Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.     

A girl with mosaicism for a dicentric X chromosome (45,X/46,X,dic(X) (Xqter→p22::p22→qter))

Summary A 12-year-old girl was examined for growth retardation and a few very discrete dysmorphologic stigmata of Turner's syndrome; the genitalia were infantile yet both ovaries possessed functioning follicles. R- and C-banding techniques and Brdu treatment demonstrated a 45,X formula in 95% of lymphocytes, with 5% presenting a 46,X,dic(X) formula. Cytogenetic and clinical problems raised by this observation are discussed in relation to data from the literature.This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (C.R.L. 75-10-42-24) and from the C.R.E.M.A.G.     

Array CGH characterization of an unbalanced X-autosome translocation associated with Xq27.2–qter deletion, 11q24.3–qter duplication and Xq22.3–q27.1 duplication in a girl with primary amenorrhea and mental retardation

We present array comparative genomic hybridization (aCGH) characterization of an unbalanced X-autosome translocation with an Xq interstitial segmental duplication in a 16-year-old girl with primary ovarian failure, mental retardation, attention deficit disorder, learning difficulty and facial dysmorphism. aCGH analysis revealed an Xq27.2–q28 deletion, an 11q24.3–q25 duplication, and an inverted duplication of Xq22.3–q27.1. The karyotype was 46,X,der(X)t(X;11)(q27.2;q24.3) dup(X)(q27.1q22.3). We discuss the genotype–phenotype correlation in this case. Our case provides evidence for an association of primary amenorrhea and mental retardation with concomitant unbalanced X-autosome translocation and X chromosome rearrangement.     

Clostridium botulinum types A,B, C1, and E produce proteins with or without hemagglutinating activity: Do they share common amino acid sequences and genes?

Clostridium botulinum produce the antigenically distinct 150 kD neurotoxin serotypes (e.g., A, B, C₁, and E) and simultaneously proteins, A Hn⁺, B Hn⁺, C Hn⁺, and E Hn^?, that have high, low, and no hemagglutinating activity. A Hn⁺ and B Hn⁺ are serologically cross-reactive. A Hn⁺, B Hn⁺, and C Hn⁺ found as large aggregates (900–220 kD) can be dissociated on SDS-PAGE into multiple subunits, the smallest for A Hn⁺, B Hn⁺ is 17 kD and 27 kD for C Hn⁺. The 116 kD E Hn^? does not aggregate. We determined the sequences of 10–33 amino terminal residues of the 17, 21.5, 35, and 57 kD subunits of A Hn⁺ and B Hn⁺. Each of these subunits have unique sequences, indicating that the larger units studied are not homomers or heteromers of smaller units. The subunits of A Hn⁺ and B Hn⁺ of comparable size have striking sequence identity (e.g., 21.5 kD subunits from the two are identical and 57 kD subunits have 80% identity).In vitro proteolysis of 116 kD E Hn^? with different proteases did not impart hemagglutinating activity to the fragments. The 116 kD E Hn^? and one of its proteolytic fragments (87 kD) were partially sequenced. Sixty-two base pairs downstream from the termination codon of the cloned 33 kD subunit of C Hn⁺, there is an initiation codon followed by an open reading frame for at least 34 amino acid residues (Tsuzukiet al., 1990). The derived amino acid sequence of this open reading frame, we found, has 73–84% sequence identity with those of the 17 kD subunits of A Hn⁺ and B Hn⁺ and significant identity with the N-terminal of E Hn^?. These highly conserved sequences show existence of genetic linkage among the Hn⁺ and Hn^? proteins.     

Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna—A Randomized,Cross-Over Clinical Study

Purpose

Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines.

Methods

Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m²) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy.

Results

Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration.

Conclusions

The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI.

Trial Registration

clinicaltrials.gov NCT01205503.     

A case of Kearns–Sayre syndrome with two novel deletions (9.768 and 7.253 kb) of the mtDNA associated with the common deletion in blood leukocytes,buccal mucosa and hair follicles

Kearns–Sayre syndrome is a mitochondrial disorder characterized by the emergence before the age of 20 years of progressive external ophthalmoplegia, pigmentary retinopathy, with other heterogeneous clinical manifestations. Generally, mitochondrial DNA deletions were associated with KSS but the size and position of these deletions differ among patients. This study reported a Tunisian patient with typical features of KSS. Long-range PCR amplification of the mtDNA in different tissues from this patient showed multiple mitochondrial deletions: two novel 9.768 and 7.253 kb deletions spanning respectively nucleotides 6124–15,893 and 8572–15,826 associated with the common 4.977 kb deletion.     

