March 2000: A 16 year old female with a cerebellar mass.

The March COM: A 16 year old female presented with headaches and cerebellar dysfunction. MR images showed a mass lesion of the right cerebellar hemisphere with mass effect on the medulla. The mass exhibited a striated pattern of alternating isointense and hypointense zones on T1-weighted images that did not contrast enhance. The lesion was hyperintense on T2-weighted images, and also showed a striated appearance. A suboccipital craniotomy and resection of the lesion was performed. Microscopically, the specimen consisted of widened folia and a disorganized cerebellar architectonic pattern in which the internal granular cell layer was occupied by a population of large dysmorphic nerve cell bodies. Patient's diagnosed with Lhermitte-Duclos disease must be adequately evaluated for Cowden's syndrome.

Quantitative trait loci controlling halothane sensitivity in Caenorhabditis elegans.

Genetic analysis is an essential tool for defining the molecular mechanisms whereby volatile anesthetics (VA) disrupt nervous system function. However, the degree of natural variation of the genetic determinants of VA sensitivity has not been determined nor have mutagenesis approaches been very successful at isolating significantly resistant mutant strains. Thus, a quantitative genetic approach was taken toward these goals. Recombinant-inbred strains derived from two evolutionarily distinct lineages of the nematode Caenorhabditis elegans were tested for sensitivity to clinically relevant concentrations (0.3-0.5 mM) of the VA halothane. The halothane sensitivities of coordinated movement and male mating behavior were highly variant among the recombinant-inbred strains with a range of EC50 values of 13- and 4-fold, respectively. Both traits were highly heritable (H2 = 0.82, 0.87, respectively). Several strains were found to be significantly resistant to halothane when compared with the wild-type strain N2. A major locus or loci mapping to the middle of chromosome V accounted for more than 40% of the phenotypic variance for both traits. Five weaker loci, four of which interact, explained most of the remaining variance. None of the halothane-sensitivity quantitative trait loci significantly affected behavior in the absence of halothane or halothane's potency for C. elegans immobilization, which requires 5-fold higher drug concentrations. Thus, the quantitative trait loci are unlikely to result from differences in halothane-independent (native) behavior or differences in halothane metabolism or permeability. Rather, these loci may code for targets and/or downstream effectors of halothane in the C. elegans nervous system or for modifiers of such gene products.

Defining genes that govern longevity in Caenorhabditis elegans.

We previously identified five regions on the chromosomal map of Caenorhabditis elegans, containing genes that help specify life span in this species, by comparing the genotypes of young and long-lived progeny from a cross between strains Bristol-N2 and Bergerac-BO [Ebert et al. (1993): Genetics 135:1003-1010]. Analyses of additional crosses, and of putative polymorphisms for the implicated genes, are necessary to clarify the roles of naturally occurring polymorphic alleles in determining longevity. We therefore carried out a second multigenerational cross, between strains Bristol-N2 and DH424 (both nonmutators at 20 degrees C), to create a different heterogeneous recombinant-inbred population. We again found strong evidence implicating multiple genes, which differ between the parental strains, in the determination of life span. Increased variance of survival, for F2 and homozygous F25 worms relative to F1 hybrids, is consistent with such alleles assorting randomly in the cross progeny. Moreover, chromosome mapping data corroborate the polygenic nature of this quantitative trait. Genotypes of young and very long-lived adult worms from a synchronous F15 population were determined by polymerase chain reaction, to identify the parental strain of origin for each of 10 polymorphic loci. Two regions, on chromosomes II and IV, each contain at least one gene with allelic differences in associated longevity. A recombinant-inbred Bergerac-BO x Bristol-N2 population, derived from the earlier cross between those strains, was exposed to an acute toxic level of hydrogen peroxide. Genotyping of H2O2-resistant worms implicated at least one of the five chromosomal regions previously identified in the same cross progeny as harboring a longevity-determining gene. Superoxide dismutase and catalase levels, determined for the three parental strains as they aged, confirm the existence of polymorphisms in the corresponding genes (or their regulatory mechanisms) inferred from the chromosome-II mapping data, and are consistent with the hypothesis that increased longevity is conferred by high levels of these enzymes late in life.

Genetics of aging: current animal models.

Studies are summarized for three organisms-Caenorhabditis elegans, Mus musculus, and Drosophila melanogaster-utilizing three distinct approaches to the identification of longevity-determining genes: the analysis of mutations that affect life span, the use of transgenic animals to assess the effects of specific gene expression on longevity, and selective breeding to identify naturally occurring allelic variations between strains that have differential effects on life span. Correlative studies of age-dependent changes in physiology, or in cellular and molecular constituents, generally cannot discern cause from effect. In contrast, analyses of genetic influences on longevity can permit underlying mechanisms to be reliably inferred; because genotype remains essentially constant throughout life, longevity comparisons of animals differing only in genetic constitution must reflect the effects of genes on long-term survival. Understanding the genetic regulation of life span may thus lead to methods of intervention in age-associated deterioration and disease.

Strain evolution in Caenorhabditis elegans: transposable elements as markers of interstrain evolutionary history.

