A novel HLA allele, HLA-A*02:393, identified in a two generation Italian family.

HLA-A*02:393 differs by a single nucleotide substitution from both A*02:26 (A524G) and from A*02:40:01 (T527A).

Frustration in smectic layers of polar Gay-Berne systems.

The main focus of the present paper is studying dipolar frustration within smectic- A(d) layers as induced by dipole-dipole interactions. Our reference point is the Gay-Berne system with kappa=4, kappa'=5, mu=2 and nu=1, which in the phase diagram shows a stable "island" of smectic- A phase with a short-range hexagonal order within each layer [Phys. Rev. E 57, 6685 (1998)]. We carry out isothermal-isobaric Monte Carlo simulations for a dipolar version of this model, where the Gay-Berne interaction is supplemented by interaction between longitudinal dipole moments. For a fixed off-center position of the dipoles we increase value of the dipole moment and follow evolution of the liquid-crystalline part of the phase diagram focusing on changes of the nematic-smectic- A phase boundaries and on structural response of the smectic- A layers. For weak dipoles only the classical smectic- A phase is stabilized, which then transforms into smectic- A(d) with layers being formed by two ferroelectrically polarized sublayers of opposite polarization. Average positions of dipoles that contribute to the polarization of a sublayer are located in a common plane, referred to as a dipolar plane. For not too strong dipole-dipole interactions increasing magnitude of the dipole moment causes stabilization of nematic at the expense of smectic- A(d). Under the same conditions the layer spacing increases and the distance between the dipolar planes within layers decreases. Each smectic sublayer is characterized by a short-range hexagonal order of the molecular centers of mass. With the dipole moment exceeding the threshold value, the polarization planes that built up the layers start to merge, which sets in the dipolar frustration. This, in turn, forces the system to develop a competition between frustrated hexagonal- and frustration-free tetragonal local order within each layer. When the local hexagonal order is transformed into the tetragonal one the stability range of smectic-A(d) increases with increasing dipole moment at the expense of the nematic phase. Similar competition is observed in crystalline phases. For small dipole moment only crystalline structures with long-range hexagonal order appear stable. They evolve with dipolar strength into monoclinic and tetragonal lattices.

Nematic-smectic-A phase boundary of ideally oriented Gay-Berne system: local density functional versus isothermal-isobaric Monte Carlo simulation.

The main focus of the present paper is on studying the nematic-smectic- A phase boundary of an ideally oriented Gay-Berne system. The phase diagram is determined by means of an isothermal-isobaric Monte Carlo simulation. The results are compared with predictions of the local density functional expanded up to second and third order in the one-particle distribution function. It is shown that generally the second-order expansion does not give satisfactory predictions for smectics. Going beyond the leading order yields good quantitative agreement at moderate densities. With increasing density the relative error of the local density functional calculations increases, but usually does not exceed 10% in densities. We conclude that the density functional approach could be competitive to time-consuming simulations in determining phase diagrams of spatially and orientationally ordered liquid crystalline structures.

Correlations in the isotropic phases of chiral liquid crystals: the role of helicity modes.

The phenomenological theory of chiral liquid crystals is further developed by generalizing the model of self-consistent correlations [J. Englert, L. Longa, H. Stark, and H.-R. Trebin, Phys. Rev. Lett. 81, 1457 (1998)]. In the present approach, not only a leading helicity mode of the tensor order parameter is retained but also the remaining four modes. By considering a full fluctuating spectrum of the order parameter, the role of correlations between helicity modes in the isotropic phases is studied. Additionally, an exact form of the two-point correlation function in real space is derived and its properties are thoroughly discussed. It is shown that for chiral isotropic liquids purely chiral modes could be identified that do not exist for an ordinary liquid. Detailed results of the numerical calculations are compared with those obtained from the earlier model and these show regions where the coupling between the modes becomes important, in agreement with the available experimental data. Though the analysis up to first-order cumulant expansion does not predict a direct phase transition between the blue phase III and the isotropic phase, it is fairly easy to identify two differently correlated regions in a temperature-chirality plane. Various structural quantities, such as optical activity and specific heat, also reveal a behavior characteristic of two isotropic phases with different correlation lengths.

