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In its recent treaties, the European Union (EU) has established a new model of investor-State dispute settlement (ISDS). The EU’s new model entails the replacement of ad hoc arbitration with standing, treaty-based investment tribunals, staffed with judges appointed by the states parties. Awards produced by the EU’s new process will be subject to appellate review on issues of law and fact. The EU has indicated that it will pursue a treaty to multilateralize its new tribunal system. This article addresses the compatibility of the EU’s new ISDS model with existing instruments of the investment treaty regime: first, whether the introduction of an appellate mechanism or, indeed, the total reworking of ISDS to establish investment tribunals, renders instruments like the ICSID Convention and the New York Convention inapplicable to the modified process of ISDS; second, how the integration of any appellate mechanism with existing international investment treaties might technically be achieved.

Background: Recent studies have shown that psoriasis is associated with risk factors for cardiovascular diseases (CVDs). ; