNS. Prevention and treatment of the neurological complications of HIV, and eradication of persistent virus from the CNS compartment are major priorities for the HIV-CNS research. Here we give an overview of the progress of research on HIV-CNS disease, define new challenges and research areas, and highlight domestic and global priorities.


Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome.
Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 (PSEN1). Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing. Four patients, aged 25-45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in PSEN1 (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing. Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.


Detection and Isolation of the "Top Seven" Shiga Toxin-Producing Escherichia coli in Ground Beef: Comparison of RapidFinder Kits to the U.S. Department of Agriculture Microbiology Laboratory Guidebook Method.
Shiga toxin-producing Escherichia coli (STEC) O157:H7 and serogroups O26, O45, O103, O111, O121, and O145 are often referred to as the "top seven" STEC, and these have been declared to be adulterants in beef by the U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS). The aim of this work was to compare the methods described in the USDA FSIS Microbiology Laboratory Guidebook (MLG) to a two-stage Applied Biosystems RapidFinder STEC real-time PCR method to test for the top seven STEC in raw ground beef. The specificity of the RapidFinder workflow that targets non-O157 STEC O-antigen genes, stx1, stx2, and eae, and E. coli O157-specific targets was determined with 132 top seven STEC strains and 283 exclusion strains. All inclusion strains were positive, and all exclusion strains gave negative results with the RapidFinder assay. Strains carrying all of the known variants of stx1 and stx2, including stx2f and stx2g, were also detected. For RapidFinder analysis, 375-g ground beef samples spiked with ≥4 CFU of representative STEC strains were enriched in 1 L of tryptic soy broth (TSB) for 10 h at 42 ± 1°C, and for the MLG method, 325-g samples were similarly spiked and enriched in 975 mL of modified TSB for 15 h at 42 ± 1°C. Following DNA extraction, real-time PCR was performed using RapidFinder Express software, and for the MLG method, the BAX Real-Time PCR STEC Suite and the BAX Real-Time E. coli O157:H7 assay were used with the BAX System Q7 software. Following immunomagnetic separation, presumptive colonies from modified Rainbow agar O157 plates were confirmed by the real-time PCR assays. Results of the RapidFinder and BAX assays were similar; all samples were positive after 10 and 15 h of enrichment, respectively. Isolation and confirmation of isolates was possible on all samples, except that two O111:NM strains could not be isolated from a portion of the inoculated samples. Thus, the RapidFinder system can be used for routine and rapid detection of the top seven STEC in beef.


Profiling antibody responses to infections by Chlamydia abortus enables identification of potential virulence factors and candidates for serodiagnosis.
Enzootic abortion of ewes (EAE) due to infection with the obligate intracellular pathogen Chlamydia (C.) abortus is an important zoonosis leading to considerable economic loss to agriculture worldwide. The pathogen can be transmitted to humans and may lead to serious infection in pregnant women. Knowledge about epidemiology, clinical course and transmission to humans is hampered by the lack of reliable diagnostic tools. Immunoreactive proteins, which are expressed in infected animals and humans, may serve as novel candidates for diagnostic marker proteins and represent putative virulence factors. In order to broaden the spectrum of immunogenic C. abortus proteins we applied 2D immunoblot analysis and screening of an expression library using human and animal sera. We have identified 48 immunoreactive proteins representing potential diagnostic markers and also putative virulence factors, such as CAB080 (homologue of the "macrophage infectivity potentiator", MIP), CAB167 (homologue of the "translocated actin recruitment protein", TARP), CAB712 (homologue of the "chlamydial protease-like activity factor", CPAF), CAB776 (homologue of the "Polymorphic membrane protein D", PmpD), and the "hypothetical proteins" CAB063, CAB408 and CAB821, which are predicted to be type III secreted. We selected two putative virulence factors for further characterization, i.e. CAB080 (cMIP) and CAB063, and studied their expression profiles at transcript and protein levels. Analysis of the subcellular localization of both proteins throughout the developmental cycle revealed CAB063 being the first C. abortus protein shown to be translocated to the host cell nucleus.


