The RAB3-RIM Pathway Is Essential for the Release of Neuromodulators

Neurons secrete neuromodulators/neuropeptides from dense-core vesicles (DCVs) by a largely unknown mechanism. Persoon et al. identify RAB3 and RIM1/2 as essential factors. RAB3’s indispensable role is the first distinct feature of DCV secretion as compared to synaptic vesicle secretion

A quantitative comparison of opacities calculated using the distorted-wave and R-matirx methods

peer reviewe

Guideline implementation, drug sequencing, and quality of care in heart failure:design and rationale of TITRATE-HF

Aims: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. Methods and results: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in &gt;40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. Conclusions: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.</p

A simplified model of stress-slip relationships : application to the Frøy field, northern North Sea

Tectonophysics, v. 357, n. 1-4, p. 103-118, 2002. http://dx.doi.org/10.1016/S0040-1951(02)00364-5International audienc

Visual evoked potentials in children with developmental coordination disorder

Children who demonstrate problems with skilled movement in the absence of physical handicap are formally designated as suffering from developmental coordination disorder (DCD). Diagnosis of DCD was confirmed by the 'movement assessment battery for children'. Visually evoked potentials (VEPs) were recorded to evaluate the integrity of the visual pathway and to rule out the presence of any neurological lesions affecting visual input. Binocular, pattern onset VEPs were recorded in 14 children with DCD aged between five and seven years, and an age-matched control group using pattern onset, high contrast, grating stimuli. Implicit times to the first and second peaks and troughs were measured, and results between the two groups were compared. Inattention and movement artefact meant that VEPs were more difficult to record within the DCD group, resulting in smaller amplitudes of the waveform, but no significant differences in the implicit times were observed between the DCD group and controls. Further research is required to determine the specific source of the neurological deficits in DCD but a problem with the integrity of the afferent visual pathway does not appear to be a causal factor

Chemotherapy : friend or foe to cancer vaccines?

Cancer vaccines are oil the threshold of taking their place alongside the more traditional cancer treatment modalities of surgery, radiation therapy and chemotherapy. The toxicology and immunopharmacology of therapeutic cancer vaccines, particularly those that secrete granulocyte macrophage colony stimulating factor (GM-CSF), are currently under active clinical investigation. Interestingly drugs traditionally used for tumor cytoreduction can have both positive and negative effects on host immunity. Exploration of the potential pharmacodynamic interactions of antineoplastic drugs with GM-CSF-secreting vaccines has revealed that low doses of some chemotherapeutics can augment the antitumor immunity induced by GM-CSF-secreting vaccines. These interactions will require through preclinical evaluation to maximize the clinical impact of this type of therapeutic cancer vaccine

3-D magnetotelluric inversion and model validation with gravity data for the investigation of flood basalts and associated volcanic rifted margins

International audience20 magnetotelluric (MT) soundings were collected on the Isle of Skye, Scotland to provide a high-resolution three-dimensional (3-D) electrical resistivity model of a volcanic province within the framework of a project jointly interpreting gravity, seismic, geological and MT data. The full 3-D inversion of the MT data jointly interpreted with gravity data reveals upper crustal structure. The main features of the model are interpreted in conjunction with previous geological mapping and borehole data. Our model extends to 13 km depth, several kilometres below the top of the Lewisian basement. The top of the Lewisian basement is at approximately 7–8 km depth and the topography of its surface was controlled by Precambrian rifting, during which a 4.5 km thick sequence of Torridonian sediments was deposited. The Mesozoic sediments above, which can reach up to 2.2 km thick, have small-scale depocentres and are covered by up to 600 m of Tertiary lava flows. The interpretation of the resistivity model shows that 3-D MT inversion is an appropriate tool to image sedimentary structures beneath extrusive basalt units, where conventional seismic reflection methods may fail

A quantitative comparison of opacities calculated using the distorted-wave and R-matirx methods

peer reviewe

Assisted circulation using the Tandemheart®, percutaneous transseptal left ventricular assist device, during percutaneous aortic valve implantation: The Rotterdam experience

Aims: The morbidity and mortality of surgical aortic valve replacement are increased in elderly patients with multiple high risk comorbid conditions. Percutaneous prosthetic aortic valve replacement (PAVR) via the femoral arterial approach is feasible in selected patients, who are poor operative candidates, with satisfactory short term outcomes. It is conceivable that patients with poor LV function may benefit from periprocedural cardio-circulatory support. We evaluated the short-term safety and efficacy of using the TandemHeart® PTVA® System (p-LVAD) to deliver extracorporeal circulatory support in patients undergoing PAVR. Methods and results: Between April 2006 and May 2007 the TandemHeart® was used in 10 patients (age: range 64-85, median 80) undergoing elective PAVR using the CoreValve™ Revalving System. The median (range) time for implementation of circulatory support was 32 (22-40) minutes. A pump flow up to 4.6 L/min was achieved. Systemic haemodynamics were maintained in all but one patient. The median (range) systemic arterial pressure (MBP) was 77 (67-89) mmHg at baseline and 76 (61-91) mmHg after pump functioning. A major systolic blood pressure drop (systolic blood pressure < 70 mmHg, pulse pressure < 10 mmHg, occurred in one patient due to PAVR related pericardial tamponade. Median (range) duration of supp

Testing the four-stage model of the strategic role of operations in a UK context

This paper reports on research aimed at operationalising the Hayes and Wheelwright four‐stage model describing the strategic role of operations. Although this model has classic status in operations management, it is little tested in practice. A questionnaire derived from the model was administered in a large‐scale postal survey of managers in a variety of UK manufacturing and service organisations. Analysis of the responses indicates that only a little over half of respondents were able to provide an assessment of their organisation's operations that fitted the logic of the four‐stage model. This seems to imply that managers have difficulty in assessing the strategic role played by their operations in an internally consistent and coherent manner. The results question the utility of the model and raise concerns about its validity