Loose Folds Research Articles

New insights into the pathogenesis of autosomal‐dominant cutis laxa with report of fiveELNmutations

Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in five probands with ADCL features and found five de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5), and c.2124del25 (CL-6). Four probands (CL-1,-2,-3,-6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF-β) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF-β signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis.

Generalized acquired cutis laxa treated with facial plastic surgery

Auteur(s) : Yanning XUE1, Hao CHEN2, Xuesi ZENG2, Yiqun JIANG2, Jianfang SUN2 fangmin5758@yahoo.com.cn 1 Jiangsu Province hospital of traditional Chinese medicine, 155 Han-zhong Road, 210029 Nanjing, Jiangsu Province, China 2 Institute of Dermatology, Chinese Academy of Medical Sciences, 12 Jiang-wang-miao Road, Nanjing city, 210042 Jiangsu Province, China Cutis laxa (dermatochalasis, generalized elastolysis) is an uncommon disorder characterized by laxity of the skin, which hangs in loose folds, [...]

Gastroesophageal flap valve status distinguishes clinical phenotypes of large hiatal hernia.

To investigate two distinct clinical phenotypes of reflux esophagitis and intra-hernial ulcer (Cameron lesions) in patients with large hiatal hernias. A case series study was performed with 16 831 patients who underwent diagnostic esophagogastroduodenoscopy for 2 years at an academic referral center. A hiatus diameter ≥ 4 cm was defined as a large hernia. A sharp fold that surrounded the cardia was designated as an intact gastroesophageal flap valve (GEFV), and a loose fold or disappearance of the fold was classified as an impaired GEFV. We studied the associations between large hiatal hernias and the distinct clinical phenotypes (reflux esophagitis and Cameron lesions), and analyzed factors that distinguished the clinical phenotypes. Large hiatal hernias were found in 49 (0.3%) of 16,831 patients. Cameron lesions and reflux esophagitis were observed in 10% and 47% of these patients, and 0% and 8% of the patients without large hiatal hernias, which indicated significant associations between large hiatal hernias and these diseases. However, there was no coincidence of the two distinct disorders. Univariate analysis demonstrated significant associations between Cameron lesions and the clinico-endoscopic factors such as nonsteroidal anti-inflammatory drug (NSAID) intake (80% in Cameron lesion cases vs 18% in non-Cameron lesion cases, P = 0.015) and intact GEFV (100% in Cameron lesion cases vs 18% in non-Cameron lesion cases, P = 0.0007). In contrast, reflux esophagitis was linked with impaired GEFV (44% in reflux esophagitis cases vs 8% in non-reflux esophagitis cases, P = 0.01). Multivariate regression analysis confirmed these significant associations. GEFV status and NSAID intake distinguish clinical phenotypes of large hiatal hernias. Cameron lesions are associated with intact GEFV and NSAID intake.

Aspects of Italian Baroque Art: I. Bernini’s Non-Figural Draperies as “Simbolic Forms”; II. Directional Reading in Caravaggio

The sculptural rendering of loose folds of clothing was part of the classical legacy, which was a salient characteristic of Bernini's figural sculpture. The expressive potential of non-figural drapes was an innovation which has seldom received adequate attention. At first sight the evocative dynamism of such independent draperies carved in marble may seem like a sort of Abstract Expressionism avant la lettre but Bernini employed the effect as a “Symbolic Form” in Ernst Cassirer's famous definition, a concrete object communicating an intelligible meaning.

No mutation of elastin and fibulin-5 genes in a patient with acquired cutis laxa associated with chronic urticaria

Conflicts of interest: none declared. Funding sources: none disclosed. Madam, Cutis laxa (CL) is a rare disorder of unknown cause characterized by progressive looseness of the skin associated with abnormalities of other organs and structures containing elastic tissue such as lung, vasculature or gastrointestinal tract. The primary change is in the elastic fibre, which is almost absent or decreased in the dermis. Both inherited and acquired forms exist. The acquired form is less common than the inherited mode. The involved areas of the skin hang in loose pendulous folds. These findings may be localized or generalized.1 Approximately half the patients with acquired CL have a preceding or accompanying inflammatory eruption with erythematous papules or plaques.2 Mutations in the elastin (ELN) or fibulin‐5 (FBLN5) genes have been identified in inherited CL. The association of the gene mutations with acquired CL is not clear, although Hu et al.3 reported a patient with acquired CL preceded by Toxocara canis parasitism and chronic urticaria; molecular genetic analysis revealed inherited mutations in the ELN and FBLN5 genes that resulted in functional alterations in the corresponding gene products. Here we report a patient with acquired CL accompanied by chronic urticaria but no mutation in the ELN and FBLN5 genes.

