Medical Library

Keratoprosthesis in the treatment of severe ocular trauma / La kératoprothèse dans le traitement d\’un grave traumatisme oculaire.

Aquavella JV.

The roles of MAPKs in disease.

MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.Cell Research advance online publication 18 March 2008. doi: 10.1038/cr.2008.37.

Lawrence MC, Jivan A, Shao C, Duan L, Goad D, Zaganjor E, Osborne J, McGlynn K, Stippec S, Earnest S, Chen W, Cobb MH.

1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.

Migratory properties of cultured olfactory ensheathing cells by single-cell migration assay.

Olfactory ensheathing cells (OECs) are a unique type of glial cells that have axonal growth-promoting properties. OEC transplantation has emerged as a promising experimental therapy of axonal injuries and demyelinating diseases. However, some fundamental cellular properties of OECs remain unclear. In this study, we found that the distinct OEC subpopulations exhibited different migratory properties based on time-lapse imaging of single isolated cells, possibly due to their different cytoskeletal organizations. Moreover, OEC subpopulations displayed different attractive migratory responses to a gradient of lysophosphatidic acid (LPA) in single-cell migration assays. Finally, we found that OEC subpopulations transformed into each other spontaneously. Together, these results demonstrate, for the first time to our knowledge, that distinct OEC subpopulations display different migratory properties in vitro and provide new evidence to support the notion of OECs as a single cell type with malleable functional phenotypes.Cell Research advance online publication 18 March 2008; doi: 10.1038/cr.2008.38.

Huang ZH, Wang Y, Cao L, Su ZD, Zhu YL, Chen YZ, Yuan XB, He C.

[1] 1Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China [2] 2Department of Neurobiology, Second Military Medical University, Shanghai 200433, China.

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment.

We evaluated the cost-effectiveness of a range of smoking cessation drug treatments, including varenicline, transdermal nicotine (TN), bupropion and the use of a genetic test to choose between TN and bupropion. We performed Monte Carlo simulation with sensitivity analysis, informing analyses with published estimates of model parameters and current prices for genetic testing and smoking-cessation therapy. The primary outcomes were discounted life-years (LY) and lifetime tobacco-cessation treatment costs. In the base case, varenicline treatment was optimal with an ICER, compared to bupropion, of $2985/LY saved. In sensitivity analyses, varenicline was in all cases (and bupropion in most cases) admissible; only under favorable assumptions was the genetically tailored approach competitive. Our data suggest that an untailored approach of treatment with either bupropion or varenicline is a cost-effective form of tobacco dependence treatment, but a tailored approach for selecting between TN and bupropion can be cost-effective under plausible assumptions.The Pharmacogenomics Journal advance online publication, 18 March 2008; doi:10.1038/sj.tpj.6500492.

Heitjan DF, Asch DA, Ray R, Rukstalis M, Patterson F, Lerman C.

[1] 1Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA [2] 2The Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [3] 3Center for Health Equity Research and Promotion, Philadelphia Veterans Administration Medical Center, Philadelphia, PA, USA.

Interaction between polymorphisms in the renin-angiotensin-system and angiotensin-converting enzyme inhibitor or beta-blocker use and the risk of myocardial infarction and stroke.

This study investigates whether the interaction between angiotensin-converting enzyme (ACE) inhibitors or beta-blockers and the ACE insertion/deletion (I/D) polymorphism or angiotensin receptor II type 1 (AGTR1) 573C/T polymorphism modifies the risk of myocardial infarction (MI) or stroke. In total, 4097 subjects with hypertension were included in this study. The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model. The risk of MI was reduced in current users of ACE inhibitors with the AGTR1 573CT or CC genotype compared to ACE inhibitors with the AGTR1 573TT genotype (synergy index (SI):0.32; 95% confidence interval (CI): 0.14-0.70). No significant drug-gene interaction was found on the risk of stroke (SI:0.82; 95% CI: 0.44-1.52) or in beta-blocker users. Also, no significant drug-gene interaction was found with the ACE I/D polymorphism. In conclusion, subjects with at least one copy of the AGTR1 573C allele might have more benefit from ACE inhibitor therapy.The Pharmacogenomics Journal advance online publication, 18 March 2008; doi:10.1038/sj.tpj.6500493.

Schelleman H, Klungel OH, Witteman JC, Breteler MM, Hofman A, van Duijn CM, de Boer A, Ch Stricker BH.

[1] 1Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands [2] 2Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.

Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3\’-untranslated region.

RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10-0.54, P=0.001) in the overall sample, and 0.20 (0.07-0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11-0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3\’-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression.The Pharmacogenomics Journal advance online publication, 18 March 2008; doi:10.1038/tpj.2008.6.

Greenbaum L, Smith RC, Rigbi A, Strous R, Teltsh O, Kanyas K, Korner M, Lancet D, Ben-Asher E, Lerer B.

1Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah–Hebrew University Medical Center, Jerusalem, Israel.

Dendritic cells: driving the differentiation programme of T cells in viral infections.