Evolutionary relationships across taxa can be deduced from sequence divergence of proteins, RNA, or DNA; sequences which diverge rapidly, such as those of mitochondrial genes, have been especially useful for comparisons of closely related species, and--within limits--of strains within a species. We have utilized the transposable element Tc1 as a polymorphic marker to evaluate the evolutionary relationships among nine Caenorhabditis elegans strains. For five low-Tc1-copy strains, we compared patterns of restriction fragments hybridizing to a cloned Tc1 probe. Twenty of the 40 Tc1 insertion sites thus characterized were common to all five strains, and so presumably preceded strain divergence; the 20 differential bands were used to construct a maximum-parsimony tree relating these strains. In four high-copy-number stocks (three wild-type strains and a subline), we determined occupancy of 35 individual Tc1 insertion sites by a polymerase chain reaction assay. Surprisingly, the high-copy strains share a common subset of these Tc1 insertions, and the chromosomal distribution of conserved Tc1 sites is "clustered" with respect to the other elements tested. These data imply a close evolutionary relationship among the high-copy strains, such that two of these strains appear to have been derived from the highest-copy-number lineage (represented by two stocks) through crossing with a low-Tc1 strain. Abundances of Tc1 elements were also estimated for the four high-copy-number stocks, at approximately 200-500 copies per haploid genome, by quantitative dot-blot hybridization relative to two low-copy strains. Annealing with 32P-labeled probes corresponding to full-length Tc1, an oligonucleotide within the Tc1 terminal inverted repeats, and an internal Tc1 oligonucleotide, gave essentially identical results--indicating that Tc1 termini exist in the genome primarily as components of full-length Tc1 elements. A composite evolutionary tree is proposed, based on the locations and numbers of Tc1 elements in these strains, which is consistent with a four-branch intraspecific tree deduced previously by maximum-parsimony analyses of mitochondrial sequence changes; it also serves to elucidate the evolutionary history of transposon mobility.

Longevity-determining genes in Caenorhabditis elegans: chromosomal mapping of multiple noninteractive loci.

We have used chromosome mapping with polymorphic markers to define genetic components governing life span in the nematode Caenorhabditis elegans. A complex recombinant-inbred population was derived from an interstrain cross, yielding > 1000 genotypes, each a composite of homozygous segments from the two parental strains. Genotypes were analyzed for the last-surviving 1-5% of worms in aging cohorts, and for young controls, by multiplex polymerase chain reaction using polymorphic markers to distinguish the parental alleles. We identified five regions of the genome at which one parental allele was significantly enriched in long-lived subpopulations. At four of five loci, the same alleles were selected in aging cohorts maintained under two different conditions, implying that these genes determine life span in differing environments.

Flexner's model and the future of medical education.

Less attention has been paid to Flexner's educational philosophy as compared with the recommendations he made to reform American medical education in Bulletin No. 4 of the Carnegie Foundation, the so-called "Flexner Report." His philosophy begins with the education of the child, having much in common with the educational theories of John Dewey, and is based on learning by observing and doing. Flexner believed that all education should be utilitarian and should prepare the individual for the responsibilities of citizenship and for an occupation or a profession. He also believed that general education lasted too long in this country. Based on Flexner's educational philosophy rather than the four-year medical school model that bears his name, the education of the physician is reexamined. Recommendations are made concerning the interface between the last two years of college and the first two years of medical school that would better equip the future physician to face the complexities of medical practice in the next century. Further, if medical schools were given responsibility for graduate medical education, as has been recommended by prestigious committees in the past, it would be possible to integrate the medical school clinical years with those of residency training and thereby improve the educational experience. A consideration of the education of the physician as a continuum, beginning in the third year of college and ending with the conclusion of residency training, also would be entirely consistent with Flexner's educational views.(ABSTRACT TRUNCATED AT 250 WORDS)

The new health era.

Medical care is unlike any other service or commodity; everyone requires it, but not everyone can afford it. As a result, we all must decide how much we are willing to pay individually and collectively. The following article examines the unique factors shaping our current health care system and those factors likely to mold our health care system in the face of a new era.

Academic health centers.

There are 123 academic health centers in the United States, and they are markedly diverse in organization and function. Some have large research programs, others emphasize the education of nurses and allied health professionals, but all have one characteristic in common--namely, the dominant role of the medical school-teaching hospital combination. Their evolution has been shaped to a great degree by four federal initiatives: funding of research and research training by the National Institutes of Health, legislation that permitted close relations between Veterans Administration hospitals and medical schools, health-manpower legislation, and Medicare and Medicaid. Although academic health centers were created to foster the integration of structure and function, federal funding has always been categorical in support of research, teaching, or patient care. No federal funding was ever intended to stabilize the overall academic health center as an institution. This mattered little during a period of expansion, but the future of academic health centers is now uncertain in a period of federal cutbacks, rising health-care costs, and worry about an oversupply of physicians. Academic health centers must enter a new phase of institutional planning for which they are ill equipped. Special interests must be submerged for the good of the whole, diversity must be encouraged, and each center should exploit its own special strengths.