Arterialization of the portal vein in pediatric liver transplantation

Portal vein arterialization (PVA) is an acquired concept in shunt surgery for portal hypertension. This technique, recently described as both a temporary and permanent procedure in adult liver transplantation, is reported by the authors in two cases of pediatric transplantation. The indication was low portal blood flow after reperfusion with poor graft function due to persistence of spontaneous retroperitoneal venous shunts. In both cases described, PVA allowed for satisfactory macroscopic liver reperfusion. The increase in portal blood flow from 150 to 500 ml/min in the second patient enabled the liver to be reperfused correctly and led to successful transplantation. The graft function in both cases improved in the 1st postoperative week, but thrombosis of the PVA occurred in the 1st patient 2 months after transplantation. Signs of hepatic hyperarterialization occurred in the second patient and this necessitated a dearterialization of the portal vein 2 weeks later. Although the benefit of this procedure appears to be beyond doubt in the immediate postoperative period, we have no data on long-term arterialization. We do think that PVA can be performed in pediatric liver transplantation, but it may need to be done only in special, individual situations when no valid alternative can be proposed, such as in the absence of a mesenteric vein and/or the presence of spontaneous retroperitoneal venous shunts. Received: 24 June 1997 Received after revision: 27 November 1997 Accepted: 28 November 1997     

Morphology and electrophysiological properties of cutaneous sensilla in agamid lizards

The external morphology of agamid cutaneous sensilla has been studied by means of the scanning electron microscope (SEM). Electrophysiological recordings from single organs were obtained in response to mechanical bending of the centrally located long seta. In this way the mechanoreceptive function of reptilian cutaneous sensilla has been established for the first time.Dedicated to Prof. Dr. G. Pfefferkorn on the occasion of his 65th birthday.     

Mannich-Basen von Hydroxy-indolen, 2. Mitt

Mannich Bases of Hydroxyindoles, II¹ The 2-hydroxy-cyclohept[b]indolones 2a-c react with bis(dimethylamino)methane to yield the phenol Mannich bases 3a-c . The 1,3-benzoxazine derivatives 5a-c are synthesized from 2a,b,d and hexahydrotriethyl-1,3,5-triazine 4 . Reaction of 6-hydroxyindole 6 with triazine 4 yields benzoxazine 7 .     

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.     

A structure-guided approach to an orthogonal estrogen-receptor-based gene switch activated by ligands suitable for in vivo studies

A strategy to obtain a fully orthogonal estrogen-receptor-based gene switch responsive to molecules with acceptable pharmacological properties is presented. From a series of tetrahydrofluorenones active on the wild-type estrogen receptor (ER) an inactive analogue is chosen as a new lead compound. Coevolution of receptor mutants and ligands leads to an ER-based gene switch suitable for studies in animal models.     

Antisense-mediated melanoma inhibitor of apoptosis protein downregulation sensitizes G361 melanoma cells to cisplatin

Malignant melanoma is an aggressive form of skin cancer that is highly resistant to conventional therapies. The melanoma inhibitor of apoptosis protein is a potent inhibitor of apoptosis and is overexpressed in melanoma cells, but undetectable in most normal tissues including melanocytes. We designed 20-mer phosphorothioate antisense oligonucleotides complementary to five putatively single-stranded sites on the melanoma inhibitor of apoptosis protein mRNA and investigated their ability to sensitize G361 melanoma cells to cisplatin. Inhibition of melanoma inhibitor of apoptosis protein mRNA and protein expression were measured by real-time polymerase chain reaction and immunoblotting. Cell viability and apoptosis were quantitated by colorimetric viability assays and by annexin V staining, respectively. Oligonucleotide M706 was identified as the most efficient antisense sequence which downregulated melanoma inhibitor of apoptosis protein mRNA and protein levels in G361 cells by 68 and 78%, respectively. The specificity of target downregulation was confirmed using scrambled sequence control oligonucleotides that only marginally decreased melanoma inhibitor of apoptosis protein expression. Whereas downregulation of melanoma inhibitor of apoptosis protein moderately inhibited cell growth by 26%, in combination with cisplatin, this resulted in a supra-additive effect with almost 57% reduction in G361 cell viability compared with cisplatin alone (17%) (P<0.05). Cell death was mainly due to apoptosis as demonstrated by a 3- to 4-fold increase in annexin V-positive cells and typical morphological changes compared with controls. In summary, we describe a new antisense oligonucleotide that efficiently downregulates melanoma inhibitor of apoptosis protein expression and sensitizes melanoma cells to cisplatin.     

