Sondengesteuerte Choriozottenbiopsietechnik — eine prospektive randomisierte Studie

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Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.     

Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair

The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.      

Survival of corneal grafts after severe burns of the eye

The authors investigated 32 human corneal buttons of patients suffering from severe eye burns. The keratoplasties were performed in different periods after the burn and collected within five years. Grafts were followed-up until they failed because of ulceration or until rehabilitating keratoplasties were performed. Early (up to six months after the burn) and late (more than 12 months after the burn) obtained corneas showed different cellular reactions in the corneal stroma. Inflammatory cells such as granulocytes and lymphocytes decreased with increasing periods after the burn. More than 12 months after the burn, minor inflammatory cellular reactions but increasing scar formation could be found. Four out of 19 early-, two out of eight intermediate- (between six and 12 months after the burn) and one of the late performed keratoplasties failed and had to be replaced by new corneal grafts. Due to the conditions in the graft beds the explanted corneal grafts showed a cellular reaction in the stroma comparable to the previously explanted burnt corneae. Further complications occurred because of problems concerning the ocular surface. After preliminary therapeutical keratoplasties rehabilitating keratoplasties could be successfully performed in four cases between 19 and 39 months.     

Antibody-based profiling of the phosphoinositide 3-kinase pathway in clinical prostate cancer.

PURPOSE: As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited. EXPERIMENTAL DESIGN: Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples. Results and CONCLUSIONS: Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer.     

Acute simultaneous proximal occlusion of two major coronary arteries in acute myocardial infarction: successful treatment with percutaneous coronary intervention

Background: Acute myocardial infarction (AMI) due to acute simultaneous proximal occlusion of two major coronary arteries (ASOMC) is a rare but life‐threatening situation. Most patients die suddenly or go into cardiogenic shock (CS). In patients with AMI due to ASOMC identified by coronary angiography (CA), percutaneous coronary intervention (PCI) performed in both infarct‐related arteries (IRAs) at the same time as diagnostic CA is the fastest option to complete revascularization. However, no prospective studies regarding the outcome of such procedures have been published so far. Methods: In this prospective single‐center study, between October 2004 and March 2007, consecutive patients with acute coronary syndrome (ACS) reporting to our university hospital and regional referral center were evaluated for ASOMC by means of emergent CA. When diagnosed with ASOMC, PCI of the IRAs was performed. Clinical data were obtained at baseline, discharge, after 6 months, and after 1 year. Results: Out of 417 patients with ACS, 379 patients (90.9%) suffered an AMI. In 5 patients CA revealed an ASOMC. PCI was performed in 4 patients. One patient with severe triple‐vessel disease was referred for emergent coronary artery bypass graft (CABG) surgery after conventional PCI of one IRA. One patient died in‐hospital due to early in‐stent thrombosis after PCI. At 6‐month follow‐up and at 1‐year follow‐up, 4 patients were alive. Conclusion: In spite of the complex interventions, PCI patients had low in‐hospital mortality and good clinical results at 1‐year follow‐up. Our observations are important in the clinical decision‐making process of AMI due to ASOMC.     

Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

New insight into active muscarinic receptors with the novel radioagonist [H]iperoxo

Activation of G protein-coupled receptors involves major conformational changes of the receptor protein ranging from the extracellular transmitter binding site to the intracellular G protein binding surface. GPCRs such as the muscarinic acetylcholine receptors are commonly probed with radioantagonists rather than radioagonists due to better physicochemical stability, higher affinity, and indifference towards receptor coupling states of the former. Here we introduce tritiated iperoxo, a superagonist at muscarinic M₂ receptors with very high affinity. In membrane suspensions of transfected CHO-cells, [³H]iperoxo – unlike the common radioagonists [³H]acetylcholine and [³H]oxotremorine M – allowed labelling of each of the five muscarinic receptor subtypes in radioagonist displacement and saturation binding studies. [³H]iperoxo revealed considerable differences in affinity between the even- and the odd-numbered muscarinic receptor subtypes with affinities for the M₂ and M₄ receptor in the picomolar range. Probing ternary complex formation on the M₂ receptor, [³H]iperoxo dissociation was not influenced by an archetypal allosteric inverse agonist, reflecting activation-related rearrangement of the extracellular loop region. At the inner side of M₂, the preferred G_i protein acted as a positive allosteric modulator of [³H]iperoxo binding, whereas G_s and G_q were neutral in spite of their robust coupling to the activated receptor. In intact CHO-hM₂ cells, endogenous guanylnucleotides promoted receptor/G protein-dissociation resulting in low-affinity agonist binding which, nevertheless, was still reported by [³H]iperoxo. Taken together, the muscarinic superagonist [³H]iperoxo is the best tool currently available for direct probing activation-related conformational transitions of muscarinic receptors.