Growth hormone signalling: sprouting links between pathways, human genetics and therapeutic options.

Our molecular understanding of growth hormone-induced signal transduction has improved significantly over the past decades. At the same time, human population genetics and the analysis of genetically engineered animals have led to the discovery of genes that control specific aspects of the overall growth process. Although, currently, growth disorders are still diagnosed and treated on empirical bases, it might soon be possible to stratify patients predominantly by genetic defect, with treatment based on our molecular understanding of the role of the affected gene in the disease.     

Skeletonization of internal thoracic artery affects its innervation and reactivity.

OBJECTIVE: The studies showing the superior characteristics of ITA graft and its impact on the clinical results of coronary artery surgery were performed with ITA harvested almost exclusively as a pedicle. This study assesses the impact of ITA skeletonization on its innervation and reactivity. METHODS: Segments of skeletonized and non-skeletonized ITA were stained with antibodies against protein S-100 to look for the presence of sympathetic nerve fibers. The functional studies were performed on segments of discarded human pedicled ITA that were divided into two 3mm rings, one skeletonized and another non-skeletonized. We compared concentration-effect relationships for the contraction to norepinephrine and endothelium-dependent relaxation to acetylcholine and bradykinin, as well as endothelium-independent relaxation to sodium nitroprusside in skeletonized and non-skeletonized segments of the same ITA. RESULTS: Skeletonized ITA was devoid of protein S-100 positive nerve fibers. It contracted stronger (maximal response 37.0+/-2.04 vs. 25.4+/-1.83mN (P<0.001)) and was twice as sensitive to norepinephrine: pD(2) 6.03+/-0.10 vs. 5.70+/-0.12 (P=0.035). The endothelium-dependent relaxation responses did not differ between skeletonized and non-skeletonized ITA rings. The skeletonized ITA rings appeared over 10 times more sensitive to sodium nitroprusside: pD(2) 6.66+/-0.20 vs. 5.59+/-0.37 (P=0.012)-potency ratio 11.61. The maximal responses did not differ significantly: 112.0+/-6.71 vs. 129.4+/-16.4% (P=0.33). CONCLUSIONS: Skeletonization results in sympathectomy of ITA. It has no effect on endothelium-dependent relaxation but increases reactivity of ITA to norepinephrine. This augmented response to alpha-agonist is small, in comparison with over a ten-fold increase in sensitivity to sodium nitroprusside. Pedicled and skeletonized ITA are functionally significantly different vessels when studied in vitro.     

Brain uptake of radiolabeled N‐oleoyl‐dopamine in the rat

N‐acyl‐dopamines are a novel class of biologically active lipids that have recently been identified in the brain and have the potential to interact with neural signaling pathways. This study seeks to determine the ability of N‐oleoyl‐dopamine, a synthetic amide of oleic acid and dopamine, to cross the blood brain barrier. We determined the tissue content of radioactivity in selected brain regions, in a short‐run study design, following injections of [³H]N‐oleoyl‐dopamine (0.4 µCi) into the internal carotid artery in the rat. These results were compared with intracarotid injections of [³H]dopamine and with intravenous injections of both radiolabeled compounds. The level of radioactivity was determined using liquid scintillation and was expressed as the percentage of its total dose injected per gram of tissue. We found that the 15‐min brain uptake of radioactivity, with no distinct regional variations, amounted to about 6% following the intracarotid [³H]N‐oleoyl‐dopamine, which was a significant 3–4‐fold increase over that following similar administration of [³H]dopamine. Intravenous injections of [³H]N‐oleoyl‐dopamine gave a much smaller yield of radioactivity in brain tissue samples which was still severalfold greater than that for intravenous [³H]dopamine. Qualitative thin‐layered chromatography screening showed the presence of unchanged N‐oleoyl‐dopamine in the brain following injections. We conclude that N‐oleoyl‐dopamine has an appreciable ability to cross the blood‐brain barrier, which contrasts the limited transfer of dopamine alone. N‐oleoyl‐dopamine might exert physiological effects due to its known affinity for the central vanilloid receptors or to better satisfying the brain tissue demand for dopamine. The study suggests a potential pharmacological role for N‐oleoyl‐dopamine delivered exogenously in helping regulate the brain function. Drug Dev. Res. 60:217–224, 2003. © 2003 Wiley‐Liss, Inc.     

Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas

A prospective, randomized trial evaluates the effects of two postoperative treatment regimens on survival in 198 adult patients with supratentorial gliomas. All patients were irradiated with 6 000 rads after possibly radical removal of tumors. CCNU administration in the dosis of 100 mg/sq m of body surface every 6–8 weeks following surgery proved to have no significant effect on the survival of patients. The median survival time in patients receiving radiation therapy alone was 61±7 weeks, while in those receiving additional chemotherapy was 56±4 weeks. Tumor histological malignancy and patients age were found to be the only important prognostic factors, irrespective of the treatment modality. Address for offprints: T Trojanowski, Department of Neurosurgery, Medical School, Jaczewskiego 8, 20-950 Lublin, Poland     

Effects of montelukast treatment on clinical and inflammatory variables in patients with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), the inflammatory process contributes to progressive lung tissue damage. Cysteinyl leukotrienes have been found in the sputum of patients with CF at high concentrations sufficient to cause potent biological effects. OBJECTIVE: To evaluate the effect of anti-inflammatory treatment with montelukast sodium in patients with CF. METHODS: Twenty-six patients aged 6 to 18 years were recruited to this 20-week, randomized, double-blind, placebo-controlled, crossover trial. Patients received montelukast or placebo for 8 weeks in addition to their regular CF treatment. Before and after treatment, findings from spirometry, whole-body plethysmography, and the clinical wheezing and cough scales were evaluated. At the same time, serum and sputum samples were obtained for the measurement of eosinophil cationic protein, interleukin 10 (IL-10), IL-8, and myeloperoxidase levels. RESULTS: Twenty-three patients completed the study. Compared with placebo use, montelukast treatment significantly improved forced expiratory volume in I second, peak expiratory flow, and forced expiratory flow between 25% and 75% and significantly decreased cough and wheezing scale scores (P < .001 for all). There were no significant changes in vital capacity, thoracic gas volume, airway resistance, and residual volume after treatment. Compared with placebo use, montelukast treatment decreased serum and sputum levels of eosinophil cationic protein and IL-8, decreased sputum levels of myeloperoxidase, and increased serum and sputum levels of IL-10 (P < .001 for all). CONCLUSIONS: Montelukast may have measurable anti-inflammatory properties in patients with CF.     

Plasma levels of alpha beta peptides are altered in amnestic mild cognitive impairment but not in sporadic Alzheimer's disease

Plasma alpha beta levels have been examined in sporadic Alzheimer's disease yielding conflicting results; both no difference and an increase in plasma concentrations of alpha beta42 and alpha beta40 in sporadic cases of AD as compared to controls have been reported. Elevated plasma alpha beta42 levels may be detected several years before the onset of symptoms (in mild cognitive impairment stadium). Levels of alpha beta40 and alpha beta42 were measured in plasma from 54 patients with AD, 39 subjects with MCI and 35 controls using a commercially available ELISA. Mean plasma alpha beta42 levels were significantly higher in MCI as compared to both AD (P < 0.001) and control subjects (P < 0.001), while alpha beta40 did not differ between the groups. No correlations were observed between alpha beta levels and age, MMSE scores or gender. According to ROC curve analysis the maximum accuracy in discriminating MCI versus both controls and AD subjects has been achieved using a cut-off value of 3.8.     

CTLA-4 (CD152) gene polymorphism at position 49 in exon 1 in Graves' disease in a Polish population of the Lower Silesian region

INTRODUCTION: Graves' disease ((GD)is an autoimmune disease believed to be caused by a combination of environmental and genetic factors. The gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)is one of the candidate genes for conferring susceptibility to thyroid autoimmunity. he aim of the study was to investigate the association between the exon 1 CTLA-4 gene polymorphism A(49)G and susceptibility to GD and Graves ' ophthalmopathy (GO)as well as its severity in a Polish population of the Lower Silesia region. MATERIALS AND METHODS: We analyzed the A(49)G exon 1 CTLA-4 gene polymorphism in 99 unrelated Polish patients with GD, of whom 50 had clinically evident GO (NOSPECS class III and higher), and 154 matched healthy subjects from the Lower Silesia region. Genomic DNA was isolated from whole frozen blood using the NucleoSpin Blood kit. A/G transition was genotyped by polymerase chain reaction followed by labeling with the SnaPshot kit of PE Applied Biosystems and detected using an ABI PRISM 310 capillary genetic analyzer. RESULTS: The distribution of CTLA-4 exon 1 A(49)G enotype, allele, and phenotypic frequencies did not differ between patients with GD and healthy subjects. There was a significantly lower frequency of the AA genotype in the group of patients with clinically evident GO than in patients without severe GO (22% vs. 43%; p=0.02, OR=2.6). CONCLUSIONS: Our results showed that the AA genotype in patients with GD is associated with a lower risk of GO severity.