Expression profiling identifies the CRH/CRH-R1 system as a modulator of neurovascular gene activity.

Corticotropin-releasing hormone receptor type 1 (CRH-R1)-deficient mice display reduced anxiety-like behavior, a chronic corticosterone deficit, and an impaired neuroendocrine stress response caused by disruption of the hypothalamic-pituitary-adrenocortical (HPA) axis. The molecular substrates and pathways of CRH/CRH-R1-dependent signaling mechanisms underlying the behavioral phenotype as well as the consequences of lifelong glucocorticoid deficit remain largely obscure. To dissect involved neuronal circuitries, we performed comparative expression profiling of brains of CRH-R1 mutant and wild-type mice using our custom made MPIP (Max Planck Institute of Psychiatry) 17k cDNA microarray. Microarray analysis yielded 107 genes showing altered expression levels when comparing CRH-R1 knockout mice with wild-type littermates. A significant proportion of differentially expressed genes was related to control of HPA and hypothalamic-pituitary-thyroid (HPT) axes reflecting not only the disturbance of the HPA axis in CRH-R1 mutant mice but also the interplay of both neuroendocrine systems. The spatial analysis of regulated genes revealed a prevalence for genes expressed in the cerebral microvasculature. This phenotype was confirmed by the successful cross-validation of regulated genes in CRH overexpressing mice. Analysis of the cerebral vasculature of CRH-R1 mutant and CRH overexpressing mice revealed alterations of functional rather than structural properties. A direct role of the CRH/CRH-R1 system was supported by demonstrating Crhr1 expression in the adult murine cerebral vasculature. In conclusion, these data suggest a novel, previously unknown role of the CRH/CRH-R1 system in modulating neurovascular gene expression and function.     

Anaphylaxis to isosulfan blue and cross-reactivity to patent blue V: case report and review of the nomenclature of vital blue dyes.

BACKGROUND: Blue dyes used for lymphatic mapping in sentinel lymph node biopsy cause intraoperative anaphylactic reactions in up to 2.7% of patients. With increasing implementation of this technique, the incidence of anaphylaxis to these dyes can be expected to increase. In the literature, the chemically often unrelated and inconsistently designated dyes have been confused, adding to other inconsistencies in the nomenclature. OBJECTIVE: To demonstrate the nomenclature, chemical and physiologic differences, and allergenicity of the various blue dyes used in a medical context. METHODS: We describe a patient with an intraoperative grade IV anaphylactic reaction to isosulfan blue. Immediate-type hypersensitivity was proved by positive skin test reactions and CD63 expression to isosulfan blue and cross-reactivity to patent blue V. RESULTS: A review of the literature clarified the exact nomenclature of the blue dyes and the possible pitfalls of confusing nomenclature in the context of structurally closely related dyes with different allergenic properties. For the detection of type I hypersensitivity, intracutaneous tests are valuable tools. An IgE-mediated mechanism has been shown recently. In most cases, sensitization exists without known previous exposure in a medical context. This may be due to the widespread use of such dyes in objects of everyday life. Preoperative antiallergic medication use does not prevent anaphylactic reactions but apparently reduces their severity. CONCLUSION: For better comparison and precision, the Chemical Abstracts Service number of the respective dye should always be given.     

Blood coagulation activation and fibrinolysis during a downhill marathon run.

Prolonged physical exercise is associated with multiple changes in blood hemostasis. Eccentric muscle activation induces microtrauma of skeletal muscles, inducing an inflammatory response. Since there is a link between inflammation and coagulation we speculated that downhill running strongly activates the coagulation system. Thirteen volunteers participated in the Tyrolean Speed Marathon (42,195 m downhill race, 795 m vertical distance). Venous blood was collected 3 days (T1) and 3 h (T2) before the run, within 30 min after finishing (T3) and 1 day thereafter (T4). We measured the following key parameters: creatine kinase, myoglobin, thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen, plasminogen-activator-inhibitor-1 antigen and thrombelastography with ROTEM [intrinsic pathway (InTEM) clotting time, clot formation time, maximum clot firmness, alpha angle]. Thrombin generation was evaluated by the Thrombin Dynamic Test and the Technothrombin TGA test. Creatine kinase and myoglobin were elevated at T3 and further increased at T4. Thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen and plasminogen-activator-inhibitor-1 antigen were significantly increased at T3. ROTEM analysis exhibited a shortening of InTEM clotting time and clot formation time after the marathon, and an increase in InTEM maximum clot firmness and alpha angle. Changes in TGA were indicative for thrombin generation after the marathon. We demonstrated that a downhill marathon induces an activation of coagulation, as measured by specific parameters for coagulation, ROTEM and thrombin generation assays. These changes were paralleled by an activation of fibrinolysis indicating a preserved hemostatic balance.     

Season of birth and risk of atopic disease among children and adolescents.

BACKGROUND: Season of birth (SOB) has been regarded as a risk factor for atopy. The aim of this study was to explore the relationship between season of birth (SOB) and later development of atopic disease in children and adolescents. METHODS: A total of 1,007 randomly selected subjects, 7 to 17 years of age, who were living in urban Copenhagen, Denmark were studied. All participants were interviewed about respiratory symptoms and possible risk factors for atopic disease. Skin test reactivity, serum total immunoglobulin E (IgE), and airway responsiveness were measured using standard techniques. RESULTS: The overall risk of atopy, as judged by skin test reactivity and serum total IgE, was the same regardless of SOB. On the contrary, asthma was more common in subjects born in the autumn compared with subjects born during the remaining part of the year (12.4% vs. 5.6%), OR = 2.40, 95% CI (1.56-3.94), p < 0.001. This was observed both for atopic asthma OR = 2.41, 95% CI (1.25-4.64), p = 0.007, non-atopic asthma, OR = 2.35, 95% CI (1.14-4.83), p = 0.02, and house dust mite (HDM) sensitive airway hyperresponsiveness, OR = 3.00, 95% CI (1.44-6.24), p = 0.002. Rhinitis and pollen allergy were not significantly related to SOB. CONCLUSIONS: Atopy itself is independent of season of birth, whereas asthma is more prevalent among subjects born during the autumn. Regarding asthma, these results suggest that the first months of life enclose a period of particular vulnerability towards environmental risk factors, especially exposure to aeroallergens like HDM.     