Intrinsically disordered γ-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure

The retinal phosphodiesterase (PDE6) inhibitory gamma-subunit (PDEgamma) plays a central role in vertebrate phototransduction through alternate interactions with the catalytic alphabeta-subunits of PDE6 and the alpha-subunit of transducin (alpha(t)). Detailed structural analysis of PDEgamma has been hampered by its intrinsic disorder. We present here the NMR solution structure of PDEgamma, which reveals a loose fold with transient structural features resembling those seen previously in the x-ray structure of PDEgamma(46-87) when bound to alpha(t) in the transition-state complex. NMR mapping of the interaction between PDEgamma(46-87) and the chimeric PDE5/6 catalytic domain confirmed that C-terminal residues 74-87 of PDEgamma are involved in the association and demonstrated that its W70 indole group, which is critical for subsequent binding to alpha(t), is left free at this stage. These results indicate that the interaction between PDEgamma and alpha(t) during the phototransduction cascade involves the selection of preconfigured transient conformations.

Radiation effects and re-crystallization mechanism of syndiotactic polystyrene with β′-crystalline form

The double melting behavior of syndiotactic polystyrene (sPS) with β′-form crystallites was systematically investigated by several analytical techniques, including differential scanning calorimetry (DSC), polarized light microscopy (PLM), transmission electron microscopy (TEM), as well as wide-angle and small-angle X-ray scattering (WAXD, SAXS). For preventing the possible chain re-organization during intermediate melting, a high-energy electron beam (e-beam) radiation was carried out on the melt-crystallized samples to chemically cross-link the amorphous chains between lamellar crystals. The WAXD intensity profiles of the irradiated sPS samples revealed that no crystal transformation took place, and the crystallinity fraction remained unchanged for a received dose up to 2.4MGy. As the received dose was increased, however, the high melting temperature peak was gradually diminished and finally disappeared after 1.8MGy e-beam radiation, suggesting that the double melting phenomenon was mainly attributed to the melting/re-crystallization/re-melting behavior. The re-crystallization mechanism of sPS samples was studied using DSC and PLM to reveal the effects of heating rate and annealing temperature on the Avrami exponent and re-crystallization rate constant. In addition, the lamellar morphologies of the re-crystallized samples were also investigated by means of SAXS and TEM. With increasing heating rate or annealing temperature, the derived Avrami exponent was slightly decreased from 1.4 to 1.1; in comparison, the re-crystallization rate showed a shallow maximum at a rate of 10°C/min, but it became evidently reduced at high annealing temperatures. Based on the morphological observations, we proposed that the re-crystallization of β′-form sPS crystals involved with the presence of broad lamellar thickness distribution as well as abundant irregular loose folding chains on the lamellar surfaces, which became tightened and crystallized into the un-melted lamellae when the neighboring thinner lamellae trapped in-between were melted. Thus, the high melting temperature is dependent on the average thickness of lamellae consisting of the un-melted lamellae developed initially and thickened ones associated with re-crystallization.

Cutis Laxa Associated with Central Hypothyroidism owing to Isolated Thyrotropin Deficiency in a Newborn

Cutis laxa is an uncommon entity characterized by laxity of the skin, which hangs in loose folds, producing an appearance of premature aging. It can be subdivided into congenital and acquired forms. Genetic forms of cutis laxa include at least three forms of recessive disease, an X-linked form also termed occipital horn syndrome and an autosomal dominant form. Isolated pituitary hormone deficiency can be induced by many causes including mechanical destruction of the hypothalamo-pituitary axis, neoplasm, inflammation, and injury and genetic defects of pituitary hormone production and secretion. Isolated-thyrotropin deficiency has been considered to be a rare disease. We report a newborn with autosomal recessive form of congenital cutis laxa, who had congenital hypothyroidism owing to isolated thyrotropin deficiency. To the best of our knowledge, this is the first instance of this association to be reported in the literature.

