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. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

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. C. glutamicum cells harbouring pck on plasmid showed about tenfold higher specific PEP carboxykinase activities than the wildtype. Inactivation of the chromosomal pck gene led to the absence of PEP carboxykinase activity and the inability to grow on acetate or lactate indicating that the enzyme is essential for growth on these carbon sources and thus, for gluconeogenesis. The growth on glucose was not affected. Examination of glutamate production by the recombinant C. glutamicum strains revealed that the PEP carboxykinase-deficient mutant showed about fourfold higher, the pck-overexpressing strain two- to threefold lower glutamate production than the parental strain. Inactivation and overexpression of pck in a lysine-producer of C. glutamicum led to an only 20% higher and lower lysine accumulation, respectively. The results show that PEP carboxykinase activity in C. glutamicum is counteractive to the production of glutamate and lysine and indicate that the enzyme is an important target in the development of strains producing amino acids derived from citric acid cycle intermediates.

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. Vomiting occurred in 34.4%, nausea in 39.3% of the patients. Patients < 2 years of age and boys > 13 years vomited rarely, whereas girls > 13 years vomited frequently. The use of propofol was associated with a decreased rate of PONV. Administration of drugs for reversal of neuromuscular blockade, postoperative opioids and certain operative procedures were associated with an increased rate of PONV. Patients with a history of motion sickness and or previous PONV also had an increased rate of PONV. The majority of the patients perceived PONV as a very unpleasant experience. Possible measures to reduce its incidence include: administration of prophylactic antiemetic drugs for high-risk patients (3-13 years, girls > 13 years, history of motion sickness and or previous PONV) who are undergoing surgical procedures with a high incidence of PONV. Adjustment of anaesthetic technique as wider use of propofol, NSAIDs or regional analgesia instead of opioids for postoperative pain relief and avoidance of neuromuscular reversal agents if possible.

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. Echocardiography showed endocarditis of the mitral valve and diffuse myocarditis. The heart failure resolved under steroid treatment. Our experience supports the early use of steroids in treating myocarditis due to NLE. Intrauterine steroid treatment in the presence of fetal hydrops and congenital heart block is discussed.

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 (31.4%), bilateral vocal cord paralysis (22.2%), congenital airway malformations (22.2%) and tumours (11.1%). No epiglottis and no emergency situation had to be managed by tracheostomy. Operation was uneventful in all, but 8 patients (7.4%) developed a pneumothorax in the postoperative period. Twenty-one (19.5%) had severe complications during the cannulation period (tube obstruction in 11 patients with cardiorespiratory arrest in 4; dislocation of the tube in 6 patients). Fifteen patients (13.8%) had severe complications after decannulation (2 had a cardiorespiratory arrest); all 15 had to be recannulated. At the end of the study period 85 patients (78.7%) were successfully decannulated with a median period of tracheostomy of 486 days (8 days-6.6 years). The median hospital stay was 159 days (13 days-2.7 years). All patients could be discharged. Eight patients (7.4%) died but no death was related to tracheostomy. In summary the mortality rate is lower than reported in previous reviews and tracheostomy is a safe operation even in small children but cannula-related complications may lead to life-threatening events. The management of tracheostomized small children and infants in a highly staffed and monitored intensive care unit has allowed better handling of complications and has resulted in a reduction in cannula-related deaths.

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. In spite of multiple surgical excisions and topic treatment with 5-fluorouracil the papillomata extended to the lung parenchyma. At the age of 16 years he developed a squamous-cell carcinoma of the lung and died 4 months later. Transformation to pulmonary carcinoma is a rare complication in non-irradiated patients with lung papillomatosis. We found only 11 similar cases in the literature.

[Polyneuropathy and fasciitis in eosinophilia-myalgia syndrome]. / Polyneuropathie und Fasziitis beim Eosinophilie-Myalgie-Syndrom (EMS).

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. Reporting on an own case and reviewing the literature, clinicopathological aspects and the problems of treatment are discussed. In contrast with the majority of published cases, which showed predominance of axonal damage, our patient displayed the clinical and electro-physiologic characteristics of demyelinating neuropathy.

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. This method consists of extreme haemodilution, combined with mild hypothermia and controlled hypotension. After induction of anaesthesia the haematocrit is reduced to 0.20-0.25 by withdrawal of the patient's blood and replacement with Ringer's Lactate in a 3:1 Ringer's blood ratio. The patient's own blood is retransfused if the haematocrit falls below 0.12-0.14 or at the end of surgery. In 12 cases an intraoperative blood recovery system (Cell Saver) was used as an additional autotransfusion technique. During haemodilution no acidosis or rise in serum lactate was found. If the haematocrit fell below 0.20, there was a significant fall of central venous oxygen saturation attributed to increased tissue oxygen extraction. During the first 12-24 postoperative hours all patients showed peripheral oedema and massive diuresis with a tendency to hypovolaemia. In this period close monitoring in the intensive care unit was necessary. Haematocrit and reticulocyte count normalised within 4 weeks. Compared to an earlier series of spondylodesis, wherein all patients received banked blood, homologous blood transfusion was reduced by about 75%. This was due not only to autotransfusion techniques, but also to painstaking surgical haemostasis and restrictive indications for homologous 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. This is the first family with both mentally retarded and nonretarded affected members with congenital laryngeal abductor paralysis. Inheritance is most likely autosomal dominant with variable expression, but autosomal recessive inheritance, with both parents carriers and the mother an affected homozygote, and X linked inheritance are also possible.

[The collecting principle in pediatrics and neonatology]. / Das Holprinzip in der Pädiatrie und Neonatologie.

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. Our statistics from the last 12 years show an increasing number of transports, with the majority of patients being referred from peripheral hospitals.

[Activities of intensive care units in 1986]. / Activité des unités de soins intensifs en 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. Sixteen isolated fetal minipig lungs of day 95 (85% of the total gestation period) were used. From one pair of lungs one lung served as control (group 1), whereas the other was treated with DPPC (group II). In both groups the lungs were rinsed first with a fluorocarbon (FC-72, surface tension 12 mN/m). This maneuver was followed by an artificial ventilation with an aerosol of either salt solution (group I) or DPPC (group II) for 40 min. To characterize lung mechanics, static pressure volume curves were registered at 0, 20, and 40 min after fluorocarbon lavage. Airway opening pressure (pi), end-inspiratory volume (vi), and weight-specific end-inspiratory lung compliance (ci) were investigated. As biochemical parameters of the lungs we determined phospholipidphosphate content and DPPC, sphingomyelin (SM), and lysophosphaditylcholine (LPC) of the lung tissue. Significant differences were found with regard to phospholipidphosphate and DPPC content. No difference was seen in static pressure volume diagrams at the end of the investigation period.

[Continuous monitoring of blood gases in newborn infants]. / Die kontinuierliche Uberwachung der Blutgase beim Neugeborenen.

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. Since the expense of monitoring is high, oxygen therapy and management of respiratory insufficiency in the newborns concerned should be transferred to centers for neonatal intensive care.

[Pediatric anesthesia (author's transl)]. / Kinderanästhesie

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. The pediatric anesthesist strongly wish therefore that also the specialists like the ophthalmologist make use of the specialised children's hospital for operative purposes.

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.