Over 50 years ago, Benedict (2) published his extensive monograph on the metabolism of fasting in man, in which he demonstrated that carbohydrate stores provide a small but significant component of the body's fuel for only the first few days. Thereafter, protein and fat are the sole sources of fuel, the former contributing 15 % of the calories and the latter the balance.The primary role of fat as fuel was apparent to Benedict and his contemporaries; it is plentiful and expendable. The significance of the protein requirement, however, was less clear; in fact, it was not fully understood until nearly 20 years later when the obligatory dependence of the central nervous system on glucose was firmly established (3). Since glycogen stores in man were known to approximate only 200 g, it was readily apparent that glucose has to be derived from protein in order to maintain cerebral metabolism during a prolonged fast. More recently, our understanding of the fasted state has been further clarified by the demonstration that free fatty acid is both the major transport form of lipid leaving adipose tissue (4, 5) and a substrate that is * Submitted for publication January 26, 1966; accepted August 4, 1966. Supported in part by grants from the U. readily utilized by liver, muscle, and many other tissues.Although the above findings provide a basis for understanding the metabolism of fasting, certain areas such as the physiologic role of hormones and the mechanisms controlling glucose production and utilization remain poorly defined. In addition, estimates of glucose turnover (6)(7)(8)(9)(10)(11)(12) or splanchnic glucose production (13-15) during a short fast all greatly exceed the amount that can be contributed by gluconeogenesis (as reflected by urinary nitrogen loss). This study was, therefore, designed to obtain base-line information concerning the metabolic and hormonal response to fasting in normal subjects and in two subjects with mild diabetes in the hope that such information would provide at least partial insight into some of these problems. In brief, we found in the normal subjects that the well-integrated release of peripheral fuels and the maintenance of blood glucose concentrations were probably related to insulin concentrations, suggesting but not necessarily proving that insulin is the primary signal responsible for fuel control during starvation. The studies also suggested that glu-, cose metabolism, particularly by brain, must be decreased in order for man to survive prolonged periods of caloric deprivation. MethodsSubjects. Six normal male subjects were selected to provide a diverse spectrum of body size and shape (Table I). Five (N1, Ns, N4, N5, and N.) were divinity students, and the sixth (N2) was a sporting-goods salesman. All were in perfect health and had been consuming an average diet estimated to contain over 250 g of carbohydrate and 80 g of protein with variable amounts of fat. Subjects N2 and N4 were intentionally selected because of a family history of diabetes; their mothers had maturity-onset...

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Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical manifestations. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors, which are resistant to conventional therapies. Experimental Design: To identify new signaling pathways involved in the malignant transformation of plexiform neurofibromas, we applied a 22,000-oligonucleotide microarray approach to a series of plexiform neurofibromas and malignant peripheral nerve sheath tumors. Changes in the expression of selected genes were then confirmed by real-time quantitative reverse transcription-PCR. Results: We identified two tenascin gene family members that were significantly deregulated in both human NF1-associated tumors and NF1-deficient primary cells: Tenascin C (TNC) was up-regulated whereas tenascin XB (TNXB) was down-regulated during tumor progression. TNC activation is mainly due to the up-regulation of large TNC splice variants. Immunohistochemical studies showed that TNC transcripts are translated into TNC protein in TNC-overexpressing tumors. Aberrant transcriptional activation of TNC seems to be principally mediated by activator protein transcription factor complexes. Conclusion:TNXB andTNC may be involved in the malignant transformation of plexiform neurofibromas. Anti-TNC antibodies, already used successfully in clinical trials to treat malignant human gliomas, may be an appropriate new therapeutic strategy for NF1.

Introduction: Myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) syndrome, a maternally inherited disorder that is among the most common mitochondrial DNA (mtDNA) diseases, is usually associated with the m.3242A.G mutation of the mitochondrial tRNA leu gene. Very few data are available with respect to prenatal diagnosis of this serious disease. The rate of mutant versus wild-type mtDNA (heteroplasmy) in fetal DNA is indeed considered to be a poor indicator of postnatal outcome. Materials and methods: Taking advantage of a novel semi-quantitative polymerase chain reaction test for m.3243A.G mutant load assessment, we carried out nine prenatal diagnoses in five unrelated women, using two different fetal tissues (chorionic villi v amniocytes) sampled at two or three different stages of pregnancy. Results: Two of the five women, although not carrying m.3243A.G in blood or extra-blood tissues, were, however, considered at risk for transmission of the mutation, as they were closely related to MELASaffected individuals. The absence of 3243A.G in the blood of first degree relatives was associated with no mutated mtDNA in the cardiovascular system (CVS) or amniocytes, and their three children are healthy, with a follow-up of 3 months-3 years. Among the six fetuses from the three carrier women, three were shown to be homoplasmic (0% mutant load), the remaining three being heteroplasmic, with a mutant load ranging from 23% to 63%. The fetal mutant load was fairly stable at two or three different stages of pregnancy in CVS and amniocytes. Although pregnancy was terminated in the case of the fetus with a 63% mutant load, all other children are healthy with a follow-up of 3 months-6 years. Conclusion: These data suggest that a prenatal diagnosis for MELAS syndrome might be helpful for at-risk families.