Endothelial nitric oxide synthase gene T-786C and 27-bp repeat gene polymorphisms in retinopathy of prematurity

PURPOSE: Retinopathy of prematurity (ROP), which is associated with abnormal retinal vessel development, is the leading cause of visual loss in preterm infants. Endothelial nitric oxide synthase (eNOS) is believed to play a central role in both retinal angiogenesis and vasculogenesis. The aim of this study was to investigate functional genetic polymorphisms of eNOS in the pathogenesis of ROP. METHODS: eNOS T(−786)C and 27-bp repeat (eNOS, b: wild-type, a: mutant) genotypes were determined using allele-specific polymerase chain reaction in 105 low birth weight (LBW) preterm infants treated for ROP (treated group). A control group was set up and composed of 127 LBW infants with stage 1 or 2 ROP that did not not require treatment (untreated group). RESULTS: The genotype distribution of eNOS 27-bp repeat polymorphism was found to significantly differ (p=0.015) between the two groups, whereas the genotype distribution of eNOS T(−786)C did not differ (p=0.984) between the groups. There was no difference in the distribution of either the “a” allele (p=0.153) nor of the C allele (p=0.867) in a groups comparison. Multiple logistic regression analysis revealed that male gender (p=0.046) and eNOS aa genotype (p=0.047 versus ab genotype and p=0.022 versus bb genotype) were significantly associated severe ROP that required treatment. The haplotype estimations based on the detected genotype distributions showed that the prevalence of aT and bT haplotypes was significantly increased in the group treated for ROP. CONCLUSIONS: Functional eNOS 27-bp repeat polymorphism might be associated with the risk of severe ROP, however we found no association between the eNOS T(−786)C and the pathogenesis of ROP

Miocene to Holocene exhumation of metamorphic crustal wedges in the NW Himalaya: evidence for tectonic extrusion coupled to fluvial erosion

[1] The Himalayan crystalline core zone exposed along the Sutlej Valley (India) is composed of two high‐grade metamorphic gneiss sheets that were successively underthrusted and tectonically extruded, as a consequence of the foreland‐directed propagation of crustal deformation in the Indian plate margin. The High Himalayan Crystalline Sequence (HHCS) is composed of amphibolite facies to migmatitic paragneisses, metamorphosed at temperatures up to 750°C at 30 km depth between Eocene and early Miocene. During early Miocene, combined thrusting along the Main Central Thrust (MCT) and extension along the Sangla Detachment induced the rapid exhumation and cooling of the HHCS, whereas exhumation was mainly controlled by erosion since middle Miocene. The Lesser Himalayan Crystalline Sequence (LHCS) is composed of amphibolite facies para‐ and orthogneisses, metamorphosed at temperatures up to 700°C during underthrusting down to 30 km depth beneath the MCT. The LHCS cooled very rapidly since late Miocene, as a consequence of exhumation controlled by thrusting along the Munsiari Thrust and extension in the MCT hanging wall. This renewed phase of tectonic extrusion at the Himalayan front is still active, as indicated by the present‐day regional seismicity, and by hydrothermal circulation linked to elevated near‐surface geothermal gradients in the LHCS. As recently evidenced in the Himalayan syntaxes, active exhumation of deep crustal rocks along the Sutlej Valley is spatially correlated with the high erosional potential of this major trans‐Himalayan river. This correlation supports the emerging view of a positive feedback during continental collision between crustal‐scale tectono‐thermal reworking and efficient erosion along major river systems

Exhumation history of the Higher Himalayan Crystalline along Dhauliganga-Goriganga river valleys, NW India: new constraints from fission track analysis

New apatite and zircon fission track data collected from two transects along the Dhauliganga and Goriganga rivers in the NW Himalaya document exhumation of the Higher Himalayan Crystalline units. Despite sharing the same structural configuration and rock types and being separated by only 60 km, the two study areas show very different patterns of exhumation. Fission track (FT) data from the Dhauliganga section show systematic changes in age (individual apatite FT ages range from 0.9 ± 0.3 to 3.6 ± 0.5 Ma, r 2 = 0.82) that record faster exhumation across a zone that extends from the Main Central Thrust to north of the Vaikrita thrust. By contrast, FT results from the Goriganga Valley show a stepwise change in ages across the Vaikrita thrust that suggests Quaternary thrust sense displacement. Footwall samples yield a weighted mean apatite age of 1.6 ± 0.1 Ma compared to 0.7 ± 0.04 Ma in the hanging wall. A constant zircon fission track age of 1.8 ± 0.4 Ma across both the footwall and hanging wall shows the 0.9 Ma difference in apatite ages is due to movement on the Vaikrita thrust that initiated soon after ∼1.8 Ma. The Goriganga section provides clear evidence for >1 Ma of tectonic deformation in the brittle crust that contrasts with previous exhumation studies in other areas of the high Himalaya ranges; these studies have been unable to decouple the role of climate erosion from tectonics. One possibility why there is a clear tectonic signal in the Goriganga Valley is that climate erosion has not yet fully adjusted to the tectonic perturbation

