APC mutations in colorectal tumors with mismatch repair deficiency.

We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)n tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair.     

γ-Aminobutyric acid type A/benzodiazepine receptors regulate rat retina neurosteroidogenesis

It has been previously shown that retinal ganglion cells have the ability to synthesize steroids including neuroactive steroids such as pregnenolone sulfate. Since ganglion cells possess GABA_A/benzodiazepine (BZ) receptors and neurosteroids modulate retinal GABA_A receptor function, we investigated the role of these receptors in isolated rat retina neurosteroidogenesis. Ligands for central-type BZ receptors stimulated retinal pregnenolone synthesis. Clonazepam was the most potent ligand examined acting at nanomolar concentrations. Moreover, the effective steroidogenesis stimulatory dose (ED₅₀) for these ligands and theK_i to inhibit [³-H]flunitrazepam binding showed a coefficient of correlation ofr = 0.87, suggesting the involvement of the central-type BZ receptors in this event. Ro 5-4864, which preferentially binds to peripheral-type BZ receptors, was less efficacious and potent whereas PK 11195 did not affect the basal pregnenolone formation and did not antagonize the Ro 5-4864 stimulated steroid synthesis. The GABAergic agonist muscimol, stimulated neurosteroid synthesis and this effect was reversed by the GABAergic antagonists bicuculline and picrotoxinin. In addition, these antagonists decreased basal pregnenolone formation, suggesting a tonic GABAergic control of the steroidogenic pathway, and reduced clonazepam-stimulated steroidogenesis. These results, together with the reported ability of neurosteroids to modulate GABA_A receptor function, suggest a novel regulatory mechanism to control the inhibitory transmission.     

MHC class II antigens on lung epithelial of human fetuses and neonates. Ontogeny and expression in lungs with histologic evidence of infection.

An immunohistochemical study with anti-HLA-DP, anti-HLA-DQ and anti-HLA-DR monoclonal antibodies was carried out on lung tissue from 29 fetuses and 19 infants that died within the 1st year of life. The aim of the study was to verify the influence of lung maturation and lung inflammation, caused by intrauterine infection, on the expression of MHC class II antigens on lung epithelia. No positive reaction of lung epithelia was noticed in 6 fetuses of less than 21 weeks' gestation. In fetuses of more than 21 weeks' gestation, lung inflammation strongly correlated with the expression of MHC class II subregion products on lung epithelia. All 4 fetuses with histopathologic evidence of lung infection but only 4 out of 23 fetuses without lung inflammation bore HLA-DR antigens on their immature cuboidal alveolar epithelium. Within the bronchial epithelial layers only scattered MHC class II positive epithelia were found. After birth, MHC class II antigens were almost constantly detected on cuboidal type II pneumocytes of inflamed and noninflamed lung tissue as well. Only 3 infants that died within the 1st week of life did not show any MHC class II antigen expression on their lung epithelia.     

Metastatic epidural spinal cord compression.

It is important to remember that ESCC is a complication of systemic malignancy and usually denotes disseminated disease with poor survival rates. Early diagnosis is crucial. The initial symptom is almost always back pain, which is local, radicular, or both. Following neurologic examination and radiography, MRI scanning or myelography/CT is immediately indicated if radiculopathy or myelopathy is present or if the radiographs of the spine are abnormal. In cancer patients with local back pain and normal findings on neurologic examination and radiography of the spine, there is still a probability of 0.1 of significant ESCC. Therefore, urgent CT/MRI scanning is justified. At present, the best treatment for ESCC remains unknown. In the majority of patients, radiotherapy is the most readily available and appropriate option because it is equal in effect to posterior decompressive laminectomy in both radiosensitive and radioresistant tumors. In patients with posterior epidural disease without tissue diagnosis, laminectomy with or without stabilization should be performed. Posterior decompressive laminectomy alone is contraindicated in patients with vertebral collapse. In selected instances of anterior epidural compression without tissue diagnosis or after failure of radiotherapy, an anterior surgical approach or synchronous vertebral decompression with posterior stabilization may be indicated. In the future, after appropriate clinical trials, vertebral body resection may be the optimal approach in de novo selected patients with ESCC with radioresistant tumors and limited systemic spread of the disease.     

Intraoperative Kontrastechokardiographie zum Nachweis eines funktionell offenen Foramen ovale unter Durchführung eines Provokationstests mit PEEP-Beatmung

Intraoperative paradoxical air embolism may occur even if a patent foramen ovale (PFO) is excluded by contrast transoesophagal echocardiography (TEE) under 20?cmH₂O positive airway pressure. It is questionable whether the combination of PEEP and ventilation with a large tidal volume increases the sensivity of contrast TEE in detecting a PFO. Methods. Eighty healthy patients (ASA status I, II) scheduled for surgery in the supine position and ranging from 25 to 72 years of age were investigated by TEE, which was performed in the biatrial viewing mode (short axis). Echocardiographic contrast (10?ml agitated gelatine solution) was injected during two different ventilation manoeuvres. Manoeuvre I: Contrast injection during the application of 20?cmH₂O positive airway pressure for 5?s. The pressure was released when the right atrium became completely opacified by echo targets. The injected bolus was observed throughout the ventilatory cycle, with special attention being given to early expiration and systole. A right-to-left shunt was assumed if five echo targets were observed in the left atrium. Manoeuvre II: Contrast injection during ventilation with PEEP (15?cmH₂O), a tidal volume of 1,200?ml, and a respiratory rate of 6/min. Results. The frequency of a PFO causing a right-to-left interatrial shunt was 8.7% (7 cases) in manoeuvre I and 15% (12 cases) in manoeuvre II. In one case a PFO was diagnosed intraoperatively by chance. Discussion. The use of provocation manoeuvres including ventilation with PEEP and high tidal volumes might improve the ability to detect a PFO presenting with right-to-left interatrial shunt by intraoperative contrast TEE, but does not have 100% sensitivity. However, our results clearly indicate that ventilation with PEEP and high tidal volumes may predispose to paradoxical embolism.     

Phenolic metabolites of thioridazine in man

After oral administration of thioridazine or mesoridazine to man, faecal extracts contained mainly unconjugated 7-hydroxy-thioridazine and its demethylated analogue, together with some 3-hydroxy-thioridazine, and 7-hydroxy derivatives of sulphoridazine and desmethyl sulphoridazine. In contrast, urine contained free 7-hydroxy-mesoridazine, and no free 7-hydroxy-thioridazine was detectable. Conjugates of all these phenols were also found. After oral sulphoridazine administration (thioridazine side-chain sulphone), urine contained mainly 7-hydroxy-sulphoridazine and faeces both 7-hydroxy-sulphoridazine and its desmethyl analogue. Sulphoridazine metabolism is therefore much simpler than that of thioridazine. This different elimination pattern in faeces and urine may be due to reduction of sulphoxides but not sulphones by intestinal bacteria.     

Treatment of hepatic metastases in ocular melanoma. Embolization of the hepatic artery with polyvinyl sponge and cisplatin

Patients with ocular melanoma have a high incidence of hepatic metastases, which primarily determine their length of survival. In an attempt to control the neoplastic disease in the liver, embolization of the hepatic artery with a combination of polyvinyl sponge (Ivalon) and a suspension of cisplatin was performed in two patients with hepatic metastases from ocular melanoma. Dramatic regression of the hepatic metastases, lasting 19 and six months, occurred in these two patients after one or two such treatments. Our preliminary, albeit successful, experience with this therapeutic approach suggests that it may offer relatively prolonged periods of remission and warrants further investigation.