Notes: We present a general theory of equilibrium polymerization in a binary mixture by applying the n-vector model for magnetism in a weak field. Results are given for the temperature dependence of the order parameters, polymer length, and phase diagrams in the concentration–temperature plane. In addition to phase separations between two monomer phases and between a monomer and a polymer phase, the phase diagrams show the possibility of coexistence between two polymer phases with a critical point. It is shown that our theory becomes identical to the earlier theory for equilibrium copolymerization of Tobolsky and Owen when the molecular field approximation and some additional approximations are used.

Notes: Abstract: Epidermolysis bullosa simplex (EBS) is a group of autosomal dominantly inherited skin disorders characterized by the development of intra-epidermal skin blisters on mild mechanical trauma. The three major clinical subtypes (Weber-Cockayne, Koebner and Dowling-Meara) are all caused by mutations in either the keratin 5 (KRT5) or keratin 14 (KRT14) gene.Previously, we identified three novel KRT14 missense mutations in Danish EBS patients associated with the three different forms of EBS (1). The identified KRT14 mutations represent the full spectrum of the classical EBS subtypes. In the present study we investigated these mutations in a cellular expression system in order to analyse their effects on the keratin cytoskeleton. KRT14 expression vectors were constructed by fusing the nucleotide sequence encoding the FLAG reporter peptide to the 3′ end of the KRT14 cDNA sequences. The expression vectors were transiently transfected into normal human primary keratinocytes (NHK), HaCaT or HeLa cells in order to analyze the ability of the mutant K14 proteins to integrate into the existing endogenous keratin filament network (KFN).No effect on the keratin cytoskeleton was observed upon transfection of NHK with the various K14 constructs neither with nor without a subsequently induced heat-stress. In contrast, all constructs, including wild-type K14, caused collapse of the endogenous KFN in a small fraction of the transfected HeLa and HaCaT cells. However, overexpression of the mutation associated with the most severe form of the disease, EBS Dowling-Meara, resulted in a higher number of transfected HaCaT cells with KFN collapse (P 〈 0.001). Thus, although a background KFN perturbance was observed upon transfection with the wild-type K14 construct, the mutant protein associated with the most severe form of EBS worsened the KFN perturbation significantly compared with the mutant proteins associated with the milder forms of the disease and the normal K14 protein. This shows that the clinical severity of disease-associated mutations identified in patients can be tested using this expression system, although it can not at present be used to discriminate between the milder forms.Assessment of the endogenous K14 protein expression in NHK and HaCaT cells indicated that the higher level of endogenous keratin expression in NHK might make these cells more resistant to perturbation of the keratin cytoskeleton by overexpressed K14 protein than HaCaT cells.

Notes: Abstract Parietal cell vagotomy (PCV) and the Hill antireflux procedure were used in 108 patients with reflux esophagitis. The addition of PCV provides better access to the cardia and ensures that more extensive vagotomy than intended does not occur. Furthermore, a reduction in the basal acid output (BAO) is preferable. In patients still symptomatic after surgery, the BAO was unchanged, while in those without postoperative symptoms a significant decrease in BAO was found (p 〈 0.01). Gastroesophageal sphincter pressure was significantly higher postoperatively in all patients. Complications were few; 92% were asymptomatic at 2 months, 88% at 1 year, and 71% at 2 years. A remarkable reduction in pulmonary symptoms after operation indicates a close relationship between chronic pulmonary disease and gastroesophageal reflux in some patients.

Notes: Zusammenfassung Die relativenβ-Ausbeuten der (n, 2n)-Prozesse an verschiedenen Kernen wurden gemessen. Die Messungen wurden mit verschiedenen Neutronenquellen gemacht. Die Ergebnisse werden mit denen anderer Autoren verglichen. Die von Bothe und Gentner gemessenen (γ, n)-Ausbeuten werden den hier gefundenen (n, 2n)-Ausbeuten gegenübergestellt, und die Beziehungen zwischen den beiden Reaktionsarten werden diskutiert. Die Abhängigkeit des (n, 2n)-Wirkungsquerschnitts vom Element und von der Primärneutronen-Energie wird an Hand der Ausbeutemessungen und einer theoretischen Formel von Weisskopf und Ewing erörtert. Eine Zusammenfassung befindet sich am Schluß der Arbeit.

