Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid.

RamB, a novel transcriptional regulator of genes involved in acetate metabolism of Corynebacterium glutamicum.

The adaptation of Corynebacterium glutamicum to acetate as a carbon and energy source involves transcriptional regulation of the pta-ack operon coding for the acetate-activating enzymes phosphotransacetylase and acetate kinase and of the aceA and aceB genes coding for the glyoxylate cycle enzymes isocitrate lyase and malate synthase, respectively. Deletion and mutation analysis of the respective promoter regions led to the identification of highly conserved 13-bp motifs (AA/GAACTTTGCAAA) as cis-regulatory elements for expression of the pta-ack operon and the aceA and aceB genes. By use of DNA affinity chromatography, a 53-kDa protein specifically binding to the promoter/operator region of the pta-ack operon was purified.

Characterization of the phosphoenolpyruvate carboxykinase gene from Corynebacterium glutamicum and significance of the enzyme for growth and amino acid production.

Corynebacterium glutamicum possesses phosphoenolpyruvate (PEP) carboxykinase, oxaloacetate decarboxylase and malic enzyme, all three in principle being able to catalyze the first step in gluconeogenesis. To investigate the role of PEP carboxykinase for growth and amino acid production, the respective pck gene was isolated, characterized and used for construction and analysis of mutants and overexpressing strains. Sequence analysis of the pck gene predicts a polypeptide of 610 amino acids showing up to 64% identity with ITP-/GTP-dependent PEP carboxykinases from other organisms.

Postoperative nausea and vomiting (PONV) in children.

Postoperative nausea and vomiting (PONV) are common and unpleasant complications. The aim of this study was to evaluate possible aetiologies of PONV in children and to formulate measures to reduce its incidence. During four months 780 patients requiring anaesthesia were studied prospectively.

Neonatal lupus erythematosus with congenital heart block and severe heart failure due to myocarditis and endocardititis of the mitral valve.

We report a case of neonatal lupus erythematosus (NLE) with congenital heart block and severe myocardial failure, which was followed from the 25th week of gestation because of fetal bradycardia. The child was delivered at the 37th week of gestation by elective cesarean section because of echocardiographically documented heart enlargement, pericardial effusion and moderate insufficiency of the mitral and tricuspid valves. In spite of immediate pacing, intubation and supportive treatment, the newborn developed progressive heart failure.

Tracheostomy in children.

We reviewed the records of 108 patients who had a tracheostomy performed over a 10-year period from July 1979 to April 1989. Median age at tracheostomy was 6 months (1 week-15 years). Indications for surgery were acquired subglottic stenosis (31.

Squamous-cell carcinoma arising in a non-irradiated child with recurrent respiratory papillomatosis.

We describe a patient with recurrent respiratory papillomatosis (RRP) associated with human papilloma virus (HPV), who developed a fatal squamous cell carcinoma of the lung. At the age of 1 year he presented with hoarseness, dyspnoea and inspiratory stridor but the diagnosis of RRP was made only 1 year later. At the age of 4 years he was tracheostomized because of upper airway obstruction.

[Polyneuropathy and fasciitis in eosinophilia-myalgia syndrome].

Eosinophilia-Myalgia-Syndrome (EMS), a newly recognized illness, was described first in October 1989, when it formed an epidemic in the USA and later also in Europe. In the meantime, ingestion of L-tryptophan containing products has been recognized to trigger this syndrome, but the pathophysiological basics are still subject to speculation. Often starting with a flu-like period, the disease is dominated by dermatologic (fasciitis) and neurologic (neuropathy, myopathy) symptoms in the subsequent stages.

Normovolaemic haemodilution and intraoperative auto-transfusion in children: experience with 30 cases of spinal fusion.

Based on 30 cases of ventral and/or dorsal spondylodesis in children and adolescents between 3.4 and 19.9 years of age, this report describes a method for the minimization of homologous blood transfusion.

Familial congenital laryngeal abductor paralysis: different expression in a family with one male and three females affected.