Sequential 99mTc-hydrazinonicotinamide-annexin V imaging for predicting response to chemotherapy.

This study was undertaken to evaluate changes in relative (99m)Tc-hydrazinonicotinamide (HYNIC)-annexin V tumor uptake over time in patients undergoing chemotherapeutic treatment at baseline and at 5-7 h and 40-44 h after treatment initiation. Imaging results are related to clinical outcomes, as assessed with response evaluation criteria in solid tumors (RECIST). METHODS: We prospectively included 20 patients (11 men and 9 women; mean age, 59.8 y; range, 22-75 y) scheduled for chemotherapy (n = 19) or bisphosphonate treatment (n = 1). Curable disease was present in 5 patients. The other patients had metastatic disease and were treated in a palliative setting. Three of the 20 enrolled patients were excluded from analysis: 1 patient ultimately refused the proposed chemotherapy treatment; because of difficulties with the labeling procedure, 1 patient did not receive a pretreatment scan; and 1 patient presented with an allergic reaction (rash and nausea) to the (99m)Tc-HYNIC-annexin V formulation. The remaining 17 patients underwent 3 scintigraphic scans with (99m)Tc-HYNIC-annexin V: before treatment and 5-7 h and 40-44 h after treatment initiation. The tumor response was evaluated with RECIST and related to observed changes in the ratios of tumor activity to background activity for the largest known lesion; values exceeding 25% the baseline value on either the 5- to 7-h scan or the 40- to 44-h scan were considered significant. RESULTS: With the proposed sequential imaging protocol and a 25% change threshold, responders to treatment could be separated from nonresponders with a 94% accuracy (16/17 patients). CONCLUSION: Sequential (99m)Tc-HYNIC-annexin V imaging may allow for assessment of the response to chemotherapy within 3 d after treatment initiation.     

Cardiac efficiency and oxygen consumption measured with 11C-acetate PET after long-term cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is a treatment option in patients with severe heart failure and left bundle-branch block (LBBB). This study evaluated the effects of 4 and 13 mo of CRT on myocardial oxygen consumption (MVO2) and cardiac efficiency as compared with mild heart failure patients without LBBB. METHODS: Sixteen patients with severe heart failure and LBBB due to idiopathic cardiomyopathy were studied at baseline and after 4 and after 13 mo of therapy. Thirteen patients with mild heart failure without LBBB served as a comparison group. The clearance rate (k2) of 11C-acetate was measured with PET to assess MVO2. Stroke volume was derived from the dynamic PET data according to the Stewart-Hamilton principle and, furthermore, cardiac efficiency using the work metabolic index. RESULTS: After 4 mo of CRT, stroke volume index (SVI) increased by 50% (P = 0.012) and cardiac efficiency increased by 41% (P < 0.001). Global k2 remained unchanged but regional k2 demonstrated a more homogeneous distribution pattern. The parameters showed no significant changes during therapy. Under CRT, cardiac efficiency, SVI, and the distribution pattern of regional k2 did not differ from mild heart failure patients without LBBB. CONCLUSION: CRT improves cardiac efficiency for at least 13 mo, as demonstrated by a higher SVI, whereas MVO2 remains unchanged. Cardiac efficiency, SVI, and the MVO2 distribution pattern reach the level of patients with mild heart failure without LBBB. The unfavorable hemodynamic performance in heart failure with LBBB is effectively restored by long-term CRT to the level of an earlier disease state.     

Tissue-engineered trachea: History, problems and the future.

This review tries to summarize the efforts over the past 20 years to construct a tissue-engineered trachea. After illustrating the main technical bottlenecks faced nowadays, we discuss what might be the solutions to these bottlenecks. You may find out why the focus in this research field shifts dramatically from the construction of a tubular cartilage tissue to reepithelialization and revascularization of the prosthesis. In the end we propose a novel concept of 'in vivo bioreactor', defined as the design of a perfusion system inside the scaffold, and explain its potential application in the construction of a tissue-engineered trachea.     

Combining spin echoes with gradient echoes in the context of the global coherent free precession pulse sequence.

To extend the signal longevity of magnetically excited spins in flowing fluids while in a state of global coherent free precession (GCFP), a refocusing radiofrequency (RF) pulse and bipolar gradient waveforms were combined with the GCFP sequence. The data demonstrate that RF refocusing in the presence of flowing blood is possible, but the improvement in signal amplitude depends on the static magnetic field homogeneity along the direction of motion and the displacement of the spins between the excitation and the RF refocusing pulse, as well as displacement during subsequent RF refocusing pulses. The least amount of phase dispersion and thus the longest lasting signal is obtained with the shortest echo spacing where only one line of data is recorded between two RF refocusing pulses. This approach was successfully used in a phantom and in vivo to image fast and slow blood flow. Depending on the experimental conditions, signal persistence is improved significantly compared to playing the same sequence without RF refocusing, but the improvement is limited by the product of blood flow velocity and the time between RF refocusing pulses.