Overcoming Radioresistance: Small Molecule Radiosensitisers and Hypoxia-activated Prodrugs.

The role of hypoxia in radiation resistance is well established and many approaches to overcome hypoxia in tumours have been explored, with variable success. Two small molecule strategies for targeting hypoxia have dominated preclinical and clinical efforts. One approach has been the use of electron-affinic nitroheterocycles as oxygen-mimetic sensitisers. These agents are best exemplified by the 5-nitroimidazole nimorazole, which has limited use in conjunction with radiotherapy in head and neck squamous cell carcinoma. The second approach seeks to leverage tumour hypoxia as a tumour-specific address for hypoxia-activated prodrugs. These prodrugs are selectively activated by reductases under hypoxia to release cytotoxins, which in some instances may diffuse to kill surrounding oxic tumour tissue. A number of these hypoxia-activated prodrugs have been examined in clinical trial and the merits and shortcomings of recent examples are discussed. There has been an evolution from delivering DNA-interactive cytotoxins to molecularly targeted agents. Efforts to implement these strategies clinically continue today, but success has been elusive. Several issues have been identified that compromised these clinical campaigns. A failure to consider the extravascular transport and the micropharmacokinetic properties of the prodrugs has reduced efficacy. One key element for these 'targeted' approaches is the need to co-develop biomarkers to identify appropriate patients. Hypoxia-activated prodrugs require biomarkers for hypoxia, but also for appropriate activating reductases in tumours, as well as markers of intrinsic sensitivity to the released drug. The field is still evolving and changes in radiation delivery and the impact of immune-oncology will provide fertile ground for future innovation.

Blind adaptive filtering for non-invasive extraction of the fetal electrocardiogram and its non-stationarities.

The objective is to extract automatically a beat-to-beat fetal electrocardiogram (fECG) from a maternal electrocardiogram (mECG) using surface electrodes placed on the maternal abdomen and to derive fetal PR, QT, QTc, and QS durations to allow early diagnosis and monitoring treatment of certain fetal cardiac disorders. mECG and abdominal noise in abdominal maternal recordings can be orders of magnitude stronger than the fECG signal and the P and T waves that are embedded in them. A two-stage blind adaptive filtering algorithm was used for fECG extraction, the first stage using frequency-domain electrocardiogram features and the second considering time-domain features. Three channels of abdominal recordings were obtained from 12 patients at 20-40 weeks of gestation. In each case beat-to-beat unaveraged fECGs were isolated. The combined filter allowed identification of diagnostically important PR, QT, and RR durations. Comparison with synthetic data is also included.

An illustrated guide to endotracheal intubation in small non-human primates.

Endotracheal intubation allows precise delivery of inhaled anaesthetic agents. Intubation in small non-human primates (less than 1 kg), is straightforward, using commercially available equipment, and careful positioning of the animal. Equipment and methods are fully described and illustrated.

Immunization with recombinant BCG-SIV elicits SIV-specific cytotoxic T lymphocytes in rhesus monkeys.

Because the transmission of HIV is likely to occur through cell-associated virus, an effective HIV vaccine should be capable of eliciting HIV-specific CTL. We have employed the simian immunodeficiency virus (SIV)/rhesus monkey model to explore the use of the attenuated tuberculosis bacillus, Calmette Guérin bacillus (BCG), as a vaccine vehicle to elicit AIDS virus-specific CTL. BCG was engineered to express SIVmac gag under the control of hsp70 regulatory sequences. Immunization with this rBCG-SIVmac gag elicited MHC class I-restricted, CD8+ SIVmac gag-specific CTL in rhesus monkeys. In fact, SIVmac gag-specific CTL could be cloned readily from peripheral blood lymphocytes of these immunized monkeys. These findings provide further evidence for the power of BCG as a vaccine vector and its continued exploration as a vehicle for eliciting HIV-specific immunity.

Laryngeal and laryngotracheoesophageal clefts: role of early surgical repair.

An uncommon congenital anomaly of the developing aerodigestive tract is the congenital laryngeal cleft and its extension, the congenital laryngotracheoesophageal (LTE) cleft. Because of the subtle findings sometimes seen with clefts confined to the larynx, the diagnosis may be difficult. The potential problems of airway obstruction and repeated aspiration frequently associated with laryngeal and LTE clefts mandate early surgical repair. Over the past 3 years, 14 patients with congenital laryngeal or LTE clefts have been managed at Children's Hospital Medical Center, Cincinnati, Ohio. This report details our experience and philosophy regarding the diagnosis and management of the condition, and presents the histopathologic findings of a case of complete LTE cleft in which surgical repair was delayed and death resulted.

Mycobacterium kansasii in a rhesus monkey.

The incidence of pulmonary disease caused by "atypical" mycobacteria has been increasing gradually in the human population since the 1950s. Mycobacterium kansasii and Mycobacterium intracellulare are the two organisms most responsible for this trend. A rhesus monkey was euthanatized and necropsied after reacting positive to mammalian Old Tuberculin on semi-annual testing. Histopathology demonstrated the presence of small numbers of acid fast organisms in pulmonary lesions. Further microbiological testing identified the causative organism as M. kansasii.

A new microprocessor-controlled anaesthetic machine.