A quantitative synthesis of the medicinal ethnobotany of the Malinké of Mali and the Asháninka of Peru, with a new theoretical framework

Background

Although ethnomedically and taxonomically guided searches for new medicinal plants can improve the percentage of plants found containing active compounds when compared to random sampling, ethnobotany has fulfilled little of its promise in the last few decades to deliver a bounty of new, laboratory-proven medicinal plants and compounds. It is quite difficult to test, isolate, and elucidate the structure and mechanism of compounds from the plethora of new medicinal plant uses described each year with limited laboratory time and resources and the high cost of clinical trials of new drug candidates.

Methods

A new quantitative theoretical framework of mathematical formulas called "relational efficacy" is proposed that should narrow down this search for new plant-derived medicines based on the hypothesis that closely related plants used to treat closely related diseases in distantly related cultures have a higher probability of being effective because they are more likely to be independent discoveries of similar plant compounds and disease mechanisms. A prerequisite to this hypothesis, the idea that empirical testing in traditional medicine will lead to choosing similar medicinal plants and therefore the medicinal flora of two distant cultures will prove to be more similar than their general flora, is tested using resampling statistics on cross-cultural field data of the plants used by the Malinké of Mali and the Asháninka of Peru to treat the diseases malaria, African sleeping sickness, Chagas' disease, leishmaniasis, diabetes, eczema, asthma, and uterine fibroids.

Results

In this case, the similarity of the medicinal floras is found to be significantly greater than the similarity of the general floras, but only when the diseases in question are grouped into the categories of parasitic and autoimmune diseases.