Polymer fragmentation in extensional flow.

In this paper we present an analysis of fragmentation of dilute polymer solutions in extensional flow. The transition rate is investigated both from theoretical and computational approaches, where the existence of a Gaussian distribution for the breaking bonds has been controversial. We give as well an explanation for the low fragmentation frequency found in DNA experiments.

Synchronization induced by Langevin dynamics.

Equilibrium Langevin dynamics of one-dimensional Lennard-Jones chains is studied. It is shown that depending on the noise strength, the friction constant and the number of particles, chains can synchronize, break, or remain desynchronized. Generally the synchronization time and the maximal Lyapunov exponent are found to depend on the number of particles and the ratio of noise strength to friction constant.

TSC1 and TSC2 deletions differ in size, preference for recombinatorial sequences, and location within the gene.

Large TSC gene rearrangements are not rare findings in tuberous sclerosis. Interestingly, all deletions, duplications and inversions so far described involve TSC2, none being associated with TSC1. In order to shed light on the structural basis of the preferential DNA rearrangements in TSC2 over TSC1 and to assess, in an unselected patient population, the prevalence of large re-arrangements in both TSC loci, we screened 202 tuberous sclerosis patients consecutively referred at our center. Southern blot analysis on EcoRI+HindIII double-digested DNA identified 19 partial or full-length gene deletions: three involved TSC1 and sixteen TSC2. The breakpoint sequence of seven internal deletions, three in TSC1 and four in TSC2, allowed us to speculate on the mechanism favoring TSC2 unequal recombinations and to identify a deletion hot spot that lies in TSC1 and that may be relevant in the routine genetic testing of tuberous sclerosis. Briefly, three major features appear to distinguish TSC1 from TSC2 deletions: (1) deletion size: all TSC1 deletions are within the transcriptional unit, whereas 12 of the 16 TSC2 deletions have at least one external breakpoint; (2) location within the gene: all TSC1 deletions are confined to the 3'end of the gene (all three 5' breakpoints being located in intron 20) thus resulting in the same frameshift mutation following amino acid K875, whereas the TSC2 internal breakpoints appear to be scattered along the gene; (3) preference for recombinatorial sequences: six out of eight internal TSC2 breakpoints map within Alu repeats, whereas none of the three TSC1 deletions appear to be Alu-mediated. Indeed, in the latter gene, unique structural features (a purine-rich tract flanked by pyrimidine-rich segments) surrounding one of the two identified breakpoint cluster regions might play a role in promoting inappropriate recombinations.

Does the tuberous sclerosis complex include intracranial aneurysms? A case report with a review of the literature.

BACKGROUND: Tuberous sclerosis is a protean, genetically determined disease that may involve any organ or tissue and lead to a great number of symptoms and clinical features. OBJECTIVE: Diagnosis can be very difficult in cases with incomplete manifestations (formes fruste) lacking the classic signs of the disease. MATERIALS AND METHODS: We report a case fulfilling the diagnostic criteria for tuberous sclerosis (shagreen patches, hypomelanotic macules, renal cysts and angiomyolipomas, and "migration tracts" in the cerebral white matter) in association with a giant intracranial aneurysm, but lacking mental retardation, epilepsy and facial angiofibroma. RESULTS: Fourteen other cases of tuberous sclerosis and intracranial aneurysms, all but one without any clear sign of polycystic kidney disease, were found in the literature. CONCLUSION: We suggest that vascular dysplasias in general and aneurysms (mainly intracranial) in particular can be added to the other non-primary diagnostic features for the clinical diagnosis of tuberous sclerosis.

Carcinomalike monotypic epithelioid angiomyolipoma in patients without evidence of tuberous sclerosis: a clinicopathologic and genetic study.