Efficacy and safety profile of a herbal drug containing nasturtium herb and horseradish root in acute sinusitis, acute bronchitis and acute urinary tract infection in comparison with other treatments in the daily practice/results of a prospective cohort study

PATIENTS AND METHODS: In a prospective cohort study from 251 centers in Germany patients with age of 4 years or above who were treated due to acute sinusitis, bronchitis or urinary tract infections (UTI) in the period from 1st March 2004 - 30th July 2005, were elected. They were included in the study analysis, if they had no exclusion criteria (severe diseases, need for antibiotic therapy, participation in another trial) and came to the final investigation. The patients were treated either with the nasturtium herb and horseradish root containing herbal drug Angocin Anti-Infekt N (test group, n = 1223) or with standard antibiotic therapy (control group, n = 426). Treatment, dosage and treatment duration were determined by the physician in accordance with the patient. 536 subjects (408 test, 128 control patients) suffered from acute sinusitis, 634 subjects (469 test, 165 control patients) from acute bronchitis and 479 subjects (346 test, 133 control patients) from UTI. At study start and end the severity of the symptoms were judged by the investigator and quantified with 4 scores (0 = no symptom, 3 severe symptom). During the treatment information on use of medication, concomitant procedures and adverse events (AEs) in a patient diary. At the end of the study (disease free or after 7-14 days) the patient returned to the investigator, who recorded the vital parameters, finally judged the treatment efficacy and potential persisting symptoms on the basis of score values. Primary efficacy criterion was the change of the complaints quantified by the change of the relative symptom score averaged over all symptoms and related to the baseline value. RESULTS: In patients with acute sinusitis the mean relative reduction of the averaged symptom score was 81.3% for the test group and 84.6% for the control group, in patients with acute bronchitis the mean reduction was 78.3% for the test group and 80.3% for the control group, in patients with UTI 81.2% for the test group and 87.9% for the control group. The 95% confidence interval for the difference of the expected reductions between test and control group was -8.5% to 1.8% for acute sinusitis, 7.6% to 3.6% for acute bronchitis and -13.1% to -0.1% for UTI. Non-inferiority of the test treatment, i.e. if the lower limit of the 95% confidence interval is greater than 10%, could be stated for acute sinusitis and bronchitis. In UTI the non-inferiority level was exceeded only by 3%. Complementary procedures were less in the test group than in the control group. For 1.5 % of test patients and 6.8% of control patients AEs were observed CONCLUSION: Therapy with the herbal drug in the indications acute sinusitis, acute bronchitis und acute urinary tract infection is - with regard to its efficacy comparable to the treatment with standard antibiotics. The application of supportive procedures and the administration of concurrent medication were less expressed in the group treated with the herbal drug. In the above mentioned indications the group treated with the herbal drug displayed a clear advantageous safety profile compared to the group treated with standard antibiotics.     

Topical pimecrolimus for skin disease other than atopic dermatitis

Pimecrolimus is an ascomycin macrolactam. It is a specific calcineurin inhibitor that allows topical application. The highly lipophilic nature of this compound reduces the risk of systemic absorption through normal and inflammed skin. Pimecrolimus shows activity not only against T-cell activation, but also against mast cells and pruritus. Pimecrolimus 1% cream is approved for atopic dermatitis, and also has a great potential in other inflammatory skin diseases. Clinical trials have been performed in contact- and seborrhoeic dermatitis, genital lichen sclerosus, intertriginous psoriasis and cutaneous lupus erythematosus. In other diseases, the available data are limited to small case series, or individual cases of graft-versus-host disease or Netherton's disease. Although the use of calcineurin inhibitors in the treatment of vitiligo is promising, detailed studies with pimecrolimus and ultraviolet-irradiation are necessary and there is a need for prospective randomised, double-blind controlled trials.     

The pricing of U.S. hospital services: chaos behind a veil of secrecy

Although Americans and foreigners alike tend to think of the U.S. health care system as being a "market-driven" system, the prices actually paid for health care goods and services in that system have remained remarkably opaque. This paper describes how U.S. hospitals now price their services to the various third-party payers and self-paying patients, and how that system would have to be changed to accommodate the increasingly popular concept of "consumer-directed health care."