Protective immunity against viral pathogens depends on the generation and maintenance of a small population of memory CD8(+) T cells. Successful memory cell generation begins with early interactions between naïve T cell and dendritic cells (DCs) within the inflammatory milieu of the secondary lymphoid tissues. Recent insights into the role of different populations of DCs, and kinetics of antigen presentation, during viral infections have helped to understand how DCs can shape the immune response. Here, we review the recent progress that has been made towards defining how specific DC subsets drive effector CD8(+) T-cell expansion and differentiation into memory cells. Further, we endeavour to examine how the molecular signals imparted by DCs coordinate to generate protective CD8(+) T-cell immunity.Immunology and Cell Biology advance online publication, 18 March 2008; doi:10.1038/icb.2008.15.

Masson F, Mount AM, Wilson NS, Belz GT.

1Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Non-invasive assessment of lower extremity muscle composition after incomplete spinal cord injury.

Study Design: Cross-sectional study.Objective: (1) To quantify intramyocellular lipid (IMCL) content of the soleus muscle. (2) To assess the T(2) relaxation rates in the lower extremity skeletal muscles in persons with incomplete spinal cord injury (SCI).Setting: Academic Institution, Florida.Methods: Eight subjects (42+/-10 years old; 70+/-12 kg; 176+/-10 cm) with chronic (17+/-9 months post injury) motor SCI (C4-T12; ASIA C or D) and eight matched healthy controls were tested. Localized unsuppressed proton spectroscopy (H-MRS) was performed to estimate total lipid content and individual lipid components; IMCL and extramyocellular lipid (EMCL) from the soleus muscle. T(2)-weighted imaging of lower extremity muscles yielded muscle T(2) rates.Results: The IMCL content of the soleus muscle was 3.3 times higher in the patient group as compared to controls (P=0.002; 0.0401 (0.0234-0.0849) versus 0.0123 (0.0090-0.0175)). Similarly, EMCL measures were 4.5 times higher as compared to the controls (P=0.002). Significant differences were observed in the T(2) relaxation times of the soleus and gastrocnemius muscles (P<0.05).Conclusion: The increased levels of IMCL might interfere with the glucose uptake in skeletal muscle; potentially predisposing persons with incomplete SCI to the development of peripheral insulin resistance. Marked elevations in the T(2) relaxation times of the locomotor muscles are reflective of an altered muscle composition.Spinal Cord advance online publication, 18 March 2008; doi:10.1038/sc.2008.10.

Shah PK, Gregory CM, Stevens JE, Pathare NC, Jayaraman A, Behrman AL, Walter GA, Vandenborne K.

1Department of Physical Therapy, University of Florida, Gainesville, FL, USA.

Can cell therapy heal a spinal cord injury?

Study design:Literature survey.Objectives:To summarize and discuss current possibilities and success rates for the treatment of spinal cord injury in animal models.Settings:University of Antwerp, Belgium.Methods:We searched Pubmed for publications from 1997 onwards. Seven older papers were used for completion of data.Results:Despite major progress in pharmacological and surgical approaches, a spinal cord injury still remains a very complex medical and psychological challenge, both for the patients and their relatives, as well as for the involved physicians, with currently no existing curative therapy. For a future efficient treatment, one has to consider and combine four main approaches: (1) tissue or cell transplantation, (2) providing growth-stimulating factors (neurotrophic factors), (3) blocking factors which inhibit neural regeneration and (4) modulation of inflammatory response following spinal cord injury.Conclusions:Although different treatment options have proven to be successful in animal models, they also provide a realistic view on a complex therapeutical approach, which needs to be further investigated in many carefully designed animal studies before human applications can be considered.Spinal Cord advance online publication, 18 March 2008; doi:10.1038/sc.2008.13.

Ronsyn MW, Berneman ZN, Van Tendeloo VF, Jorens PG, Ponsaerts P.

[1] 1Division of Clinical Pharmacotherapy, University of Antwerp, Antwerp, Belgium [2] 2Centre for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.

The use of tracheal stoma stents in high spinal cord injury: a patient-friendly alternative to long-term tracheostomy tubes.

Study design:Case series.Setting:North West Regional Spinal Injuries Unit, Southport and Formby District General Hospital, UK.Objectives:To identify a novel type of tracheal stents for use in patients with high spinal cord injury. Patients with high spinal cord injury (above C4) frequently have significant respiratory impairment and may require long-term access to the trachea for respiratory support. For the most part, tracheostomy tubes are used for this purpose but a tracheal stoma stent can offer a suitable alternative in selected cases and deserves wider recognition.Methods:Following completion of a patient questionnaire survey, the authors describe the use of stoma stents in nine patients, five of whom had full-time diaphragm pacing. The stent in these cases is for retention of access for positive pressure ventilation, and for the prevention of obstructive sleep apnoea. This was also the indication in one self-ventilating patient with tetraplegia and sleep apnoea. Two patients with recurrent chest infections, in whom chest physiotherapy was difficult, benefited from the stoma stents. One patient, after ventilator weaning, required a further 4 months of tracheal access on account of episodic hypoventilation and temporarily had a tracheal stent as an inpatient.Conclusion:Patients who have had the benefit of tracheal stents report significant improvement in relation to local discomfort, tracheobronchial secretions and vocalization. With suitable training, the stents can be changed and cleaned easily in the home setting.Spinal Cord advance online publication, 18 March 2008; doi:10.1038/sc.2008.18.

Hall AM, Watt JW.

1North West Regional Spinal Injuries Centre, Southport and Formby District General Hospital, Southport, UK.