A revised model of DNA packaging into chromosomes is presented. Its features are consistent with observed structural dimensions and the molecular periodicities related to transcription, replication and matrix attachment domains. Thetransitions between euchromatic, heterochromatic and metaphase states are explained simply. Molecular and physical properties of chromosomal bands, and their correlation with specific DNA sequence motifs are discussed.Key terms: Chromatin, chromosome structure, matrix, replication, Giemsa bands, repeated DNA The higher order molecular and physical structure of chromosomes is still poorly understood. The winding of the DNA double helix around histones to form 10 nm thick nucleosomes or "beads on a string," and the subsequent coiling of nucleosomes into solenoids of -30 nm x 10 nm is by now well-established. Each solenoid turn however encompasses only -1.2 kb of DNA, and is too small to embrace complex transcriptional and replication domains that may span several hundred kilobases of DNA. These larger "functional" units of DNA are likely to be arranged into hierarchical structures that can be recognized and conveniently utilized in a n orderly fashion. On a purely structural level, the delineation of metaphase chromosome bands by Giemsa staining suggests that such hierarchies exist; Giemsa bands encompass megabase (Mb) stretches of DNA and are not meaningless artifacts; for example, Giemsalight bands are preferentially digested by trypsin, indicating structural andior molecular components are specifically organized in these compartments, and overall binding patterns may be conserved in evolution (27). Furthermore, domains of similar large size, that may correspond to Giemsa bands, are involved in sister chromatid exchanges, translocations and replication. Sam Latt made many original contributions to the molecular organization of the genome, and one of his eminent contributions was the delineation of sister chromatid exchanges (32). In his honor, we present a physical model of chromosome structure that encompasses units of this size.We here build an updated model that incorporates the longer features of molecular gene organization that have become apparent in the last 10 years. Such features include units that range in size from very long linear lengths of DNA, as defined by chromosome banding techniques, pulse-field gel electrophoresis (PFGE), and high-resolution non-isotopic in-situ hybridization, through smaller DNA lengths of 30-120kb that periodically attach to matrix proteins and replication complexes. To date, no model of chromosome structure adequately addresses the folding or compaction of these longer DNA lengths in both interphase and metaphase chromosomes of known dimensions. Since these dimensional constraints are essential to any realistic model of chromosome folding, we first address the actual sizes of chromosome domains i n both interphase and metaphase chromosomes. The structure of interphase chromosomes is pivotal, since interphase cells carry out key functions such as...

Seasonal and climatic variations have been linked to the occurrence of some types of cerebrovascular disease; however, the conditions that lead to intracranial aneurysm rupture are not known. The purpose of the present study was to determine whether seasonal and climatic conditions are related to intracranial aneurysm rupture. Data provided by the Connecticut Health Information Management and Exchange were analyzed for all patients with a primary diagnosis of aneurysmal subarachnoid hemorrhage (SAH) for the fiscal years 1981, 1983, 1985, 1987, 1988, and 1989. Patient records were correlated with climatic conditions for the years 1981 to 1989 obtained from the National Climatic Data Center, National Oceanic and Atmospheric Administration, National Environmental Satellite Data, and Information Service. During the time periods studied, 1487 patients with a primary diagnosis of aneurysmal SAH were treated by reporting hospitals. Seasonal variation in the incidence of aneurysmal SAH and admission clustering were observed but differed significantly between men and women. Men showed a single large peak in late fall (Roger's r = 11.5, p < 0.005), whereas women had an annual peak occurring in late spring (Roger's r = 10.3, p < 0.01). Substantial climatic change occurred during the 72 hours prior to 10 of the 14 clusters of men who were admitted (p < 0.01, Yates' corrected chi-square 7.33, df = 1). In contrast, clusters of women admitted were not related to preceding climatic change (p > 0.25, Yates' corrected chi-square 0.06, df = 1). Hospital admissions for aneurysmal SAH display seasonal fluctuation, with women showing a different seasonal pattern from men. Changing climatic conditions precede aneurysm rupture in men but not in women, which suggests that weather is causally related to aneurysm rupture in men, and that factors that lead to aneurysm rupture in women may be different from those in men. These data do not explain why weather fronts or gradients are associated with aneurysm rupture in men.

By in situ hybridization, short interspersed repeated DNA elements (SINEs), exemplified by Alu repeats, are located principally in Giemsa-light human metaphase chromosome bands. In contrast, the L1 family of long interspersed repeats (LINEs) preferentially cluster in Giemsa-dark bands. These SINE/LINE patterns also generally correspond to early and later replication band patterns. In order to provide a molecular link between structurally visible chromosome bands and a framework of interspersed repeats, we investigated patterns of SINE and LINE hybridization using pulse-field gel electrophoresis (PFGE). Interspersed SINEs and LINEs hybridize with high intensity to specific size fragments of 0.2-3 megabase pairs (Mb). Using appropriate restriction enzymes and pulse-field conditions, a number of fragments were delineated that were either SINE or LINE rich, and were mutually exclusive. Control studies with a human endogenous retroviral repeat that is related in sequence to the major LINE family, delineated a subset of fragments of 0.07-0.4 Mb with unequal intensity. Thus these less numerous repeats also appear to cluster selectively in DNA domains that are larger than a chromosome loop (60-120 kb). In summary, PFGE studies independently confirm the clustering of interspersed repeats on contiguous DNA loops. Selective clustering of repeat motifs may contribute to special structural or functional properties of large chromosome domains, such as chromatin extension/condensation or replication characteristics. In some cases the DNA fragments defined by these repeats approach the size of tandem satellite arrays.

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Over a 24-month period, 291 patients were consecutively admitted to the West Haven Veterans Administration Medical Center with new ischemic neurological symptoms. Of these, 90 patients (31%) developed ischemic neurological symptoms while taking aspirin (aspirin treatment failure). Of those in whom aspirin treatment failed. 66 patients had ischemic symptoms in the distribution of the carotid artery. Aspirin treatment failed in 21 patients with severe carotid stenosis (&gt;75% stenosis). Eleven of these 21 patients had cerebral infarctions while taking aspirin, and 7 of these 11 infarcts occurred without the prior warning of transient ischemic attacks. Aspirin treatment failed in 45 patients with lesser degrees of carotid stenosis. Transient ischemic attack without permanent ischemia was the most common manifestation of failure in these patients. Infarction occurred in only 12 of these 45 patients and in only 4 patients did infarction occur without warning. We conclude that patients with symptomatic high-grade carotid stenosis (&gt;75%) in whom aspirin treatment failed are likely to suffer an infarct without warning as the first sign of treatment failure (P&lt; 0.033). We suggest that this subgroup of patients should be considered for alternative forms of therapy.