European guidelines for clinical management of abnormal cervical cytology, Part 2

The current paper presents the second part of chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening . The first part of the same chapter was published in a previous issue ( Cytopathology 2008;19:342–54). This part provides guidance on how to manage and treat women with histologically confirmed cervical intraepithelial neoplasia. The paper describes the characteristics, indications and possible complications of excisional and ablative treatment methods. The three options to monitor the outcome after treatment (repeat cytology, HPV testing and colposcopy) are discussed. Specific recommendations for particular clinical situations are provided: pregnancy, immuno-suppression, HIV infection, post-menopause, adolescence and cyto-colpo-histological disparity. The paper ends with recommendations for quality assurance in patient management and some general advice on how to communicate screening, diagnosis and treatment results to the woman concerned. Finally, a data collection form is attached.     

1,4,9,10-Anthradiquinone as precursor for antitumor compounds

1,4,9,10-Anthradiquinone 5 was reacted with enamines 6 in the Nenitzescu reaction to yield unexpected 3,3a,6,12-tetrahydro-3a,7-dihydroxy-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-1-carboxylates 8A. However, anthracycline-like naphtho-condensed 5-hydroxyindoles were not obtained from this diquinone. It yielded similar reaction products of the Nenitzescu reaction like other quinones activated by two electron-withdrawing groups. Furthermore, these new compounds 8A were found to constitute precursors for the synthesis of azonines. The conversion to dibenzoazonines 13 occurred in an unusual and up to now unknown way consisting of isomerization, ring opening, and re-closure. 2-Chloro-anthradiquinone 19 reacted with enamines 6 as vinylogeous acid chloride to pyrroloanthraquinone 20. No substitution of chlorine was observed. Naphtho-condensed indoles 26 were obtained by the reactions of unsubstituted 1,4-anthraquinone 25 with enamines 6 via the normal Nenitzescu route. Indoles 26 were converted to Mannich bases, reacting further to dimers by the Diels-Alder reaction of intermediate o-quinone methides. Most of the synthesized heterocycles were evaluated for their anticancer properties in the NCI's human-disease oriented in vitro anticancer screen. Particularly, carbinolamines 8A exhibited inhibitory activity of tumor cell growth and thus they constitute a new class of lead structures for anticancer drug design.     

Expression of TWISTED DWARF1 lacking its in‐plane membrane anchor leads to increased cell elongation and hypermorphic growth

Plant growth is achieved predominantly by cellular elongation, which is thought to be controlled on several levels by apoplastic auxin. Auxin export into the apoplast is achieved by plasma membrane efflux catalysts of the PIN‐FORMED (PIN) and ATP‐binding cassette protein subfamily B/phosphor‐glycoprotein (ABCB/PGP) classes; the latter were shown to depend on interaction with the FKBP42, TWISTED DWARF1 (TWD1). Here by using a transgenic approach in combination with phenotypical, biochemical and cell biological analyses we demonstrate the importance of a putative C‐terminal in‐plane membrane anchor of TWD1 in the regulation of ABCB‐mediated auxin transport. In contrast with dwarfed twd1 loss‐of‐function alleles, TWD1 gain‐of‐function lines that lack a putative in‐plane membrane anchor (HA–TWD1‐C_t) show hypermorphic plant architecture, characterized by enhanced stem length and leaf surface but reduced shoot branching. Greater hypocotyl length is the result of enhanced cell elongation that correlates with reduced polar auxin transport capacity for HA–TWD1‐C_t. As a consequence, HA–TWD1‐C_t displays higher hypocotyl auxin accumulation, which is shown to result in elevated auxin‐induced cell elongation rates. Our data highlight the importance of C‐terminal membrane anchoring for TWD1 action, which is required for specific regulation of ABCB‐mediated auxin transport. These data support a model in which TWD1 controls lateral ABCB1‐mediated export into the apoplast, which is required for auxin‐mediated cell elongation.     

Demography of the Giant Otter (Pteronura brasiliensis) in Manu National Park,South-Eastern Peru: Implications for Conservation

The giant otter (Pteronura brasiliensis) is an endangered semi-aquatic carnivore of South America. We present findings on the demography of a population inhabiting the floodplain of Manu National Park, south-eastern Peru, arising from 14 annual dry season censuses over a 16 year period. The breeding system of territorial groups, including only a single breeding female with non-reproductive adult ‘helpers’, resulted in a low intrinsic rate of increase (0.03) and a slow recovery from decades of hunting for the pelt trade. This is explained by a combination of factors: (1) physiological traits such as late age at first reproduction and long generation time, (2) a high degree of reproductive skew, (3) small litters produced only once a year, and (4) a 50% mortality between den emergence and age of dispersal, as well as high mortality amongst dispersers (especially males). Female and male giant otters show similar traits with respect to average reproductive life-spans (female 5.4 yrs., male 5.2 yrs.) and average cub productivity (female 6.9, male 6.7 cubs per lifetime); the longest reproductive life spans were 11 and 13 years respectively. Individual reproductive success varied substantially and depended mainly on the duration of dominance tenure in the territory. When breeding females died, the reproductive position in the group was usually occupied by sisters or daughters (n = 11), with immigrant male partners. Male philopatry was not observed. The vulnerability of the Manu giant otter population to anthropogenic disturbance emphasises the importance of effective protection of core lake habitats in particular. Riverine forests are the most endangered ecosystem in the Department of Madre de Dios due to the concentration of gold mining, logging and agricultural activities in floodplains, highlighting the need for a giant otter habitat conservation corridor along the Madre de Dios River.     