Structural Approaches of Polyethylene Environmental Stress-Crack Resistance

Structural Approaches of Polyethylene Environmental Stress-Crack Resistance This work was aimed at understanding and predicting of the long-term mechanical behavior of polyethylene in relation to molecular architecture. An insight into the semi-crystalline microstructure and the chain topology consisting of intercrystalline tie chains and loose folding loops was the main objective of the study. A two-stage crystallization segregation was used for separating the chain species which can easily crystallize by regular folding from those which cannot. The natural draw ratio that develops beyond the yield point proved to be a highly sensitive parameter for probing the chain topology via the crystalline lamella fragmentation and chain unfolding under tensile drawing. Small-angle X-ray scattering provided semi-quantitative evaluation of the stacking disorder of the lamellar microstructure. The data from the three approaches provided correlations with chain architecture in very good agreement with the stress crack resistance dependency. These correlations were discussed in terms of crystallization kinetics and molecular topology. A practical issue of the work is to provide relevant tools for predicting stress cracking resistance.

Influence of breed and age on morphometry and depth of inseminating catheter penetration in the ewe cervix: A postmortem study

A detailed examination of the cervical canal in the ewe was carried out. This analysis could be used to design new catheters for artificial insemination (AI) to achieve deeper cervical penetration and therefore better fertility results. Three hundred and sixty-five cervices from four sheep breeds (Churra, Assaf, Merino, Castellana) obtained postmortem were used. Cervix morphometry and depth of cervical penetration using two types of catheters were determined. A conventional straight catheter for ovine artificial insemination (IMV ®), and a bent catheter, ending in a stainless steel needle, 9 cm in length and with an 8 mm tip bent 45°, were used. The results showed that the morphometry of the cervix depends on breed and age of the ewe. The cervices of Churra breed were shorter and narrower, and had a higher number of folds than those of other breeds. Postmortem cervical penetration was deeper when the cervices were longer and wider, and with fewer folds (Merino and Castellana breeds). In ageing ewes, the cervix tended to become longer and wider, with loose folds. This decreased structural complexity and significantly improved cervical penetration. The bent catheter allowed significantly greater cervical penetration than the straight IMV ® one.

Elastosis perforans serpiginosa-like pseudoxanthoma elasticum in a child with severe Moya Moya disease

A 2-year-old girl with Moya Moya disease who had relapsing cerebrovascular strokes presented with loose skin folds, 'chicken' skin appearance and perforating elastosis serpiginosa-like lesions in the genitocrural region. Histologically, calcified material perforating the epidermis and adjacent short curled and mineralized elastic fibres suggested a variant of pseudoxanthoma elasticum (PXE). As PXE is known to be caused by various mutations in the transmembrane transporter ABCC6 gene, we hypothesized that a novel ABCC6 mutation may underlie this unique combination of PXE and elastopathic vascular damage. Therefore, the complete ABCC6 coding region of the patient and her parents was screened for genetic alterations. No bona fide disease-causing mutation of ABCC6 could be found in the child and in her parents. However, two novel allelic amino acid substitutions (Arg1273Lys and Glu1293Lys; exon 27) were found in the girl and her father, localized in close proximity to the region that codes for the functionally critical second nucleotide-binding fold of ABCC6. Although a causal involvement of these amino acid substitutions could not be proven based on this study, both heterozygote substitutions may possibly have interacted with other undetected recessive maternal ABCC6 changes in the child. To the best of our knowledge, this is the first report of an association between early-onset PXE and severe Moya Moya syndrome possibly related to ABCC6 changes.