Notes: Zusammenfassung Es werden die mittleren Bremslängen für Neutronen in Kohle und schwerem Wasser mit verschiedenen Neutronenquellen gemessen. Aus diesen Bremslängen und der von H2O werden mittlere effektive Streuquerschnitte abgeleitet, mit deren Hilfe die Bremslängen aller aus H, D, C und O zusammengesetzten Stoffe berechnet werden können.

Notes: Abstract. A number of clinically important drugs such as the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26), the anthracyclines daunorubicin and doxorubicin (Adriamycin), and the aminoacridine amsacrine exert their cytotoxic action by stabilizing the cleavable complex formed between DNA and the nuclear enzyme topoisomerase II. We have previously demonstrated in several in vitro assays that the anthracycline aclarubicin (aclacinomycin A) inhibits cleavable-complex formation and thus antagonizes the action of drugs such as VP-16 and daunorubicin. The present study was performed to validate these in vitro data in an in vivo model. At nontoxic doses of 6 and 9 mg/kg, aclarubicin yielded a marked increase in the survival of non-tumor-bearing mice given high doses of VP-16 (80 – 90 mg/kg) in six separate experiments. In therapy experiments on mice inoculated with Ehrlich ascites tumor cells, aclarubicin given at 6 mg/kg roughly halved the increase in median life span induced by VP-16 at doses ranging from 22 to 33 mg/kg. An attempt to determine a more favorable combination of VP-16 and aclarubicin by increasing VP-16 doses failed, as the two drugs were always less effective than VP-16 alone. The way in which VP-16-induced DNA strand breaks lead to cell death remains unknown. However, VP-16 has been reported to cause apoptosis (programmed cell death) in several cell lines. To ascertain whether the protection given by aclarubicin could have a disruptive effect on the apoptotic process, we used the small intestine as an in vivo model. Whereas VP-16-induced apoptosis in crypt stem cells was detectable at a dose as low as 1.25 mg/kg, aclarubicin given at up to 20 mg/kg did not cause apoptosis. Indeed, aclarubicin caused a statistically significant reduction in the number of cells rendered apoptotic by VP-16. The present study thus confirms the previous in vitro experiments and indicates the value of including an in vivo model in a preclinical evaluation of drug combinations.

