A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve.

OBJECTIVE: Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible 'microelectrode' array, for recording and stimulation of the mouse vagus nerve. APPROACH: The array was microfabricated on an 8 µm layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. MAIN RESULTS: Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1ß), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. SIGNIFICANCE: This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice.

Investigating the informed consent process, therapeutic misconception and motivations of Egyptian research participants: a qualitative pilot study.

Few studies have explored the informed consent process among research participants in developing countries. This study aimed to evaluate the informed consent process, therapeutic misconception and motivation for participation among Egyptians participating in clinical trials. In a cross-sectional qualitative pilot study 103 participants in 10 clinical trials responded to a questionnaire. Over 90% agreed they had time to ask questions and received adequate information about the risks prior to consenting. All participants thought the research and the drug would improve their condition; only 46.1% were aware of receiving a non-approved experimental drug and 21.3% of being randomized. Reasons for participation included: better treatment (100%), to benefit society & advance science (85.4%), to receive free drugs (42.6%) and medical care (43.6%), to get hospitalized (15.8%) and to receive money or gifts (4.9%). Investigators need to emphasize the distinction between research and clinical care to address the high rate of therapeutic misconception.

Investigating the informed consent process, therapeutic misconception and motivations of Egyptian research participants:a qualitative pilot study

لا يوجد إلا القليل من الدراسات التي استكشفت عملية الموافقة المسبقة لدى المشاركين في البحوث في البلدان النامية. وقد هدفت هذه الدراسة إلى تقييم عملية الموافقة المسبقة والمفهوم العلاجي الخاطئ والدافع للمشاركة لدى المصرين المشاركين في تجارب سريرية. ففي دراسة تجريبية كيفية مستعرضة قام 103 مشاركين في 10 تجارب سريرية بالإجابة عى استبيان. فأقر أكثر من 90 % منهم بأنه كان لديهم وقت لطرح الأسئلة وبأنهم تلقوا معلومات كافية عن المخاطر قبل الموافقة. واعتقد جميع المشاركين أن البحث والدواء من شأنه أن يحسن حالتهم، وكان 46.1 % منهم فقط عى علم بأنهم يتلقون دواء تجريبياً غر معتمد، و 21.3 % عى علم بأن اختيارهم تم بصورة عشوائية. وكان من أسباب المشاركة: الحصول عى معالجة أفضل 100%، وإفادة المجتمع والتقدم في العلوم 85.4 %، والحصول عى أدوية مجانية 42.6 % ورعاية طبية مجانية 43.6 %، والحصول عى قبول في المستشفى 15.8 %، وتلقي المال أو الهدايا 4.9 %. يجب عى القائمن بالاستقصاء أن يؤكدوا عى التمييز بن الأبحاث والرعاية السريرية لمواجهة ارتفاع معدل المفهوم العلاجي الخاطئ.

Few studies have explored the informed consent process among research participants in developing countries. This study aimed to evaluate the informed consent process, therapeutic misconception and motivation for participation among Egyptians participating in clinical trials. In a cross-sectional qualitative pilot study 103 participants in 10 clinical trials responded to a questionnaire. Over 90% agreed they had time to ask questions and received adequate information about the risks prior to consenting. All participants thought the research and the drug would improve theircondition; only 46.1% were aware of receiving a non-approved experimental drug and 21.3% of being randomized.Reasons for participation included: better treatment (100%), to benefit society & advance science (85.4%), to receive free drugs (42.6%) and medical care (43.6%), to get hospitalized (15.8%) and to receive money or gifts (4.9%). Investigators needto emphasize the distinction between research and clinical care to address the high rate of therapeutic misconception