Investigation into the source of electron transfer asymmetry in bacterial reaction centers

We have investigated the primary photochemistry of two symmetry-related mutants of Rhodobacter sphaeroides in which the histidine residues associated with the central Mg2+ ions of the two bacteriochlorophylls of the dimeric primary electron donor (His-L173 and His-M202) have been changed to leucine, affording bacteriochlorophyll (BChl)/bacteriopheophytin (BPh) heterodimers. Reaction centers (RCs) from the two mutants, (L)H173L and (M)H202L, have remarkably similar spectral and kinetic properties, although they are quite different from those of wild-type RCs. In both mutants, as in wild-type RCs, electron transfer to BPhL and not to BPhM is observed. These results suggest that asymmetry in the charge distribution of the excited BChl dimer (P*) in wild-type RCs (due to differing contributions of the two opposing intradimer charge-transfer states) contributes only modestly to the directionality of electron transfer. The results also suggest that differential orbital overlap of the two BChls of P with the chromophores on the L and M polypeptides does not contribute substantially to preferential electron transfer to BPhL.     

Renal handling of inorganic mercury in mice. The early excretion phase following a single intravenous injection of mercuric chloride studied by the Silver Amplification method

The early renal excretion of mercuric mercury was studied in male BALB/c mice between 15 seconds and 30 min following a single intravenous injection of 3 mg HgCl2/kg body weight. The cytochemical Silver Amplification method applied at the light and electron microscopical levels showed mercury to be excreted by glomerular filtration and reabsorbed by proximal tubular epithelial cells by means of adsorptive endocytosis. Mercury was rapidly demonstrated in the lysosomal vacuome of proximal tubular epithelial cells. No uptake was observed from the peritubular side, and there was no evidence of tubular secretion of mercury. It is proposed that mercury is excreted in the form of mercury-protein complexes, assisted by the physiological proteinuria in mice, which is enhanced by mercury-induced damage to the glomerular structures.     

Biogeographic gradients in ecosystem processes of the invasive ecosystem engineer <Emphasis Type="Italic">Phragmites australis</Emphasis>

Latitudinal gradients in ecosystem patterns arise from complex interactions between biotic and abiotic forces operating at a range of spatial and temporal scales. Widespread invasive species, particularly invasive ecosystem engineers with large effects on their environment, may alter these gradients. We sampled 3–5 stands of the invasive common reed, Phragmites australis, in eight coastal wetlands ranging from Massachusetts (42°N) to South Carolina (32°N) to document geographic variation in P. australis primary production, associated plant and animal species diversity, and sediment carbon storage and to examine how local-, regional-, and large-scale environmental factors contribute to these patterns. Latitude best explained variation in P. australis density, but contrary to expectations, density increased with increasing latitude across our sites. Latitude also predicted macroinvertebrate species richness, which increased with latitude in a manner similar to P. australis density. In addition to latitude, P. australis leaf carbon:nitrogen ratios, distance to the open coast, and sediment oxygen levels were most important for explaining variation in P. australis production, as well as community (plant or animal species richness) and ecosystem (carbon storage) variables. The percent of developed land was positively associated with P. australis density, yet this variable had relatively low predictive power in our study. Our study provides an important biogeographic perspective for documenting and understanding variation in invasive P. australis that is fundamental both for managing the invasion and for understanding latitudinal gradients in ecosystem structure and function.     

Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules

Intellectual disability (ID) disorders are genetically and phenotypically extremely heterogeneous. Can this complexity be depicted in a comprehensive way as a means of facilitating the understanding of ID disorders and their underlying biology? We provide a curated database of 746 currently known genes, mutations in which cause ID (ID-associated genes [ID-AGs]), classified according to ID manifestation and associated clinical features. Using this integrated resource, we show that ID-AGs are substantially enriched with co-expression, protein-protein interactions, and specific biological functions. Systematic identification of highly enriched functional themes and phenotypes revealed typical phenotype combinations characterizing process-defined groups of ID disorders, such as chromatin-related disorders and deficiencies in DNA repair. Strikingly, phenotype classification efficiently breaks down ID-AGs into subsets with significantly elevated biological coherence and predictive power. Custom-made functional Drosophila datasets revealed further characteristic phenotypes among ID-AGs and specific clinical classes. Our study and resource provide systematic insights into the molecular and clinical landscape of ID disorders, represent a significant step toward overcoming current limitations in ID research, and prove the utility of systematic human and cross-species phenomics analyses in highly heterogeneous genetic disorders.