Defective protein glycosylation in patients with cutis laxa syndrome

Congenital cutis laxa is a genetically heterogeneous condition presenting with loose and redundant skin folds, decreased elasticity of the skin, connective tissue involvement and a highly variable spectrum of associated features. The most common forms are inherited in an autosomal recessive or dominant fashion. Fibulin 5 and elastin mutations were detected in a limited number of patients, but in most cases the etiology is not known. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, we performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome, including a recently developed test for defective O-glycosylation. Here, we describe five patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay and neurological findings. Three of these five children have an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were found in the FBLN5 gene. In conclusion, we have identified a new combined glycosylation defect with a distinct clinical phenotype. Our results suggest that a combined defect of glycosylation might be a causative factor in congenital cutis laxa. This is the first report where abnormal N- and O-linked glycosylation is implicated in the etiology of cutis laxa syndrome.

Acquired localized cutis laxa confined to the face: case report and review of the literature

Cutis laxa is an uncommon entity characterized by laxity of the skin, which hangs in loose folds, producing the appearance of premature aging. It can be subdivided into congenital and acquired. This latter variant is rare and the skin involvement varies from generalized to localized. We report a case of a localized acquired cutis laxa confined to the face, without preceding inflammatory lesions or systemic compromise. Four similar cases have been reported to date. The etiology remains unknown and there is no definitive treatment. A 27-year-old White woman came to our hospital with a wrinkled face, pendulous earlobes and drop eyelids. Changes began 5 years prior, and she appeared much older than her age. Histological analysis and ultrastructural examination of skin biopsy revealed reduction and fragmentation of elastic fibers, confirming the diagnosis of cutis laxa. No systemic involvement was diagnosed. The patient was submitted to plastic surgery for repair, with satisfactory results to date. Acquired localized cutis laxa confined to the face without preceding inflammatory lesions is extremely rare. The etiology remains unknown. Clinical features and histopathologic findings confirm the diagnosis. Surgical repair seems to be the only therapeutic choice, but the results are variable and temporary.

On the β Transition in High Density Polyethylene: the Effect of Transcrystallinity

AbstractSummary: Transcrystallinity in UHMWPE fiber‐reinforced HDPE composites promotes a significant β transition that is untypical of high‐density polyethylene. Surface profiling by atomic force microscopy identifies two distinct morphologies in the composite without a boundary phase between them, which coincide with the transcrystalline layer and with the bulk spherulitic matrix. As a result, the claim that attributes this transition to loose chain folds at the lamella surface is favored.Atomic force microscopy scan of the transcrystalline layer above the fiber with the impression of the fiber in the center.magnified imageAtomic force microscopy scan of the transcrystalline layer above the fiber with the impression of the fiber in the center.

L . T. Shoe Meritt, I. E. M. Edlund-Bhrry: Etruscan and Republican Roman Mouldings. A reissue of the Memoirs of the American Academy in Rome XXVIII, 1965 by Lucy T. Shoe. (University Museum Monograph 107.) Vol. I: pp. xxxvi + 233, ills. Vol. II: 78 loose folding pls. Philadelphia: The University Museum, University of Pennsylvania in cooperation with The American

L . T. Shoe Meritt, I. E. M. Edlund-Bhrry: Etruscan and Republican Roman Mouldings. A reissue of the Memoirs of the American Academy in Rome XXVIII, 1965 by Lucy T. Shoe. (University Museum Monograph 107.) Vol. I: pp. xxxvi + 233, ills. Vol. II: 78 loose folding pls. Philadelphia: The University Museum, University of Pennsylvania in cooperation with The American Academy in Rome (distributed by University of Texas Press, Austin), 2000. Cased, US$85. ISBN: 0-924171-77-4. - Volume 54 Issue 1

A concurrent occurrence of cutis laxa, Dandy‐Walker syndrome and immunodeficiency in a girl

We report on a 17‐y‐old girl with inherited cutis laxa, immunodeficiency and Dandy‐Walker syndrome. Immunodeficiency manifested itself by decreased and fluctuating levels of IgG, IgA and IgM and intermittent leucopenia causing increased susceptibility to respiratory tract infections. Dandy‐Walker syndrome (agenesis of the cerebellar vermis with a large posterior fossa cyst communicating with an enlarged 4th ventricle) was shown on a CT scan but with the exception of macrocrania, no typical signs or symptoms were observed at the age of 17. Loose hyperextensible skin with pendulous skinfolds as a manifestation of cutis laxa was observed from birth. Anomalies of the right pulmonary artery, abnormal branching of the left arteria subclavia (arteria lusoria) from the left aortic arch and bicuspidal aortic valve were also present. Conclusion: The combination of the rare disorders cutis laxa, Dandy‐Walker syndrome and immunodeficiency is reported here for the first time.