Les études ayant examiné le processus du consentement éclairé chez les participants à des études de recherche dans les pays en développement sont peu nombreuses. La présente étude visait à évaluer le processus de consentement éclairé, les idées fausses en matière de traitement et les motivations des Égyptiens pour participer à des essais cliniques. Dans une étude pilote qualitative et transversale, 103 participants dans 10 essais cliniques ont répondu à un questionnaire. Plus de 90 % ont convenu qu’ils avaient eu le temps de poser des questions et qu’ils avaient reçu des informations adéquates sur les risques avant d’accorder leur consentement. Tous les participants pensaient que la recherche et le médicament pourraient améliorer leur état ; seuls 46,1 % savaient qu’ils recevaientun médicament à l’essai n’ayant pas été autorisé et 21,3 % qu’ils étaient randomisés. Parmi les raisons pourparticiper, on peut citer : un meilleur traitement (100 %), qui sera utile pour la société et pour les progrès de lascience (85,4 %), des médicaments gratuits (42,6 %) et des soins médicaux gratuits (43,6 %), une hospitalisation(15,8 %) et des compensations financières ou matérielles (4,9 %). Les chercheurs doivent insister sur la différenceentre recherche et soins cliniques pour s’attaquer au fort pourcentage d’idées fausses en termes de traitement.

Attitudes of dental patients towards participation in research.

The attitudes of dental patients towards participation in research and the independent socioeconomic factors associated with these attitudes are not known. A self-administered questionnaire was distributed to 120 patients attending dental clinics in Amman, Jordan. For patients who had previously participated in research (n = 28), motivating factors for most (> 75%) included a desire to help others and to advance science. Most respondents (81.7%) showed interest in participating in questionnaire-based research, but fewer would participate in invasive research, e.g. biopsies (22.0%) and drilling teeth (21.2%). Reasons given for not participating in research included fear of infectious diseases (71.3%) and pain (62.1%). Factors considered important in enhancing research participation included being asked to give informed consent (98.2%), fairness in selection of participants (97.3%) and the prospect of humanitarian benefit (96.5%). Sex and education level were significantly associated with patients' perceptions for several of items. To enhance recruitment, researchers should be aware of people's perspectives regarding participation in research.

Attitudes of dental patients towards participation in research

The attitudes of dental patients towards participation in research and the independent socioeconomic factors associated with these attitudes are not known.A self-administered questionnaire was distributed to 120 patients attending dental clinics in Amman, Jordan.For patients who had previously participated in research [N = 28], motivating factors for most [>75%]included a desire to help others and to advance science.Most respondents [81.7%]showed interest in participating in questionnaire-based research, but fewer would participate in invasive research, e.g.biopsies [22.0%]and drilling teeth [21.2%]. Reasons given for not participating in research included fear of infectious diseases [71.3%]and pain [62.1%]. Factors considered important in enhancing research participation included being asked to give informed consent [98.2%], fairness in selection of participants [97.3%]and the prospect of humanitarian benefit [96.5%]. Sex and education level were significantly associated with patients' perceptions for several of items.To enhance recruitment, researchers should be aware of people's perspectives regarding participation in research

من غير المعروف ما هي مواقف مرضى طب الأسنان تجاه المساهمة في البحوث، وما هي العوامل الاقتصادية والاجتماعية المستقلة التي ترافق هذه المواقف. وقد وزع الباحثون استبيانا يدار ذاتيا على 120 مريضا يزورون عيادات طب الأسنان في عمن، الأردن، واتضح أن العوامل المحفزة الأكثر شيوعا [أكثر من 75 %]لدى المرضى الذين ساهموا من قبل في البحوث هي رغبتهم في مساعدة الآخرين والتطور العلمي، وقد أبدى معظم المستجيبين [81.7 %]الرغبة في المشاركة في البحوث المرتكزة على الاستبيانات، إلا أن عددا أقل من ذلك كان يرحب بالمشاركة في البحوث الباضعة، مثل الخزعات 22 % وحفر الأسنان 21.2 %. وكانت أسباب عدم المشاركة في البحوث تتضمن الخوف من الأمراض المعدية [71.3 %]، والألم [62.1%]ومن العوامل التي تعتبر هامة في تعزيز المساهمة في البحوث أن يطلب من المشاركين موافقة مستنيرة [98.2 %]، والإنصاف في اختيار المشاركين [97.3%]، والتطلع إلى فائدة الإنسانية [96.5 %]. وقد كان هناك ارتباط يعتد به إحصائيا بين الجنس والمستوى التعليمي وبين إدراك المرضى لعدد من بنود الاستبيان، وخلص الباحثون إلى أن عليهم أن يدركوا تطلعات الناس حول المساهمة في البحوث، من أجل تعزيز إسهامهم فيها