Selection Experiments in the Sea: What Can Experimental Evolution Tell Us About How Marine Life Will Respond to Climate Change?
AbstractRapid evolution may provide a buffer against extinction risk for some species threatened by climate change; however, the capacity to evolve rapidly enough to keep pace with changing environments is unknown for most taxa. The ecosystem-level consequences of climate adaptation are likely to be the largest in marine ecosystems, where short-lived phytoplankton with large effective population sizes make up the bulk of primary production. However, there are substantial challenges to predicting climate-driven evolution in marine systems, including multiple simultaneous axes of change and considerable heterogeneity in rates of change, as well as the biphasic life cycles of many marine metazoans, which expose different life stages to disparate sources of selection. A critical tool for addressing these challenges is experimental evolution, where populations of organisms are directly exposed to controlled sources of selection to test evolutionary responses. We review the use of experimental evolution to test the capacity to adapt to climate change stressors in marine species. The application of experimental evolution in this context has grown dramatically in the past decade, shedding light on the capacity for evolution, associated trade-offs, and the genetic architecture of stress-tolerance traits. Our goal is to highlight the utility of this approach for investigating potential responses to climate change and point a way forward for future studies.


Achievement of public health recommendations for physical activity and prevention of gains in adiposity in adults.
Physical activity (PA) is considered a cornerstone in weight control and public health guidelines recommend regular participation to prevent gains in adiposity. It may therefore come as a surprise that the cumulative evidence from observational studies to support this is not strong. A weakness of many published observational studies on this topic has been a reliance on a single baseline assessment of PA. Using only the baseline information on PA in a prospective study cause misclassification because of participants often change activity level during follow-up. In turn this causes regression dilution bias and decreases the precision of the estimate of an association between PA and adiposity. Furthermore, because gains in adiposity often are caused by a small average daily energy imbalance over many years, following individuals for longer periods of time is essential to characterize a relationship.


Regional conferences--a capacity-building mandate: report on CRCP2011-Building Bridges and Building a Regional Structure.
The Caribbean Regional Conference of Psychology was held in Nassau, The Bahamas, from 15 to 18 November 2011, under the auspices of the International Association of Applied Psychology (IAAP), the International Union of Psychological Science (IUPsyS), and the International Association for Cross-Cultural Psychology (IACCP). The conference was hosted by the Bahamas Psychological Association, and organized by a committee chaired by Dr Ava Thompson, College of the Bahamas. The CRCP2011 attracted over 400 participants from 37 countries, including 20 nations/territories in the Caribbean. A broad scientific program, organized around six conference themes, addressed strengths and challenges to psychology in the region; the current state of psychological research, assessment, and intervention; historical, cultural, and language influences; and links between Caribbean and global models. Conference outcomes included planning for a series of publications to expand on conference themes and presentations, as well as establishment of a steering group to launch a regional organization to support the science and practice of psychology in the Caribbean.


Evaluation of efficacy and tolerability of gliclazide and metformin combination: a multicentric study in patients with type 2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or metformin.
The objective of this study was to compare the effects of gliclazide/metformin on glycemic control in patients with Type 2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or metformin. This was a prospective, open-labeled, multicentric study over 12 weeks. Patients who were diagnosed of Type 2 diabetes and were uncontrolled on monotherapy with oral hypoglycemic agents, including gliclazide and metformin, characterized by HbA1c 7% or greater and 10% or less and fasting plasma glucose (FPG) 140 mg/dL or greater were enrolled in this study. The treatment regimen was started at 80 mg gliclazide plus 500 mg metformin once a day and was titrated to the next dose level depending on the clinician's judgment, not exceeding a total daily dose of 320 mg gliclazide and 2000 mg metformin. Changes from baseline HbA1c, FPG, and postprandial glucose were examined. After 12-weeks treatment, the gliclazide + metformin combination showed improvement in metabolic control as assessed by changes in HbA1c, FPG, and postprandial glucose. The primary efficacy parameter, HbA1c, was significantly reduced to 7.35 ± 1.10 at the end of treatment from the baseline value (8.51 ± 0.77) (P < 0.001). A total of 84.35% of patients showed a 0.5% or greater reduction in HbA1c and 37.39% of patients reported less than 7% HbA1c at the end of therapy. FPG and postprandial glucose were significantly reduced at the end of therapy as compared with baseline values (P < 0.001). Moreover, the lipid profile was also improved during the treatment period. The addition of gliclazide to metformin is an effective treatment for patients inadequately controlled on sulfonylurea or metformin alone. A combination of gliclazide with metformin achieves good glycemic control and improves lipid levels with better tolerability profile.