The metamorphism and exhumation of the Himalayan metamorphic core, eastern Garhwal region, India

[1] Geothermobarometric together with micro- and macro-structural data indicate ductile flow in the metamorphic core of the Himalaya in the Garhwal region of India. Peak metamorphic pressure and temperature increase dramatically across the Main Central Thrust (MCT) from ~5 kbar and ~550°C in the Lesser Himalayan Crystalline Sequence (LHCS) to ~14 kbar and ~850°C at ~3 km above the MCT in the Greater Himalayan Sequence (GHS). Pressures within the GHS then decrease upsection to ~8 kbar while temperatures remain nearly constant at ~850°C up to the structurally overlying South Tibetan Detachment (STD). The GHS exhibits sheath fold geometries are indicative of high degrees of ductile flow. Overprinting ductile structures are two populations of extensional conjugate fractures and normal faults oriented both parallel and perpendicular to the orogen. These fractures crosscut major tectonic boundaries in the region such as the MCT and STD, and are found throughout the LHCS, GHS, and Tethyan Sedimentary Sequence (TSS). The thermobarometric and metamorphic observations are consistent with a form of channel flow. However, channel flow does not account for exhumational structures that formed above the brittle-ductile transition. To explain all of the features seen in the metamorphic core of the Garhwal region of the Himalaya, both the theories of channel flow and critical taper must be taken into account. Channel flow can explain the exhumation of the GHS from the middle crust to the brittle-ductile transition. The most recent extensional deformation is consistent with a supercritical wedge

Chromosome 19p13.3 deletion in a child with Peutz-Jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: Clinical and molecular characterization of a new contiguous gene syndrome

The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome

Aldosterone Antagonists in Monotherapy Are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats

Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers

Reconciling Himalayan midcrustal discontinuities: The Main Central thrust system

The occurrence of thrust-sense tectonometamorphic discontinuities within the exhumed Himalayan metamorphic core can be explained as part of the Main Central thrust system. This imbricate thrust structure, which significantly thickened the orogenic midcrustal core, comprises a series of thrust-sense faults that all merge into a single detachment. The existence of these various structures, and their potential for complex overprinting along the main detachment, may help explain the contention surrounding the definition, mapping, and interpretation of the Main Central thrust. The unique evolution of specific segments of the Main Central thrust system along the orogen is interpreted to be a reflection of the inherent basement structure and ramp position, and structural level of exposure of the mid-crust. This helps explain the variation in the timing and structural position of tectonometamorphic discontinuities along the length of the mountain belt

Tectonic evolution of the High Himalaya in upper Lahul (NW Himalaya, India)

The Upper Lahul region in the NW Himalaya is located in the transition zone between the High Himalayan Crystalline (HHC) to the SW and the Tethyan Zone sedimentary series to the NE. The tectonic evolution of these domains during the Himalayan Orogeny is the consequence of a succession of five deformation events. An early D1 phase corresponds to synmetamorphic, NE verging folding. This deformation created the Tandi Syncline, which consists of Permian to Jurassic Tethyan metasediments cropping out in the core of a large-scale synformal fold within the HHC paragneiss. This tectonic event is interpreted as related to a NE directed nappe stacking (Shikar Beh Nappe), probably during the late Eocene to the early Oligocene. A subsequent D2a phase caused SW verging folding in the HHC. This deformation is interpreted as contemporaneous with late Oligocene to early Miocene SW directed thrusting along the Main Central Thrust. In the Tethyan Zone, a D2b phase is marked by a decollement thrust, a system of reverse faults, and gentle folds, associated with SW directed tectonic movements. This deformation is related to an imbricate structure, characteristic of a shallow structural level, and developed in the frontal part of a nappe affecting the Tethyan Zone units of SE Zanskar (Nyimaling-Tsarap Nappe). A later D3 phase generated the Chandra Dextral Shear Zone (CDSZ), a large-scale, ductile, dextral strike-slip shear zone, located in the transition zone between the HHC and the Tethyan Himalaya. The CDSZ most likely represents a part of a system of early Miocene extensional and/or dextral, strike-slip shear zones-observed at the HHC-Tethyan Zone contact along the entire Himalaya. A final D4 phase induced large-scale doming and NE:verging back folding