Les attitudes des patients dentaires vis-à-vis de la participation à la recherche et les facteurs socioéconomiques indépendants associés à ces attitudes ne sont pas connues.Un auto-questionnaire a été distribué à 120 patients consultant dans des centres de soins dentaires à Amman [Jordanie]. Parmi les facteurs de motivation pour la majorité [>75 %]des patients ayant déjà participé à une étude de recherche [n = 28], on peut citer le désir d'aider autrui et de faire avancer la science.La plupart des répondants [81, 7 %]exprimaient un intérêt pour la participation à une recherche menée à partir d'un questionnaire, mais ils étaient moins nombreux à être volontaires pour participer à une recherche invasive, telles que des biopsies [22, 0 %]et le forage de dents [21, 2 %]. La peur des maladies infectieuses [71, 3 %]et la douleur [62, 1 %]étaient les raisons citées pour ne pas participer à une recherche.Les facteurs considérés comme importants pour améliorer la participation à la recherche comprenaient l'obtention d'un consentement éclairé [98, 2 %], l'équité dans la sélection des participants [97, 3 %]et la perspective d'un avantage humanitaire [96, 5 %]. Le sexe et le niveau d'études étaient fortement associés à la perception des patients pour plusieurs items.Afin d'intensifier le recrutement, les chercheurs devraient être informés des points de vue des patients au sujet de la participation à la recherché

Biomedical informatics in the desert--a new and unique program at Arizona State University.

OBJECTIVES: A new academic Biomedical Informatics (BMI) Program in Phoenix, Arizona, embodies a unique organizational structure to draw on the strengths of a computer science and informatics school and the biomedical and clinical strengths of a college of medicine, in an effort to infuse informatics approaches broadly. METHODS: The program reflects a partnership of two state universities that situates the Arizona State University (ASU) Department of BMI on a new downtown Phoenix Biomedical Campus with the University of Arizona (UA) College of Medicine in partnership with ASU (COM-PHX). Plans call for development of faculty and expertise in the four major subdomains of BMI, as well as in various cross-cutting capabilities. RESULTS: Coming into existence in a state that is investing significantly in biomedical science and technology, BMI has already developed Masters and PhD degree programs, is working with COM-PHX to integrate informatics intensively into the education of the medical students, and has been authorized to plan for an undergraduate program in BMI. Reflecting the statewide emphasis on the biomedical and health sector, the growing faculty are engaged in a number of research partnerships and collaborative centers. CONCLUSIONS: As one of the newest academic BMI programs is taking shape in Arizona, it is embarking on a wide-ranging educational program and a broad research agenda that are now in their earliest stages.

TEM immunocytochemistry of a 48 kDa MW organic matrix phosphoprotein produced in the mantle epithelial cells of the Eastern oyster (Crassostrea virginica).

Immunohistochemical TEM of Eastern oyster (Crassostrea virginica) mantle epithelial cells using a polyclonal antibody to a gel purified 48 kDa MW oyster shell phosphoprotein revealed that it is phosphorylated in the Golgi, packaged into secretory vesicles and subsequently exocytosed across the apical membrane of specialized cells. These phosphoprotein producing cells are concentrated along the mantle side facing the shell, in the region of the outer mantle lobe. A layer of calcium enriched immuno-reactive mucous is associated with the apical microvilli of these cells. The 48 kDa phosphoprotein forms a component of the fibrous organic matrix and appears to be involved in calcium supply thus enabling crystal growth at the mineralization front.