Notes: Abstract  The catalytic cycle of topoisomerase II is the target of some of the most successful antitumor agents used today, e.g., etoposide (VP-16), in the treatment of testicular cancer and small-cell lung cancer. The cell kill mediated by topoisomerase II poisons can be antagonized by distinct drug types. Thus, we have demonstrated etoposide antagonism with the type-II anthracycline aclarubicin, the antimalarial drug chloroquine, and the cardioprotective agent ICRF-187. In other setups, combinations of agonist and antagonists have led to high-dose regimens for counteracting drug resistance. Thus, the exploitation of folinic acid rescue for methotrexate toxicity and the use of mesna to protect against cyclophosphamide toxicity have enabled the use of high-dose methotrexate and cyclophosphamide protocols. Using a similar approach, we have studied possible ways to apply antagonists to topoisomerase II poisons. NDF1-hybrid female mice were treated with the various drugs and drug combinations. Lethality (LD10 and LD50 values) was computed by use of the maximum-likelihood method, and the antitumor effect of the drugs was compared in mice inoculated i.p. with either L1210 cells or Ehrlich ascites tumor cells. In addition, the compounds were tested on L1210 cells inoculated intracranially. The toxicity of the various drugs was evaluated by weight and leukocyte counts. ICRF-187 rescues healthy mice from lethal doses of topoisomerase II poisons. In mice the ICRF-187 LD10 was 500 mg/kg. Within a wide nontoxic dose range (50–250 mg/kg) of ICRF-187 we found protection against m-AMSA and etoposide lethality. Thus, the LD10 of etoposide increased from 34 mg/kg for the single agent to 122 mg/kg for its combination with ICRF-187, corresponding to a 3.6-fold etoposide dose escalation. In contrast, ICRF-187 did not protect against lethal doses of the non-topoisomerase II-directed drug paclitaxel. We further investigated the antitumor effect of equitoxic schedules in mice inoculated i.p. with L1210 or Ehrlich ascites tumor cells. The L1210-bearing mice appeared to obtain a larger increase in life span from the etoposide and ICRF-187 combination as compared with etoposide alone, whereas this was not the case in mice inoculated with Ehrlich ascites tumor cells. As the hydrophilic ICRF-187 is not expected to cross the blood-brain barrier, in contrast to the lipophilic etoposide, we investigated the effect of the drug combination in mice inoculated intracranially with L1210 cells. We obtained a significant increase in life span in mice treated with ICRF-187 + etoposide as compared with mice treated with an equitoxic dose of etoposide alone. Thus, there appear to be potential routes by which one can benefit from this antagonism. ICRF-187 is a powerful nontoxic protector against the lethality of the topoisomerase II-directed drugs etoposide and m-AMSA in vivo. A brain tumor model demonstrates the superiority of high-dose etoposide treatment with ICRF-187 protection as compared with etoposide treatment alone. This implies that tumors in the brain can be reached by cytotoxic drug doses and that normal tissues can be protected due to differences in drug transport across the blood-brain barrier. ICRF-187 is therefore a promising lead compound for the development of schedules using high-dose topoisomerase II poisons in the treatment of brain tumors and metastases.

Notes: Abstract Infective endocarditis is associated with significant morbidity and mortality. Valvular destruction and congestive heart failure are more common in patients with echocardiographically detectable vegetations. In addition, spontaneous platelet aggregation is increased when vegetations are present on cardiac valves. The aim of the study was to assess the prognostic value of spontaneous echo contrast (SEC) imaging, as SEC is supposed to reflect red blood cell aggregates stimulated by platelet activity. We studied 293 patients with clinical signs of infective endocarditis. Vegetations, attached to the aortic or mitral valve, were found in 130 patients (44.4%) who were followed for a mean period of 12 months. In 34 of these 130 patients (26.2%) SEC was imaged during the initial transesophageal echocardiographic examination. In these patients SEC indicated a prolonged healing of infective endocarditis with a specificity of 91.2%, a sensitivity of 77.3%, a positive accuracy of 77.3%, a negative accuracy of 74.3%. Multivariate analysis revealed that SEC is a risk factor for valve replacement (p 〈 0.001) and for embolic events (p 〈 0.001), less for mortality (p 〈 0.01), and lowest for abscess formation (p 〈 0.05). The dose of ADP to induce half-maximal platelet aggregation was significantly lower in patients with SEC (0.71 ± 0.15μl) than without SEC (1.05 ± 0.12μl;p 〈 0.05), implying an increased spontaneous platelet aggregation in the presence of SEC. Our data provide evidence that systemically activated coagulation plays an important role in infective endocarditis. SEC, the echocardiographic implication of an increased platelet aggregation, predicts complications such as thromboembolic events and the need for surgery and is closely related to the prolonged healing period of infective endocarditis. In addition to demonstrating vegetations, transesophageal echocardiography provides information helpful in assigning patients to a high-risk subgroup. Transesophageal echocardiography may play an important role in assessing the clinical outcome of these patients.

Notes: Abstract Radiography and manometry of the esophagus were compared in 77 patients consecutively referred for manometric investigation on suspicion of esophageal motility disorder. Radiography and manometry were carried out simultaneously, and the results were assessed blindly. The examination comprised barium swallow, bread barium swallow, and barium swilling. Considering manometry as the standard, the overall sensitivity and specificity of the radiologic examinations were 90.4% and 92.0%, respectively. We conclude that radiology is an excellent investigation for the separation of patients with and without esophageal motility disorders, but correct subclassification often required manometry.