MISE AU POINT D'UNE TECHNIQUE D'ADMINISTRATION IN VIVO DES VECTEURS GENETIQUES DANS LEMUSCLE CARDIAQUE

Objective In order to improve the in vivo gene transfer into the heart muscle, we have designed a ECG-synchronized microinjection system that allows sequential gene delivery to the myocardium.Methods A cannula was introduced into the right carotid artery of the Wistar rat under general anesthesia.With the ECG-synchronized injection during diastole, the genetic vector (Ad CMV lacZ ) infusion was performed with various concentrations( l07 ～ l010pfu ) and different frequency ( the ratio of heart beats per injection from 1: 1 to 4: 1 ). The hearts of the rats were removed after 7 days for histological examination. Results Best results were obtained with a total vector amount of l09 pfu and a good ratio 3: 1 between heart frequency and injection frequency. The transfection efficiency was increased by use of vasodilators and by an increase of vascular permeability. No signs of myocardial ischemia or ventricular arrythmia were observed. Conclusion We have established a novel and safe method for in vivo gene transfer into the heart. Transgene expression suggests that this method may be useful technique to study cardiac function of treat cardiac diseases by means of gene theratpy.     

Poor Intraoperative Blood Glucose Control Is Associated with a Worsened Hospital Outcome after Cardiac Surgery in Diabetic Patients

Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity.

Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity.

Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0).     

Modelling Germline Mosaicism and Different New Mutation Rates Simultaneously for Appropriate Risk Calculations in Families with Duchenne Muscular Dystrophy

For several genetic diseases two biological phenomena have been recognised as important: germline mosaicism; and different new mutation rates in males and females depending on mutation type. Both principles have been investigated separately and their influence on risk estimation in families has been exemplified in the literature. The aim of this paper is to present a general model that includes mosaicism and different new mutation rates. Mosaicism is introduced by defining additional alleles at the disease locus in combination with adapted segregation rules. Taking Duchenne muscular dystrophy as an example, we derive the conditions which have to be fulfilled for a population in mutation selection equilibrium. Our approach describes the model at the population level and not in individual subjects. This has the advantage of being able to use well known algorithms for the calculation of likelihoods in pedigrees, and to include additional diagnostic information such as marker genotypes and carrier deletion test results. We demonstrate the impact of the new model on a typical pedigree. In families where the patient is not available, the distinction between point mutations and deletions is important, since often molecular diagnostic tests for females can only screen for deletions. Negative deletion test results can now be included in the risk calculations.     

Hydroxyisohexyl 3-cyclohexene carboxaldehyde allergy: relationship between patch test and repeated open application test thresholds

Background  Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) is a synthetic fragrance ingredient. Case reports of allergy to HICC appeared in the 1980s, and HICC has recently been included in the European baseline series. Human elicitation dose–response studies performed with different allergens have shown a significant relationship between the patch-test threshold and the repeated open application test (ROAT) threshold, which mimics some real-life exposure situations. Fragrance ingredients are special as significant amounts of allergen may evaporate from the skin.
Objectives  The study aimed to investigate the relationship between elicitation threshold doses at the patch test and the ROAT, using HICC as the allergen. The expected evaporation rate was calculated.
Materials and methods  Seventeen HICC-allergic persons were tested with a dilution series of HICC in a patch test and a ROAT (duration up to 21 days). Seventeen persons with no HICC allergy were included as control group for the ROAT.
Results  The response frequency to the ROAT (in μg HICC cm⁻² per application) was significantly higher than the response frequency to the patch test at one of the tested doses. Furthermore the response rate to the accumulated ROAT dose was significantly lower at half of the doses compared with the patch test. The evaporation rate of HICC was calculated to be 72% over a 24-h period.
Conclusions  The ROAT threshold in dose per area per application is lower than the patch test threshold; furthermore the accumulated ROAT threshold is higher than the patch test threshold, which can probably be explained by the evaporation of HICC from the skin in the open test.     

Surgery and Chemotherapy for Small Cell Lung Cancer in Stages I–II with or without Radiotherapy

PURPOSE: To analyze the effectiveness of surgery and chemotherapy with or without radiotherapy in the management of limited small cell lung cancer (LSCLC) in stages I and II. PATIENTS AND METHODS: 39 patients (median age 62 years) with LSCLC in stages pT1 or pT2 and pN0 or pN1 (stages IA-IIB) who had a tumor resection and systematic lymph node dissection were reviewed retrospectively. The median follow-up period was 29 months. 35 patients (90%) received a median of four cycles of a platinum-containing chemotherapy postoperatively. 16 patients (41%) received an adjuvant thoracic radiotherapy (TRT, median 50 Gy); 21 patients (54%) received a prophylactic cranial irradiation (PCI, median 30 Gy). RESULTS: The median overall survival for all patients was 47 months, resulting in actuarial 1-, 3-, and 5-year survival rates of 97%, 58%, and 49%, respectively. Distant metastases were found in 13 patients (33%) after a median of 16 months. Patients who received an adjuvant TRT showed a trend toward improved thoracic recurrence-free survival (p = 0.06) and improved overall survival (p = 0.07) compared to those treated with surgery and chemotherapy only. Brain metastasis-free survival (p = 0.01) and overall survival (p = 0.01) were improved significantly in patients who received a PCI. CONCLUSION: Surgical tumor resection may be considered for carefully selected patients. Adjuvant chemotherapy and PCI are recommended for all patients. Adjuvant TRT is currently used in patients with positive lymph nodes (pN1), because the probability of a subclinical involvement of the mediastinal lymphatic system appears to be increased in these patients.     

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Genetic variation in serotonin transporter alters resting brain function in healthy individuals.

BACKGROUND: Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. METHODS: Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. RESULTS: Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. CONCLUSIONS: The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.