If It Bleeds, It Leads

If It Bleeds, It Leads

How does heme axial ligand deletion affect the structure and the function of cytochrome b562?

We have recently generated a new mutant of cytochrome b(562) (cytb(562)) in which Met7, one of the axial heme ligands, is replaced by Ala (M7A cytb(562)). The M7A cytb(562) can bind heme and the UV-visible absorption spectrum is of a typical high-spin ferric heme. To investigate the effect of the lack of Met7 ligation on the structural integrity of cytb(562), thermal transition analyses of M7A cytb(562) were conducted. From the thermodynamic parameters obtained, it is concluded that the folding of M7A cytb(562) is comparable to the apoprotein despite the presence of heme. On the other hand, exogenous ligands such as cyanide and azide ions are readily bound to the heme iron, indicating that the axial coordination site is available for substrate binding. The peroxidase activity of this mutant is thus examined to evaluate new enzymatic function at this site and M7A cytb(562) was found to catalyze an oxidation reaction of aromatic substrates with hydrogen peroxide. These observations demonstrate that the Met7/His102 bis-ligation to the heme iron is crucial for the stable folding of cytb(562), whereas the functional conversion of cytb(562) is successfully achieved by the loose folding together with the open coordination site.

Histological anatomy of the triangular fibrocartilage complex of the human wrist

The triangular fibrocartilage complex (TFCC) was studied in serial histological sections of the human wrist to reveal its three-dimensional fine structure. The TFCC consisted of a fibrocartilaginous disc proper and other fibrous components. Three-dimensionally, the distal portion of the TFCC had a hammock-like contour that partially surrounded the carpus; while the proximal ligamentous portion corresponding to the radioulnar ligament connected the radius to the ulna. The radioulnar ligament originated at the ulna from both the fovea and the basistyloid. The fibres first gathered and then bifurcated palmarly and dorsally, enclosing and partially coalescing with the proximal side of the disc before inserting around the distal rim of the sigmoid notch of the radius. The meniscus homologue, which corresponded to the ulnar internal wall of the wrist joint, was derived from a loose synovial fold adapting to the stresses from radioulnar deviation. The distal side of the disc consisted of a dense population of chondrocytes in a collagen matrix, while the proximal side was rather rich in fibres directed radioulnarly. Inside the TFCC were loose connective tissues. The histological arrangement of the TFCC is compatible with its function of supporting the carpus, stabilizing the joints and allowing smooth motion of the wrist.

Paleolimulus, an early limuline (Xiphosurida), from Pennsylvanian‐Permian Lagerst tten of Kansas and taphonomic comparison with modernLimulus

The Pennsylvanian-Permian horseshoe crab Paleolimulus signatus (Beecher), incorporating as a junior synonym P. avitus Dunbar, is one of the earliest species of the Limulina (Xiphosurida). Some specimens from Kansas, USA, are exceptionally well preserved, retaining intact book gills and appendages. Indistinct, bilobed burrowing traces of variable width occur in association with some examples of P. signatus and may have been produced by that animal. Based on actualistic taphonomic experiments on Limulus polyphemus, ancient horseshoe crabs and other arthropods having non-mineralized exoskeletons are inferred to have become pliable soon after death or moulting, and to have disarticulated slowly prior to burial. Extreme compression, wrinkling, and loose folding of sclerites are attributed to burial of a pliable exoskeleton. Slow preburial disarticulation partly accounts for the exceptional preservation of Paleolimulus remains. Also relevant for the exceptional preservation of these arthropods was burial in estuarine, tidal flat, or lacustrine environments. Because of fluctuating salinity and possibly dessicating conditions, these settings were limiting to scavengers, burrowers, and some microbes that could potentially disarticulate or decompose xiphosurid remains.