Conclusion

If the central theoretical framework of this hypothesis is shown to be true, it will allow the synthesis of medicinal plant information from around the world to pinpoint the species with the highest potential efficacy to take into the laboratory and analyze further, ultimately saving much field and laboratory time and resources. Spanish abstract Las búsquedas que utilizan la etnomedicina y la taxonomía para descubrir nuevas plantas medicinales, pueden aumentar la probabilidad de éxito de encontrar compuestos químicos activos en plantas, en comparación con las búsquedas aleatorias. A pesar de lo anterior, en las últimas décadas, la etnobotánica no ha cumplido con las expectativas de proveer numerosas plantas medicinales y químicos nuevos una vez examinados en el laboratorio. Cada año se describen una plétora de plantas medicinales y sus usos, sin embargo las limitaciones de tiempo y recursos en los laboratorios, unidos al alto coste de los ensayos clínicos de las drogas potenciales, hacen muy difícil probar, aislar, y elucidar la estructura y el mecanismo de los compuestos de estas plantas. Se propone un nuevo marco teórico cuantitativo cuyo fin es focalizar la búsqueda de nueva plantas medicinales. Este marco teórico está basado en la hipótesis que las plantas cercanamente relacionadas, usadas para tratar enfermedades cercanamente relacionadas en culturas distantemente relacionadas, tienen una eficacia potencial más alta, debido a que es más probable que estos hallazgos sean descubrimientos independientes de compuestos químicos similares. Parte de esta hipótesis, que las escogencias racionales se hacen para elegir plantas medicinales similares y que la flora medicinal de dos culturas distantes es más similar que su flora general, se probó usando métodos estadísticos de remuestreo con datos de campo de la comunidad Malinké de Malí y de la Asháninka de Perú, y las enfermedades de paludismo, enfermedad africana del sueño, enfermedad de Chagas, leishmania, diabetes, eczema, asma, y fibromas uterinos. Se encontró, en este caso, que la similitud de las floras medicinales es significativamente mayor a la similitud de las floras generales, solamente cuando las enfermedades analizadas se agruparon en las categorías de enfermedades parasitarias y enfermedades autoinmunes. Si se demostrara que las otras partes de esta hipótesis son ciertas, se podría sintetizar la información sobre plantas medicinales alrededor del mundo, para establecer así las plantas potencialmente más eficaces para llevarlas al laboratorio y analizarlas más profundamente. French abstract Par rapport aux recherches menées de façon aléatoire, les recherches effectuées par des critères ethnobotaniques et taxonomiques ont de meilleures chances à découvrir de nouvelles plantes médicinales à produit chimique actifs. Pendant les dernières décennies pourtant, l'ethnobotanique a réalisé peu de ces promesses à révéler un grand nombre de plantes médicinales et de nouveaux produits chimiques, testés au laboratoire. Avec les ressources limitées pour la recherche au laboratoire et le coût élevé des épreuves cliniques pour trouver de nouveaux candidats aux médicaments, il est difficile d'étudier, d'isoler et d'élucider la structure et le mécanisme des produits chimiques de chacune des nombreuses plantes médicinales (et les utilisations de ces plantes) décrites chaque année. Nous proposons une nouvelle technique théorique et quantitative pour préciser la recherche de nouvelles plantes médicinales; elle est basée sur l'hypothèse que les plantes étroitement apparentées, employées pour traiter les maladies étroitement apparentées dans les cultures très éloignées les unes des autres, ont une potentialité d'efficacité supérieure parce qu'elles représentent la découverte indépendante des propriétés chimiques semblables des plantes. Une partie de cette hypothèse-qui démontre que la sélection des plantes médicinales semblables est un choix rationnel et qu'il y a davantage de ressemblance dans la flore médicinale de deux cultures éloignées que dans leur flore générale-est examinée par un re-échantillonnage des données de recherches effectuées parmi les Malinké au Mali et les Asháninka au Pérou, en particulier sur la malaria, la maladie africaine du sommeil, la maladie de Chagas, la leishmania, le diabète, l'eczéma, l'asthme et les fibromes utérins. Dans ces cas précis, la similitude de la flore médicinale s'avère sensiblement plus grande que la similitude de la flore générale, mais seulement quand les maladies en question sont regroupées ensemble comme maladies parasitaires et auto-immunitaires. Si cette hypothèse est prouvée, elle permettra la synthèse des informations recueillies sur les plantes médicinales du monde entier pour en sélectionner de façon plus précise celles qui sont les plus efficaces et qui méritent analyse plus approfondie au laboratoire. Asháninka abstract Aayiantyarori iròpero aavintane, ontzimatye ancovacovatero ayotero ovaqueraripaye incashi iyoyetziri ashaninka, ayotzityaro aajatzi iyotane viracocha paitachari "quimica" ancantero aaca oshintsinka inchashipaye. Atziri yotacotzirori cametsa, ishtoriajacotzirori iyotane ashaninkapaye te iroñàrantero maaroni ocaratzi yamenacotaqueri laboratorioki. Aaviantyarori cametsa, ayotacotero aavintarontsiyetatsiri osamani antzimaventero ishtoriatacotaro, aajatzi osheki opinata ampinaventero aparopaye inchashi, acoviriqui ayotacotero, osaretsikipaye. Tzimatsi ovaquerari quenquishiriantsitatsiri ero opinata osheki ashitoriatacotero aparopaye inchashi, asampiyetatyrey pashinipaye atziri saicatsiri intaina puitarika inchasshi yavintari, ajatzirica oshiyaro ayotzi aaca, quemetachari atziri saikatsiri nampitsiki malinke aajatzi ishiyari ashaninka saicatsiri peruki, tzimatsi inchashi aajatzi yaavintari osheki okamètsatzi aririka anteri mantsiyarentsi icantaitziri ompetarentsi catsirentsi, pochokirentsi, patsarontsi(matatsi) ashipetate maaroni, ampochavathate, ancainikentsite, oncatsithakite tsinani. Aririka añaker aajatzi ahiyaro inchashi yaavintayetari pashinipaye atziri intainasatzi irdotake ahitoriatacoperoteri anàashityard aavintarontsi ovamairiri shithanentsi, onàshitaavintarontsi tzicaacoventairi ero antane mantsiyarentsi. Omanperotatyarica iròperotzi avintarontsi, oshitovake laboratorioki aritaque iyoitanaquero maaroni quipatsiki iroperori avintarontsi.     

Identification of a putative DNA replication origin in the λ-aminobutyric acid receptor subunit β3 and α5 gene cluster on human chromosome 15q11-q13, a region associated with parental imprinting and allele-specific replication timing

The region containing the GABA_A receptor β3 and α5 subunit-encoding genes is subject to parental imprinting and is organized in different allele-specific replication timing domains. A 60-kb domain displaying a maternal early/paternal late pattern of allele-specific replication timing asynchrony is nested within a larger region displaying the opposite pattern. The proximal portion of this maternal early replicating domain is incorporated into phage clone λ84. In order to identify DNA structures which may be associated with the boundary between the replication domains, phage λ84 has been subcloned into smaller fragments and several of these have been analyzed by nucleotide sequencing. A plot of helical stability for 13 kb of contiguous sequence reveals several A +T-rich regions which display potential DNA unwinding. The plasmid subclones from phage λ84 have been analyzed for bent DNA and one of these, p82, contains bent DNA and overlaps with the region of highest potential helical instability. Of the seven plasmids tested, only p82 shows strong autonomous replication activity in an in vitro replication assay, with replication initiating within the genomic insert. These results suggest that a putative origin of DNA replication contained within p82 may play a role in establishing the allele-specific replication timing domains in the GABA_A receptor subunit gene cluster.