Formation of aluminosilicate-bearing quartz veins in the Simano nappe (Central Alps): structural, thermobarometric and oxygen isotope constraints

We combined structural analysis, thermobarometry and oxygen isotope geochemistry to constrain the evolution of kyanite and/or andalusite-bearing quartz veins from the amphibolite facies metapelites of the Simano nappe, in the Central Alps of Switzerland. The Simano nappe records a complex polyphase tectonic evolution associated with nappe stacking during Tertiary Alpine collision (D1). The second regional deformation phase (132) is responsible for the main penetrative schistosity and mineral lineation, and formed during top-to-the-north thrusting. During the next stage of deformation (D3) the aluminosilicate-bearing veins formed by crystallization in tension gashes, in tectonic shadows of boudins, as well as along shear bands associated with top-to-the-north shearing. D2 and D3 are coeval with the Early Miocene metamorphic peak, characterised by kyanite + staurolite + garnet + biotite assemblages in metapelites. The peak pressure (P) and temperature (T) conditions recorded are constrained by multiple-equilibrium thermobarometry at 630 +/- 20 degrees C and 8.5 +/- 1 kbar (similar to 27 km depth), which is in agreement with oxygen isotope thermometry indicating isotopic equilibration of quartz-kyanite pairs at 670 +/- 50 degrees C. Quartz-kyanite pairs from the aluminosilicate-bearing quartz veins yield equilibration temperatures of 645 +/- 20 degrees C, confirming that the veins formed under conditions near metamorphic peak. Quartz and kyanite from veins and the surrounding metapelites have comparable isotopic compositions. Local intergranular diffusion in the border of the veins controls the mass-transfer and the growth of the product assemblage, inducing local mobilization of SiO2 and Al2O3. Andalusite is absent from the host rocks, but it is common in quartz veins, where it often pseudomorphs kyanite. For andalusite to be stable at T-max, the pressure in the veins must have been substantially lower than lithostatic. An alternative explanation consistent with structural observations would be inheritance by andalusite of the kyanite isotopic signature during polymorphic transformation after the metamorphic peak

Tertiary Himalayan structures and metamorphism in the Kulu Valley (Mandi-Khoksar transect of the Western Himalaya) - Shikar-Beh-nappe and crystalline nappe

The Crystalline Nappe of the High Himalayan Crystalline has been examined along the Kulu Valley and its vicinity (Mandi-Khoksar transect). This nappe was believed to have undergone deformation related only to its transport towards the SW essentially during the `'Main Central Thrust event''. New data has led to the conclusion that during the Himalayan orogeny, two distinctive phases, related to two opposite transport directions, characterize the evolution of this part of the chain, before the creation of the late NE-vergent backfolding. The first phase corresponds to an early NE-vergent folding and thrusting, creating the Tandi Syncline and the NE-oriented Shikar Beh Nappe stack, with a displacement amplitude of about 50 km. Two schistosities, together with a strong stretching lineation are developed at a deep tectonic level under amphibolite facies conditions (kyanite-staurolite-garnet-two mica schists). At a higher tectonic level and in the southern part of the section (Tandy Syncline and southern Kulu Valley between Kulu and Mandi) one or two schistosities are developed in the greenschist facies grade rocks (garnet-biotite and biotite schists). These structures and the associated Barrovian type metamorphism are all related to the NE-verging Shikar Beh Nappe. The creation of the NE-verging Shikar Beh Nappe may be explained by the reactivation of a SW dipping listric normal fault of the N Indian flexural passive margin, during the early stages of the Himalayan orogeny. In the second phase, the still hot metamorphic rocks of the Shikar Beh Nappe were folded and thrust towards the SW (mainly along the MBT and the MCT with a displacement in excess of 100 km) onto the cold, low-grade metamorphic rocks of the Larji-Kulu-Rampur Window or, near Mandi, on the non-metamorphic sandstones of the Ganges Molasse (Siwaliks). Sense of shear criteria and a strong NE-SW stretching-lineation indicate that the Crystalline Nappe has been overthrusted towards the SW. Thermometry on synkinematically crystallised garnet-biotite and garnet-hornblende pairs reveals the lower amphibolite facies temperature conditions related to the Crystalline Nappe formation. From the muscovite and biotite Rb-Sr cooling ages, the Shikar Beh Nappe emplacement occurred before 32 Ma and the southwestward thrusting of the Crystalline Nappe began before 21 Ma. Our model involving two opposite directions of thrusting goes against the conventional idea of only one main SW-oriented transport direction in the High Himalayan Crystalline Nappes