Weaning from mechanical ventilation.

Weaning covers the entire process of liberating the patient from mechanical support and from the endotracheal tube. Many controversial questions remain concerning the best methods for conducting this process. An International Consensus Conference was held in April 2005 to provide recommendations regarding the management of this process. An 11-member international jury answered five pre-defined questions. 1) What is known about the epidemiology of weaning problems? 2) What is the pathophysiology of weaning failure? 3) What is the usual process of initial weaning from the ventilator? 4) Is there a role for different ventilator modes in more difficult weaning? 5) How should patients with prolonged weaning failure be managed? The main recommendations were as follows. 1) Patients should be categorised into three groups based on the difficulty and duration of the weaning process. 2) Weaning should be considered as early as possible. 3) A spontaneous breathing trial is the major diagnostic test to determine whether patients can be successfully extubated. 4) The initial trial should last 30 min and consist of either T-tube breathing or low levels of pressure support. 5) Pressure support or assist-control ventilation modes should be favoured in patients failing an initial trial/trials. 6) Noninvasive ventilation techniques should be considered in selected patients to shorten the duration of intubation but should not be routinely used as a tool for extubation failure.

Implementation of a low tidal volume ventilation protocol for patients with acute lung injury or acute respiratory distress syndrome.

The ARDS (acute respiratory distress syndrome) Network study found 22% lower mortality in acute lung injury and ARDS patients ventilated with low tidal volumes (V(T)) than in those ventilated with traditional V(T) ventilation. Several points should be considered when using the low V(T) protocol for clinical practice. Prior to implementation, hemodynamic and acid-base status, minute ventilation, and adequacy of sedation should be assessed to minimize the potential for intolerance. The volume-preset, assist-control mode is recommended for better control of V(T), and the respiratory rate should be increased as V(T) is reduced, so as to maintain minute ventilation and prevent acute hypercapnia. When unavoidable, hypercapnia should be induced slowly. Ventilator inspiratory flow (V(I)) and trigger sensitivity settings should be optimized to limit the increase in work of breathing and dyspnea. When dyspnea results in double-triggered breaths, V(T) can be titrated to 7-8 mL/kg, provided end-inspiratory plateau pressure is < or = 30 cm H(2)O. In severe acidosis (pH < 7.15) V(T) also can be increased. However, every effort should be made to maintain plateau pressure and V(T) goals by buffering severe acidosis and treating patient-ventilator asynchrony with sedation. Evaluation for weaning should occur when adequate oxygenation can be maintained on 40% oxygen and a positive end-expiratory pressure of 8 cm H(2)O. Pressure support levels between 5 and 20 cm H(2)O (above 5 cm H(2)O positive end-expiratory pressure) are used for weaning and titrated to keep the respiratory rate < 35 breaths/min. Pressure support levels should be weaned aggressively, as long as the protocol's weaning tolerance criteria can be maintained.

In vivo glycosylation of mucin tandem repeats.

The biochemical and biophysical properties of mucins are largely determined by extensive O-glycosylation of serine- and threonine-rich tandem repeat (TR) domains. In a number of human diseases aberrant O-glycosylation is associated with variations in the properties of the cell surface-associated and secreted mucins. To evaluate in vivo the O-glycosylation of mucin TR domains, we generated recombinant chimeric mucins with TR sequences from MUC2, MUC4, MUC5AC, or MUC5B, which were substituted for the native TRs of epitope-tagged MUC1 protein (MUC1F). These hybrid mucins were extensively O-glycosylated and showed the expected association with the cell surface and release into culture media. The presence of different TR domains within the chimeric mucins appears to have limited influence on their posttranslational processing. Alterations in glycosylation were detailed by fast atom bombardment mass spectrometry and reactivity with antibodies against particular blood-group and tumor-associated carbohydrate antigens. Future applications of these chimeras will include investigations of mucin posttranslational modification in the context of disease.

Identification of MUC1 proteolytic cleavage sites in vivo.

Mucins are high molecular weight glycoproteins that provide a protective layer on epithelial surfaces and are involved in cell-cell interactions, signaling, and metastasis. The identification of several membrane-tethered mucins, including MUC1, MUC3, MUC4, and MUC12, has incited interest in the processing of these mucins and the mechanisms that govern their release from the cell surface. MUC1 consists of an extracellular subunit and a membrane-associated subunit. The two moieties are produced from a single precursor polypeptide by an early proteolytic cleavage event but remain associated throughout intracellular processing and transport to the cell surface. We identified the MUC1 proteolytic cleavage site and showed it to be identical in pancreas and colon cell lines and not to be influenced by the presence of heavily glycosylated tandem repeats. The MUC1 cleavage site shows homology with sequences in other cell-surface-associated proteins and may represent a common mechanism for processing of these molecules.

Muscular alteration of gill geometry in vitro: implications for bivalve pumping processes.

In bivalves, water-pumping potential is determined both by ciliary activity and by the geometry of the system of passageways that acts as a conduit for water flow. Smooth muscles intrinsic to the gills of eulamellibranch bivalves possess the anatomical organization needed to regulate the dimensions of these water passageways. The tone of these muscles can be controlled experimentally using excitatory neurotransmitters to elicit muscle contraction and by removing Ca++ from the Ringer's solution to induce muscular relaxation. These experimental methods were used to investigate the effects of smooth muscle tone on the gill dimensions of two freshwater bivalves, Dreissena polymorpha and Corbicula fluminea, and one marine bivalve, Mercenaria mercenaria. In addition, endoscopic observations were made from the suprabranchial chamber of a freshwater unionid, Lampsilis anodontoides. Contraction of gill muscles led to a significant reduction in interfilament width, internal ostial area, and the cross-sectional area of the water tubes. Endoscopic observation from minimally disturbed L. anodontoides revealed rapid constriction of the water tubes upon contraction of the muscles of the gill and gill axis. Taken together, these data support the idea that alteration of smooth muscle tone in the gill provides a mechanism for controlling water-pumping activities.

Variability among institutional review boards' decisions within the context of a multicenter trial.

BACKGROUND: Institutional review boards (IRBs) are given discretion to interpret and apply the federal regulations governing the protection of human subjects in research. OBJECTIVE: To determine the extent of the variability among different IRBs on their approved research practices and informed consent forms within the context of a multicenter trial that used a common protocol. DESIGN: Descriptive analysis of survey information and informed consent forms. SETTING AND PARTICIPANTS: Sixteen IRBs from the institutions participating in a multicenter trial comparing lower vs. traditional tidal volume ventilation in patients with acute lung injury. MEASUREMENTS: Analysis of survey information on IRBs' approved research practices. Analysis of informed consent forms for the presence and the adequacy of description of each basic element of informed consent specified in the federal regulations. Reading levels of informed consent forms. MAIN RESULTS: Surveys and IRB-approved consent forms were obtained from all of the contacted IRBs (n = 16). Variability was observed among several of the research practices; one IRB waived the requirement for informed consent, five IRBs permitted telephone consent, and three IRBs allowed prisoners to be enrolled. Three consent forms contained all of the basic elements of informed consent outlined in the federal regulations, and 13 forms had varying numbers of these elements absent (six forms without one element, four without two, one without three, and two without four). Reading levels of the consent forms ranged from grades 8.2 to 13.4 (mean +/- sd was 11.6 +/- 1.2 grade level). CONCLUSIONS: Within a multicenter trial, IRBs reviewing a common protocol varied in several of their approved research practices and in the extent to which the basic elements of informed consent were included in their consent forms.

Kidney function and sulfate uptake and loss in the freshwater bivalve Toxolasma texasensis.