We report the clinicopathologic, immunohistochemical, ultrastructural, and genetic features of an unusual renal tumor composed of large, atypical, densely packed, clear/eosinophilic epithelioid cells. Three patients, two men and one woman (ages 31, 36, and 60 years of age, respectively), had abdominal pain. Morphologically, all cases showed aggressive features (largeness, atypical cells, sarcomatoid features, necrosis, and, in one case, invasion of the renal vein). Despite the marked morphologic resemblance of these tumors to high-grade sarcomatoid renal cell carcinoma, their phenotype (HMB45+, CD68+/-, actin+/-, and vimentin and keratin negative) is in contrast to that observed in epithelial tumors and parallels the phenotypic profile of angiomyolipoma. Ultrastructural analysis showed the presence of glycogen, mitochondria, and prominent electron-dense, membrane-bound granules in the neoplastic cells, and the absence of melanosomes or premelanosomes. Genetic study, performed using polymerase chain reaction from paraffin sections, showed a loss of heterozygosity at the TSC2-containing region on 16p in one case, and on 3p in two cases, showing that multiple genetic alterations are taking place in these tumors. Follow-up has shown local recurrence in one case after 6 years, and the patient died 1 year later of cardiorespiratory failure. The other two patients are well after 26 and 10 months. All three patients were evaluated for signs of tuberous sclerosis, and findings were negative. We suggest that these tumors should be considered close relatives of the angiomyolipoma variants, composed purely of perivascular epithelioid cells. More cases and longer follow-up durations are needed to fully evaluate its prognostic implication.

A large TSC2 and PKD1 gene deletion is associated with renal and extrarenal signs of autosomal dominant polycystic kidney disease.

BACKGROUND: The renal lesions in tuberous sclerosis complex (TSC) consist in multiple angiomyolipomas, often associated with cysts of variable size. Recently a few TSC patients with early-onset renal cysts resembling the autosomal dominant polycystic kidney disease (ADPKD) have been described. Virtually all of them showed deletions of both TSC2 and PKD1 genes. METHODS: Two unrelated families in which TSC and PKD co-segregate were investigate. 16p13.3-linked haplotype segregation, Southern blot, pulsed field gel electrophoresis, and loss of heterozygosity analyses were performed in both affected and unaffected family members. RESULTS: The proband from family 1 was first recognized as presenting typical neurological signs and skin lesions of TSC and multiple renal cysts at 12 years of age. Haemodialysis became necessary at age 28. CT and MRI scans revealed multiple cysts in the live and an asymptomatic, 3-4 mm aneurysm of the middle cerebral artery. His mother, who died at 47 of breast cancer, had ADPKD and reached the ESRD at 42. She showed facial angiofibromas. Both patients carried a submicroscopic germline deletion spanning the entire TSC2 gene and the large majority of PKD1 coding sequence. In the proband from family 2, the TSC diagnosis was made at 4 years. Enlarged polycystic kidneys causing and-stage renal failure at 19 years were observed. This patient carried a large germline, de novo deletion involving the entire TSC2 and PKD1 genes. In addition we could show in a renal hamartoma from this subject the loss of heterozygosity of markers spanning the TSC2 and PKD1 genes from the residual, normal chromosome 16 of paternal origin. CONCLUSIONS: The presence of a deletion involving both TSC2 and PKD1 genes should be considered in the clinical assessment of TSC children with an early-onset polycystic kidney disease, and more generally in all ADPKD patients who develop end-stage renal failure prior to the fourth or fifth decade of life. Finally, the occurrence of typical renal and extrarenal signs of ADPKD in a PKD1 hemizygote individual seems to support concept that a somatic inactivation of the residual PKD1 gene is required for the development of the cysts.

Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.

9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene.

Tuberous sclerosis is an autosomal dominant disease whose characteristic feature is the development of multiple hamartomas in a variety of organs and tissues. Two major loci have been identified so far: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3. Loss of heterozygosity at 16p13.3-associated markers has been recently observed in hamartomatous lesions of some tuberous sclerosis patients. Here we report the first evidence of loss of heterozygosity at the TSC1 critical region in a giant cell astrocytoma of a familial tuberous sclerosis case. Segregation analysis showed that the 9q34 haplotype lost carried the putative normal TSC1 gene. These data support the hypothesis of both a germline and somatic loss-of-function mutation for the development of tuberous sclerosis hamartomas and suggest a tumor-suppressor-like activity also for the TSC1 gene product. Finally, the possible significance of a second small region of loss of heterozygosity at 9p21, found in the same astrocytoma, is discussed.