Some practical improvements in the continual reassessment method for phase I studies

The Continual Reassessment Method (CRM) is a Bayesian phase I design whose purpose is to estimate the maximum tolerated dose of a drug that will be used in subsequent phase II and III studies. Its acceptance has been hindered by the greater duration of CRM designs compared to standard methods, as well as by concerns with excessive experimentation at high dosage levels, and with more frequent and severe toxicity. This paper presents the results of a simulation study in which one assigns more than one subject at a time to each dose level, and each dose increase is limited to one level. We show that these modifications address all of the most serious criticisms of the CRM, reducing the duration of the trial by 50-67 per cent, reducing toxicity incidence by 20-35 per cent, and lowering toxicity severity. These are achieved with minimal effects on accuracy. Most important, based on our experience at our institution, such modifications make the CRM acceptable to clinical investigators.     

Lumbosacral lipomas with spinal bifida

Spinal dysraphism is usually accompanied with lumbosacral lipoma. The neurological deficits such as lower extremities sensorimotor disturbances, bowel and bladder dysfunction are produced by tethering, compression of lipoma and direct transmission of external force on the spinal cord during growth period. 25 patients treated surgically at our hospital between May, 1985, and January, 1993, were reviewed. Surgical approach was designed for debulking the lipomatous mass, untethering and decompressing the cord, repairing the dural defect and paraspinal muscle cleft. 2-59 months (mean 37.5 mons) after operation the 2 patients whose neurological system were normal before operation remained intact. In other 23 patients, bowel function recovered in 75%, active urination restored and improved in 66.2%. Motor dysfunction and paresthesia of the lower extremities alleviated in 78.3%. A case of mild uremia returned to normal and another moderate case improved. None was deteriorated by the operative procedure except one case in which a posterior nerve root was injured.     

Segregation of germ granules in living Caenorhabditis elegans embryos: cell-type-specific mechanisms for cytoplasmic localisation

Extrinsic allergic alveolitis and pulmonary sarcoidosis are granulomatous diseases of the lung for which clinical presentation and anatomic site of granuloma formation differ. Extrinsic allergic alveolitis is caused by inhaled antigens, whereas the nature and source of the inciting antigen in sarcoidosis is unknown. To test the hypothesis that the route via which antigen is introduced to the lung contributes to the clinicopathological presentation of pulmonary granulomatous disease, rats immunized with intravenous (i.v.) Corynebacterium parvum were challenged after 2 weeks with either intratracheal (i.t.) or i.v. C. parvum. The granulomatous inflammation elicited by i.t. challenge predominantly involved alveolar spaces and histologically simulated extrinsic allergic alveolitis. In contrast, the inflammation induced by i.v. challenge was characterized by granulomatous angiitis and interstitial inflammation simulating sarcoidosis. Elevations of leukocyte counts and TNF levels in bronchoalveolar fluid, which reflect inflammation in the intra-alveolar compartment, were much more pronounced after i.t. than after i.v. challenge. Tumor necrosis factor, interleukin-6, CC chemokine, CXC chemokine, and adhesion molecule mRNA and protein expression occurred in each model. In conclusion, i.t. or i.v. challenge with C. parvum in sensitized rats caused pulmonary granulomatous inflammation that was histologically similar to human extrinsic allergic alveolitis and sarcoidosis, respectively. Although the soluble and cellular mediators of granulomatous inflammation were qualitatively similar in both disease models, the differing anatomic source of the same antigenic challenge was responsible for differing clinicopathological presentations.     

Premature separation of centromere and aneuploidy: an indicator of high risk in unaffected individuals from familial breast cancer families?

OBJECTIVES: Injury is the leading cause of death in the male working population of Brazil. An important fraction of these deaths are work related. Very few cohort studies of steel workers, and none from developing countries, have reported on mortality from injuries. This paper analyses mortality from work and non-work related injuries among Brazilian steel workers. METHODS: Deaths during employment from 1 January 1977 to 30 November 1992 were analysed in a cohort of 21,816 male steel workers. Mortality rates specific for age and calendar year among the workers were compared with those of the male population of the state where the plant is located. Work related injuries were analysed by comparing the mortality rates for different subgroups of the cohort. RESULTS: The number of deaths (391) was less than half that expected based on death rates of the general population. Over 60% (242) of deaths were due to injuries. Mortality from most causes was substantially below that in the general population, but that from unintentional injury, was 50% above that of the general population. Standardised mortality ratios (SMRs) were highest for the youngest and the oldest employees and for labourers and clerical workers. Mortality from motor vehicle injury was twice that expected from population rates (SMR = 209, 95% confidence interval (95% CI) 176-244). There was a 67% fall in the age adjusted mortality from occupational injuries in the study period. CONCLUSION: The healthy worker effect in this cohort was greater than that commonly found in studies of occupational groups in developed countries, probably because of a greater socioeconomic gap between employed and unemployed populations in Brazil, and unequal distribution of health care resources. Mortality was especially high for motor vehicle injuries. The fall in mortality from occupational injuries during the study period was probably due to improvement in safety standards, increased automation, and better medical care. There is a need to investigate risk factors for unintentional injuries among steel workers, especially those due to motor vehicle injuries. Prevention of occupational and nonoccupational injuries should be a main priority in Brazil.     

Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue

Peripheral nerve injury may lead to a chronic neuropathic pain state that results from an increase in excitability of central neurons. This central sensitization is mediated via an N-methyl-D-aspartic acid (NMDA) receptor and may involve the production of nitric oxide (NO). As NO is suggested to play a role in nociceptive transmission following nerve injury, we examined for altered NO synthase activity at multiple levels of peripheral and spinal neural tissue in a rat model of neuropathic pain. Peripheral neuropathy was induced in rats (N = 12) by ligation of the left L5 and L6 nerve roots. Six other rats had sham surgery. An ipsilateral decrease in paw withdrawal threshold to mechanical stimuli confirmed the presence of a neuropathic pain state. Samples of the lumbar and thoracic spinal cords, L4, L5, and L6 dorsal root ganglia (DRGs), and the sciatic nerves were obtained from the lesioned and contralateral sides at 2 and 4 weeks after neuropathic surgery (N = 6 per group). In the lumbar spinal cord, a bilateral decrease in nitric oxide synthase (NOS) activity was observed 2 and 4 weeks after neuropathic surgery. NOS activity was increased in the ipsilateral L5 and 6 DRGs 2 weeks following neuropathic surgery. An increase in NOS activity in the DRG may be an early mechanism for inducing more central changes. The bilaterally decreased NOS activity in the lumbar spinal cord may be secondary to a negative feedback mechanism resulting from increased NO production in the spinal dorsal root ganglia. Multiple alterations in expression of NOS activity that occur in both peripheral and central processing may play a role in the pain behavior resulting from peripheral nerve injury. (Preliminary results of these studies have been presented in abstract form at the annual meetings of the Society for Neuroscience, 1994, and the American Society of Anesthesiologists, 1994).