Toxolasma texasensis acclimated to an artificial pondwater (PW) maintained a concentration of SO4 in the blood of about 1-2 mmol l(-1) . The anion transport inhibitor DIDS (5,5'-diisothiocyanatostilbene 2, 2'-disulfonic acid) reduced the uptake of 35SO4 from the bathing medium by 54%. The clearance of polyethylene glycol (PEG) injected into the blood of T. texasensis ranged between 0.8 and 1.3 ml g(-1) dry tissue h(-1), and provided an estimate of renal filtration in PW-acclimated animals. The clearance of radioactive 35SO4 simultaneously injected into the same animal was about 16% of the PEG clearance, suggesting that sulfate was being reabsorbed by the kidney. Para-aminohippuric acid was cleared about 4.6 times faster than PEG, indicating that this organic acid was subjected to secretion in addition to filtration. When the normal osmotic gradient was abolished by acclimating T. texasensis to 10% seawater (SW), the PEG clearance decreased to 0.17 ml g(-1) dry tissue h(-1). Sulfate clearance in animals acclimated to PW or 10% SW was the same. However, in mussels acclimated to 10% SW, the calculated amount of SO4 reabsorbed was significantly reduced relative to mussels acclimated to PW. T. texasensis conserved SO4 when acclimated to PW, and reduced reabsorption when acclimated to the sulfate-rich 10% SW. When mussels acclimated to 10% SW were returned to PW, there was a transient increase in sulfate clearance during the first 8 h because filtration exceeded reabsorption.

Protective effects of low and high doses of cyclosporin A against reoxygenation injury in isolated rat cardiomyocytes are associated with differential effects on mitochondrial calcium levels.

In this study we aimed to determine the concentration range of cyclosporin A (CsA) which was effective in protecting against reoxygenation injury in isolated cardiomyocytes, and its effects on intramitochondrial free calcium levels ([Ca2+]m). We also determined whether a high [CsA] had any deleterious effect on normal myocyte function. Isolated adult rat ventricular myocytes were placed in a chamber on the stage of a fluorescence microscope for induction of hypoxia. [Ca2+]m was determined from indo-1/am loaded cells where the cytosolic fluorescence signal had been quenched by superfusion with Mn2+. Cell length was measured using an edge-tracking device. Upon induction of hypoxia, control cells underwent rigor-contracture in 37 +/- 1 min (n = 99) (T1); CsA had no effect on T1. The percentage of control cells which recovered upon reoxygenation depended on the time spent in rigor (T2). With a T2 of 21-30 min, only 36% of control cells recovered compared with 90% and 78% of cells treated with 0.2 microM and 1 microM CsA respectively. After 40 min in rigor, [Ca2+]m was 280 +/- 60 nM in control-recovered cells (50% of cells) and 543 +/- 172 nM and 153 +/- 26 nM in cells treated with 0.2 and 1 microM CsA, respectively (all CsA treated cells recovered). In normoxic studies, CsA had no effect on cell contractility or [Ca2+]m upon rapid pacing, even in presence of an elevated external [Ca2+]. In conclusion, both low and high [CsA] protected against reoxygenation injury to cardiomyocytes despite having opposing effects on [Ca2+]m, suggesting more than one mechanism of action. CsA had no effect on either cell contractility or [Ca2+]m in normoxic cells.

Description of an ethics curriculum for a medicine residency program.

This paper examines the attempts to develop and implement an ethics curriculum for the Internal Medicine Residency Program at the University of Maryland Medical Center. The objectives of the curriculum were to enhance moral reasoning skills and to promote humanistic attitudes and behavior among the residents. The diverse methodologies used to achieve these objectives included case discussions, literature reading, role playing, writing, and videos. These activities occurred predominantly within the forum of morning report sessions and ethics ward rounds. The author also describes efforts to overcome the initial constraints associated with the implementation of this curriculum and concludes by exploring future directions for the curriculum.