A brother and two sisters of remotely consanguineous parents had congenital laryngeal abductor paralysis and moderate mental retardation. In the two older sibs, mental deficiency could have resulted from birth asphyxia, but the youngest girl was already microcephalic at birth and had no apparent asphyxia. The mother, who was healthy and of normal intelligence, was found on laryngoscopy to have unilateral laryngeal abductor paralysis.

[The collecting principle in pediatrics and neonatology].

Quality medical care during transport of critically ill pediatric and neonatal patients is only possible if the referring hospital and the regional center cooperate closely. The experience of physicians and nurses involved is of great importance, and the choice of the transporting team should depend on the medical status of the patient and the skills of the physicians and nurses or paramedics. Critically ill children and neonates should be transported by specialized teams.

[Activities of intensive care units in 1986].

Based on a yearly evaluation carried out by the Swiss Society for Intensive Care Medicine and the Swiss Nurses Association, statistical reports for 1986 from 72 recognized intensive care units are presented.

Mechanical properties of fetal minipig lungs after substitution of surfactant with fluorocarbon and dipalmitoylphosphatidylcholine.

Respiratory distress syndrome (RDS) is characterized by quantitative and qualitative disturbances of surface active substances (surfactant). Therefore, intratracheal surfactant substitution is a favored subject of clinical investigations. In our study we tried to inflate and stabilize lungs in two steps: first, lungs were rinsed with a fluorocarbon and, second, artificially ventilated with a dipalmitoylphosphatidylcholine (DPPC) aerosol, the mean component of surfactant.

[Continuous monitoring of blood gases in newborn infants].

Hypoxic brain damage and retrolental fibroplasia caused by hyperoxia can be prevented only by monitoring arterial pO2 during oxygen therapy of the newborn. The accuracy of continuous transcutaneous measurement of arterial pO2 is questionable during unstable phases of adaptation to extrauterine life, and measurement of arterial pO2 with the help of an umbilical arterial catheter (or intraarterial pO2 electrode) may therefore by mandatory. Transcutaneous continuous monitoring of paCO2 appears to afford excellent results and will soon be an indispensable adjuvant for the therapy of newborns with respiratory problems.

[Pediatric anesthesia (author's transl)].

The progress of understanding the special physiology and pathology of the small child, as well as the perfection of the technical equipment for pediatric anesthesia are responsible for the fact that today practically every child even during very difficult surgical interventions can be kept with security in general anesthesia. A survey of the problems occuring in pediatric anesthesia includes the following items: preoperative examination, preparation for anesthesia and surgical intervention, techniques of anesthesia, special dangers for the newborn and small children (fluid ratio, decrease of body temperature, hypoglycemia) and postoperative treatment. The author comes to the conclusion that the best conditions for general anesthesia of the small child are only present in a children's hospital where the necessary infrastructure is available.

Laparoscopy in childhood.

The indications and technique for laparoscopy in childhood are discussed. During the last 5 years 59 laparoscopies were carried out in the Surgical Department of the University Children's Hospital, Zürich, Switzerland, These cases are described in some detail. No complications were encountered.

The use of nasal CPAP in newborns with respiratory distress syndrome.

The efficiency of applying continuous positive airway pressure (CPAP) by the nasal route was retrospectively nalyzed in 32 newborns with RDS (23 uncomplicated HMD with additional cardiac or pulmonary complications and 7 RDS of non-hyaline membrane etiology) who underwent nasal CPAP treatment at the Kinderspital Zurich from 1972--1974. 16 of the 23 infants with uncomplicated HMD were successfully treated with CPAP. They showed a significant rise in PaO2 as well as a significant drop in respiratory frequency during nasal CPAP application, the PaCO2 did not change significantly.

[The technic of infusion treatment and parenteral feeding in newborns and infants].

The various infusion techniques used in The Children's Hospital of the University Zurich are described. The undoubted advantages in the application of central venous catheters have to be weighed against some dangers, which exist even when using the best techniques. Infection is the most important danger.