This paper describes the development of a microprocessor controlled anaesthetic machine comprising an integrated anaesthetic apparatus and monitoring system. Following prolonged reliability trials in the laboratory, changes have been made to major components which were described in earlier publications.

Loss of evoked potentials during spinal surgery due to spinal cord hemorrhage.

The cortical somatosensory evoked potential (SEP) disappeared during corrective spinal surgery in a patient with muscular dystrophy. The patient died 18 hours after surgery. Autopsy revealed an intramedullary hemorrhage 4 mm in diameter in the posterior horn of the cervical spinal cord. Microscopically, hypoxic neurons were seen adjacent to the hemorrhagic area, implying that the lesion was at least 6 hours old. The hemorrhage corresponded to the loss of SEPs and confirms that spinal cord monitoring can detect such lesions.

Magnetic resonance brain images in schizophrenic and normal subjects: influence of diagnosis and education.

Evidence from computerized tomography (CT) suggests that schizophrenic patients may have smaller brains than normal subjects. Magnetic resonance imaging (MRI), which produces more clearly defined images than CT, was used to measure T1 and brain size of 24 schizophrenic and 24 normal subjects matched for age and sex but not for education. Two transverse images were obtained: slice 1 at the foramina of Monro and slice 2 at the widest part of the lateral ventricles. Adequate T1 instrumental reliability could not be demonstrated. Schizophrenic subjects had smaller right hemispheres (slice 1) and smaller frontal areas (slice 2) than normal subjects. However, when education was taken into account, only the left frontal area (slice 2) was smaller in schizophrenic than in normal subjects. Larger brain areas were associated with better cognitive test scores and fewer neurological signs. Cranial and body size were similar in both diagnostic groups.

A comparison of plating and traction in the treatment of tibial shaft fractures.

A consecutive series of fractures of the tibial shaft was studied over a 4-year period. A total of 115 fractures in 115 patients were found to be unstable and therefore unsuitable for immediate treatment in a plaster cast. Sixty-three fractures were treated by internal fixation using AO dynamic compression plates and 52 patients were treated by calcaneal traction. The two treatment groups were compared and it was found that overall each spent a similar time in hospital but the surgically treated group required a minimum of two admissions. The surgically treated group healed 6 weeks sooner than the conservatively treated group but there was an overall complication rate of 30 per cent related to the internal fixation. One hundred and three patients were seen for clinical review, and the incidence of joint stiffness is discussed.

Lateral mass fusion. A prospective study of a consecutive series with long-term follow-up.

A prospective study of a consecutive series of lateral mass fusion operations was undertaken between 1972 and 1982 in 144 patients, of whom 129 were available for review. The main indications for operation were persistent back pain associated with spondylolisthesis, localized degenerative disease of the lumbar spine and previous laminectomy and disc excision. The minimum follow-up was 2 years. Although 83% of patients were improved overall, the results in spondylolisthesis and degenerative disease without previous surgery were much better than in those who had previously had disc excision. A pseudarthrosis was found in 13% of patients and was significantly more likely (P less than 0.05) when fusion at more than one level was attempted. There were no serious long-term complications.

Innominate osteotomy in Perthes' disease. A radiological survey of results.

Perthes' disease involving the whole of the femoral head in 36 children was treated by innominate osteotomy. Radiographs of all cases were reviewed to see the effect of the osteotomy on the shape, the degree of acetabular cover and any subluxation of the diseased femoral head. All femoral heads which were circular before operation remained so, and over half of the previously deformed heads became circular after the osteotomy. The improved acetabular cover provided by the osteotomy resulted in a CE angle of 25 degrees or more in 92% of hips. Possible subluxation of the femoral head was studied by inspecting Shenton's line. If this was intact before operation it remained so; of the 14 which were broken before operation, 11 were restored to normal after osteotomy. We conclude that innominate osteotomy is a worthwhile procedure for Perthes' disease involving the whole of the femoral head.

Infantile autism reviewed: a decade of research.

Progress in the study of infantile autism over the past 10 years was reviewed in terms of classification and diagnosis, relation to other disorders, demographics, parental characteristics, genetics, intelligence, language, perceptual processes, behavioral characteristics, neurobiological, biochemical and pharmacological aspects, behavioral/educational treatment methodologies, prognosis, and theoretical considerations. This decade's research led to the now generally accepted position that infantile autism is a type of developmental disorder accompanied by severe and, to a large extent, permanent intellectual/behavioral deficits. However, its relationship to other forms of developmental disorders and to mental retardation remains to be delineated. Perceptual/cognitive/language defects appear central to the autistic syndrome, but the specific underlying mechanisms are unknown. Most studies indicate that autistic children have more signs of brain dysfunction than do normal children and about the same number as mentally retarded children. The overwhelming evidence suggests that te treatment of choice for maximal benefit to autistic children is a systematic, intrusive behavioral/educational approach. Yet, in spite of significant gains in almost all children treated, the typical prognostic picture is poor in terms of achieving self-supportive adulthood. The parents of autistic children have been found to be essentially similar to parents of children with organic brain disorders, and manifest no psychopathology which conceivably could induce the disorder. The vast majority of theoretical articles appearing in the 1970s proposed some from of neurobiological defect as the causative factor in autism. One of the major goals for future research is to undertake more extensive comparative studies on nonautistic brain dysfunctional children and autistic children that could yield cleared differential behavioral profiles and testable neurobiological hypotheses.