The Infantile Hemangioma Referral Score: A Validated Tool for Physicians.
Infantile hemangiomas (IHs) are common; some cases require timely referral and treatment to prevent complications. We developed and validated a reliable instrument for timely and adequate referral of patients with IH to experts by nonexpert primary physicians. In this multicenter, cross-sectional, observational study, we used a 3-stage process: (1) development of the Infantile Hemangioma Referral Score (IHReS) tool by IH experts who selected a representative set of 42 IH cases comprising images and a short clinical history, (2) definition of the gold standard for the 42 cases by a second independent committee of IH experts, and (3) IHReS validation by nonexpert primary physicians using the 42 gold standard cases. A total of 60 primary physicians from 7 different countries evaluated the 42 gold standard cases (without reference to the IHReS tool); 45 primary physicians evaluated these cases using the IHReS questionnaire, and 44 completed retesting using the instrument. IHReS had a sensitivity of 96.9% (95% confidence interval 96.1%-97.8%) and a specificity of 55.0% (95% confidence interval 51.0%-59.0%). The positive predictive value and negative predictive value were 40.5% and 98.3%, respectively. Validation by experts and primary physicians revealed substantial agreement for interrater reliability and intrarater repeatability. IHReS, a 2-part algorithm with a total of 12 questions, is an easy-to-use tool for primary physicians for the purpose of facilitating correct and timely referral of patients with IH. IHReS may help practitioners in their decision to refer patients to expert centers.


Scanning electron microscopy of normal rabbit aorta: injury or artifact?
The reported morphology of both normal and "injured" aortic endothelium differs significantly from one study to another. To better understand these disparities, we examined the effects of manipulating the preperfusion conditions on the subsequent morphology of normal aortic endothelium in the rabbit. Glutaraldehyde perfusion without any preperfusion with an electrolyte solution, induced vasoconstriction and the accumulation of cellular and plasma protein on the luminal surface of the aorta. Prolonged preperfusion by Ringer-Locke solution and to a lesser extent, by Krebs-Henzleit solution or modified Eagles medium, induced changes in the endothelium similar to those reported as the response to injury induced by other stimuli. Profound vessel wall alterations also occurred in animals which were shocked (through acute blood loss) or killed (by overdose of anesthetic) prior to fixation. These observations may explain, in part, the discrepancies in previous descriptions of the appearance of "normal" rabbit aortic endothelium in SEM, and suggest that the type and duration of the preperfusion must be considered to avoid morphological artifacts.


Sequence of the intercistronic region between the ribulose-1, 5-bisphosphate carboxylase/oxygenase large subunit and coupling factor beta subunit gene.
The nucleotide sequence of the region between the genes for the large subunit of ribulose-1, 5-bisphosphate carboxylase/oxygenase and the beta subunit of coupling factor from tobacco chloroplast DNA has been determined. The 5' ends of their mRNAs have been located on the DNA sequence using s1 nuclease mapping. The promoter sequences of these chloroplast genes have features in common with those of prokaryotes. E. coli RNA polymerase can recognize these sequences and start transcription at authentic initiation sites.