Effect of A-ring modifications on the DNA-binding behavior and cytotoxicity of pyrrolo[2,1-c][1,4]benzodiazepines.

Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure-reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1, 4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1, 4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration-oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs.     

Methods of measuring susceptibility of anaerobic bacteria to trovafloxacin,including quality control parameters

Three methods approved by the National Committee for Clinical Laboratory Standards for testing the susceptibility of anaerobic bacteria were used to evaluate the fluoroquinolone, trovafloxacin. The methods gave essentially comparable results with 126 anaerobes and with three quality control strains. A collaborative study defined the quality control range for trovafloxacin MICs. Trovafloxacin had good in vitro activity against the more common anaerobes (MIC 90 <- 2.0 (g/ml).Trovafloxacin (CP-99,219) is a fluoroquinolone with a broad spectrum of antibacterial activity (1–3). Its in vitro spectrum includes many anaerobic bacteria (4).The National Committee for Clinical Laboratory Standards (NCCLS) currently recommends three different methods for testing the susceptibility of anaerobic bacteria (5). The standard reference method is an agar dilution procedure using Wilkins-Chalgren agar. Two alternative methods are an agar dilution technique using Brucella blood agar and a microdilution procedure using a broth version of Wilkins-Chalgren medium. It is important to determine whether these three procedures actually produce identical test results with each antimicrobial agent likely to be tested against anaerobes.     

A cold chain friendly to people ... and the environment

The vaccination cold chain makes vaccination possible even in the most remote areas of the tropics. Efforts to achieve the World Health Organization's goal of 90% full vaccination of the world's children by the year 2000 have led to the provision of more than 2000 vaccine refrigerators in formerly war-torn Ethiopia (which has achieved 65% coverage) and 124 solar medical refrigerators in Eritrea (which has 44% coverage). Many more medical refrigerators will be necessary to extend the cold chain to those who need it most, and the cold chain requires trained workers to transport the refrigerated vaccines in ice packs kept at the correct temperature. Each ice pack should have a cold chain monitor card that changes color to indicate temperature variations and an attached vial that shatters if it becomes overfrozen. Solar-powered medical refrigerators are reliable and cost effective, but their production has slowed because of pressure to make them free of CFCs. Very few solar models have been approved and tested by the World Health Organization; one is the DULAS VC150F, which was developed over 10 years ago. In order to generate support for solar medical installations, DULAS also offers the training integral to maintenance of a cold chain.     

Biological reaction to carbon fiber implants: the formation and structure of a carbon-induced "neotendon"

In 43 young rabbits, the tendo Achilles and flexor digitorum longus tendon were excised and replaced by filamentous carbon fiber. Tendo-Achilles in controls was repaired by silk or nylon sutures or left without replacement. Concurrent excision of the posterior tibial nerve was performed in one group of the carbon-replacing tendo-Achilles operations. When fully functioning, carbon-induced "neotendon" rapidly developed from young fibroblastic tissue outgrowths of the loose mesenchymal tissue of the perineurium and adventitia of the blood vessels in the adjacent neurovascular bundle. Silk or nylon replacement of the excised Achilles tendon did not lead to successful production of a new substitute. Carbon fibers were unsatisfactory for replacement implants for the flexor digitorum longus tendons.     

Linear model for visual-vestibular interaction.

The results of experiments are evaluated in terms of a simple model for the interaction of eye movement responses to simultaneous optokinetic and vestibular stimuli. The model predictions agree with the results of these experiments and explain many clinical observations concerning the effect of vision on nystagmus. The model accounts for the dominance of the visual system's response over the vestibular system's response at low frequencies. It also accounts for the inability of patients with decreased smooth pursuit system response to suppress the vestibulo-ocular reflex during simultaneous optokinetic and vestibular stimulations. The model provides useful information for the design of combined optokinetic and vestibular stimuli for test vestibulo-ocular reflexes.     

A survey of obstetrical anaesthesia practice,teaching and research in canadian university departments of anaesthesia

A report is presented of a questionnaire survey of obstetrical anaesthesia practice patterns, academic structure, resident teaching and research programmes in Canadian University Departments of Anaesthesia. Replies were received from 13 of the 16 departments, representing 24 university-affiliated hospitals. It is apparent that the majority of these hospitals do not have adequate obstetrical anaesthesia coverage. In most instances the delivery suite is covered by the anaesthetists on duty in the operating rooms. While epidural analgesia is widely used during labour, there are some hospitals where it still has a limited use, or is not used at all. Caesarean sections are still largely done under general anaesthesia in most reporting hospitals, with a few institutions reporting an increasing use of regional (mainly epidural) anaesthesia. Resident training in this branch of anaesthesia is felt to be deficient, based on the reports from many hospitals that resident staff are frequently not in attendance at deliveries; and on the evident failure in the majority of institutions to utilize their clinical material for teaching purposes. Research programmes in obstetrical anaesthesia are rare. The most common reason cited was the difficulty experienced in obtaining research funds. It is suggested that the major problems in obstetrical anaesthesia service, teaching and research are:

1. Economic,
2. Lack of interest, and
3. Lack of manpower.

It is recommended that consideration be given to:

1. Consolidation of obstetrical services into larger units wherever practical.
2. Creation of more geographic full time appointments in obstetrical anaesthesia.
3. More efficient use of clinical material for teaching.
4. Development in individual hospitals of prenatal and public education programmes.

     

The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischemia

Summary The neuronal response to complete cerebral ischemia (CCI) of 5–15 min duration was evaluated at the light and electron microscopic level subsequent to postischemic recirculation periods of up to 60 min. Following postischemic reperfusion, the homogeneous neuronal changes characteristic of permanent CCI were modified into a heterogeneous pattern of selectively vulnerable neuronal responses. Four basic types of neuronal injury were represented within this heterogeneous neuronal population. The Type I neuronal response was most numerous and consisted of chromatin clumping, nucleolar condensation and a breakdown of polysomes. This response may represent a reversal of some of the neuronal changes observed after permanent CCI. In addition to the above changes, Type II neurons contained swollen mitochondria and Golgi saccules which appeared as microvacuoles under the light microscope. Type III neurons displayed varying degrees of neuronal shrinkage and numerous swollen mitochondria. Type IV neurons were markedly shrunken and electron-dense with few identifiable subcellular structures. The distribution of Type I neurons was random but the other neuronal responses occurred in selectively vulnerable brain regions. The number of Type II, III, and IV neurons increased with extended insult durations but were unaffected by the length of recirculation. Ten minutes of CCI represented the threshold for a significant increase in the number of severely altered neurons. These findings suggest that considerable neuronal injury may be present after 10–15 min of CCI, and the lack of a recirculation period following CCI appears to afford the brain parenchyma an extensive degree of structural protection.Supported by PHS Grant NS-12587