Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring

Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.     

Malathion and malaoxon: histopathology reexamination of the National Cancer Institute's carcinogenesis studies

In the early 1970s the National Cancer Institute (NCI) studied malathion and the oxygen analog, malaoxon, for possible carcinogenicity in rats and mice. The results from these long-term studies were reported in three NCI Technical Reports with the conclusions that neither chemical was shown to be carcinogenic in rodents. In response to the renewed public health interest and concern about the increasing use of malathion in agriculture and especially its use to eliminate Mediterranean fruit fly infestations in California and Florida during the 1980s, the National Toxicology Program (NTP) in consultation and agreement with the NCI reevaluated the histopathology of the NCI studies of malathion in Osborne-Mendel and Fischer 344 rats and of malaoxon in Fischer 344 rats. The NTP histopathology reexamination confirmed the original NCI interpretative conclusions that malathion was not carcinogenic. For the malaoxon study, the only difference between the original and subsequent interpretations was for C-cell neoplasms of the thyroid gland, in that the NTP concluded there was equivocal evidence of carcinogenicity for male and female F344 rats.     

Community hospital administration of intravenous tissue plasminogen activator in acute myocardial infarction: improved timing, thrombolytic efficacy and ventricular function

As an investigational fibrinolytic agent for acute myocardial infarction, intravenous recombinant tissue-type plasminogen activator (rt-PA) has been administered primarily in tertiary care and university centers. To determine the value of early initiation of such therapy, two satellite community hospital emergency rooms were established for use of rt-PA and the experience was compared among 142 consecutive patients who were transferred to a regional center for acute cardiac catheterization after intravenous rt-PA therapy. In Group I (n = 19), patients received rt-PA after interhospital transport to the regional center, but before cardiac catheterization. In Group II (n = 70), rt-PA therapy was initiated by the helicopter physician and nurse team after their arrival at the local community hospital emergency room. Group III patients (n = 53) had rt-PA administered in the local community hospital by the emergency room physician. Group III patients had earlier initiation of therapy (2.1 +/- 0.8 hours in Group III versus 3.8 +/- 1.2 hours in combined Groups I and II, p less than 0.001) and an increased rate of infarct vessel recanalization on the 90 minute coronary angiogram (81 in Group III versus 67% in combined Groups I and II, p = 0.057). The patients in Group III had a higher acute left ventricular ejection fraction (54 +/- 8% versus 50 +/- 9.5% in combined Groups I and II, p less than 0.01) and a trend toward an increased 7 day ejection fraction (55.5 +/- 9% versus 51.7 +/- 9.5%, respectively, p = 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)     

The anabolic actions of growth hormone and thyroxine on protein metabolism in Snell dwarf and normal mice

The individual effects of GH and thyroxine (T4) on protein metabolism were determined in dwarf and normal mice in vivo. The hormone deficiencies of dwarf mice (low serum concentrations of GH and T4) resulted in decreased protein synthesis rates in skeletal muscle and liver, but no difference in synthesis rates in heart. The efficiency of synthesis (g protein/g RNA per day; KRNA) was lower in all three tissues in dwarf compared with normal mice, but effects on RNA concentration were not consistent; there was no change in muscle, a decrease in liver and an increase in heart. Treatment of dwarf mice for 9 days with either human GH or T4 caused increases in body weight and length. Protein synthesis rates were increased in muscle, liver and heart by either hormone, though much more so with T4 than GH. In muscle and liver both GH and T4 treatment resulted in an increased RNA concentration, but T4 treatment also increased KRNA. In heart, both GH and T4 increased KRNA with no change in RNA concentration. GH caused no significant changes in protein degradation rates so that growth rates were increased. T4 increased degradation rates so that there was no increased net growth in muscle or liver; in heart, T4 did induce increased growth despite the large increase in degradation rate. Tibial length was increased by both hormones; GH treatment of dwarf mice also increased cartilage sulphate incorporation on day 9, but T4 treatment did not, suggesting that bone growth is transient with T4 treatment. Normal mice showed no changes in growth or tissue protein metabolism in response to GH, but following T4 treatment there was increased protein turnover due to higher tissue RNA concentrations, although only heart growth was increased. Thus normal mice showed almost no net response to GH or T4, but dwarf mice showed a large response to both hormones. The response was different, however, in that GH caused concomitant increases in growth rates whereas T4 altered body tissue proportions.