Intrakines—Evidence for a Trans-Cellular Mechanism of Action

Human CXCR4 is the receptor for the CXC chemokine SDF-1α and also acts as a coreceptor for T lymphotropic HIV-1 strains. Blocking the surface expression of this receptor via an intrakine approach has recently been shown to efficiently prevent HIV-1 infection of T cells. The CXC-chemokine gene is fused to an endoplasmic reticulum retention signal (KDEL) that retains the newly synthesized chemokine and its receptor within the cell, where both are subsequently degraded. We constructed MoMuLV-based vectors containing the SDF–KDEL construct driven by the “MND” long terminal repeat, using eGFP as a marker gene (MND-SDF-KDEL-IRES-eGFP) and a control vector (MND-X-IRES-eGFP). CEM human T lymphoblastic leukemia cells were transduced with the intrakine vector or the control vector. We detected a marked downregulation of CXCR4 expression in the cells transduced with the intrakine vectors as opposed to the cells transduced with the control vector. However, the eGFP-negative fraction of the cells transduced with the intrakine vector displayed the same CXCR4 downregulation as the eGFP-positive fraction, suggesting an effect in trans. The possibility of this being due to eGFP being silenced while SDF–KDEL was still expressed was excluded by Southern and Northern blot analyses. Upon cultivating the control cells with supernatant of the cells transduced with the intrakine vector, we observed a downregulation of CXCR4 expression on the control cells. Experiments using rhSDF-1α showed downregulation by the supernatant to be comparable to that achieved by the exogenous addition of 30 ng/ml SDF-1α. To assess the bioactivity of the secreted substance in the supernatant, a chemotaxis assay was performed. The transmigration observed was, once again, within the range of that achieved by the addition of 30 ng/ml SDF-1α. We conclude that the intrakine SDF–KDEL, apart from acting within the cell, is also in part secreted and causes the downregulation of the receptor by acting like a secreted chemokine.     

a Clinical Observation of Stellate Ganglion Block Used for Migraine

Stellate ganglion block (SGB) is an efficient way to treat many kinds of pain in the head, as well as the disorder of automatic nerve function. From the beginning of 1992 to the end of 1998, 80 patients with migraine in our pain－treatment department received different drug combinations and achieved satisfied result. 1 Materials and Methods 80 patients presented in this paper (52 men, 28 women), with an age from 18 to 60 years, mainly 30 to 39 years (67％ of the total). Their ASA wereⅠ to…     

Are we headed for a shortage of burn surgeons?

Newly trained burn surgeons are in high demand but low supply. The purpose of this study was to quantitate the current need for burn surgeons and to identify the need in the future. A questionnaire was sent to the 159 burn care facilities in North America listed in the 1999 to 2000 American Burn Association Directory. Of the 159 centers, 9 surveys were returned stating the center did not exist. Eighty-four (56%) of the remaining 150 centers responded. Twenty-nine percent of responding burn centers are currently attempting to recruit another burn surgeon, and an additional 38% anticipate needing to recruit one within the next 5 years. Of these, 89% anticipate difficulty finding another burn surgeon. This survey identifies a need for burn surgeons now and warns of a severe shortage in the immediate future. Current burn surgeons need to ensure that any interested trainee be mentored appropriately toward a career in burn surgery.     

What is a 'failure' of bisphosphonate therapy for osteoporosis?

Assessing the effectiveness of bisphosphonate therapy is problematic. Bone mineral density and markers of bone turnover are often used, but the true measure is prevention of new fractures.     

Development of a Fluorinated Analogue of Erlotinib for PET Imaging of EGFR Mutation–Positive NSCLC

Molecular Imaging and Biology - Positron emission tomography (PET) using [11C]erlotinib identifies non-small cell lung carcinoma (NSCLC) tumors with activating mutations in the epidermal growth...     

Choice of method for anesthesia: is there a problem?

Respiratory narcotic devices and monitoring devices have been rapidly improved since World War II; new effective and safe drugs and high-quality materials appeared. This resulted in a notable decrease of mortality caused by anesthesia: from 1 per 50 patients before the war to 1 per 200,000 patients during the last years of the twentieth century. Paradoxical as it is, anesthesia today is one of the most safe medical specializations. Then what, if not the problem of safety, makes anesthesiologists improve the methods of intraoperative protection? It will be only just to admit that the main trend in development of anesthesiology today is not improvement of its safety, but the desire to make the postoperative period as comfortable as possible for the patient and to facilitate anesthesiologist's work. The choice of method of anesthesia less and less affects the quality of intraoperative protection. Modern methods of total and local anesthesia are so universal, that can be used in patients of any age, physical status, in surgery of any duration and traumatization. One and the same method can meet the most strict requirements to outpatient and venture surgery. Hence, the initially rather long list of anesthesiological methods becomes shorter as it should meet modern requirements to the efficiency and safety of anesthesia and becomes quite short if we take into consideration patient's comfort and physician's convenience. The choice from 3-4 methods is completely determined by physician's habits or preferences or traditions of the hospital.     

The debut of a rational treatment for an inherited neuropathy?

Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating L-alanine in place of L-serine, the mutant HSAN1–associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral L-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral L-serine reduces the severity of neuropathy in the mouse model of HSAN1, these data suggest a rational candidate therapy for this devastating condition.     

Reliability of a visual test for the rapid detection of mucopolysaccharidoses: GAG-test(®)

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, characterized by the deficiency/absence of one of the enzymes involved in the intralysosomal degradation of glycosaminoglycans (GAGs). The quantitative determination of urinary GAGs using dimethylmethylene blue (DMB) shows high reliability. However, the logistics and staff for this method are not always available in primary care centers. Sending urine samples to reference laboratories increases the cost and delays the diagnosis. Thus, the aim of this article is to develop and evaluate a simple and low‐cost visual test (GAG‐test^®) for the screening of urine samples from patients under suspicion of suffering from MPS. The purpose is to narrow down the number of samples to be assayed through the quantitative method. A measure of 50 µl urine was added to 2 ml DMB solution. A color change from dark blue to purple indicates an excess of GAGs. The quantitative analyses showed a significant difference between controls' and patients' concentrations (P<0.05). After optimization of the composition, positive and negative results obtained with the qualitative test were able to discriminate between normal urines and those from patients suffering from mucopolysaccharidosis. Therefore, GAG‐test^® has proved to be a useful tool for the prior diagnosis of patients suffering from mucopolysaccharidosis, reducing the number of individuals with whom investigations should be continued. J. Clin. Lab. Anal. 25:179–184, 2011. © 2011 Wiley‐Liss, Inc.     

Action learning: a tool for the development of strategic skills for Nurse Consultants?

young s., nixon e., hinge d., mcfadyen j., wright v., lambert p., pilkington c. & newsome c. (2010) Journal of Nursing Management 18 , 105–110
Action learning: a tool for the development of strategic skills for Nurse Consultants? Aim This paper will discuss the process of action learning and the outcomes of using action learning as a tool to achieve a more strategic function from Nurse Consultant posts. Background It is documented that one of the most challenging aspect of Nurse Consultant roles, in terms of leadership, is the strategic contribution they make at a senior corporate Trust level, often across organizations and local health economies. A facilitated action learning set was established in Brighton, England, to support the strategic leadership development of eight nurse consultant posts across two NHS Trusts. Evaluation Benefits to patient care, with regard to patient pathways and cross-organizational working, have been evident outcomes associated with the nurse consultant posts involved in the action learning set. Key issues Commitment by organizational nurse leaders is essential to address the challenges facing nurse consultants to implement change at strategic levels. Conclusions The use of facilitated action learning had been a successful tool in developing the strategic skills of Nurse Consultant posts within this setting. Implications for nursing management Action learning sets may be successfully applied to a range of senior nursing posts with a strategic remit and may assist post holders in achieving better outcomes pertinent to their roles.     

Validation of a skills assessment scoring system for transesophageal echocardiographic monitoring of hemodynamics

Objective Transesophageal echocardiography (TEE) is increasingly used in hemodynamic monitoring in the intensive care unit. This paper describes and validates a scoring system for assessing competence in TEE performed by intensivists for this indication. Design Prospective study over an 18-month period. Settings Two medical intensive care units. Methods The scoring system is used to assess four aspects of TEE: quality of the views (score out of 14); semiquantitative evaluation of respiratory variations in the superior vena cava, valve regurgitation, size of the right ventricle (score out of 10); accuracy of measurement of velocity-time integrals for pulmonary and aortic flow, peak velocity of the E and A waves of mitral flow, left ventricular fractional area change (score out of 8); summary and proposed treatment (score out of 8). The scoring system was validated by using it to assess intensivists after 1 month (M1), 3 months (M3) and 6 months (M6) of training. TEE was done on a mechanically ventilated, hypotensive patient and scored by comparing the intensivist's examination with that of the expert examiner. The intensivists were divided into two groups of theoretical expertise at the start of training. Results Nineteen intensivists were evaluated. The scores at M1 for level 0 (no experience in echocardiography) and level 1 (previous experience) were, respectively, 18.5 ± 4 and 24.7 ± 5. The scores at M1, M3, and M6 were, respectively, 20.4 ± 5, 30.4 ± 5 and 35.7 ± 3. At M6, the intensivists had performed TEE 29 ± 10 times. Conclusion The scoring system was discriminatory and sensitive to change, and could be used as a tool to assess an intensivist's mastery of TEE. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. This article is discussed in the editorial available at: .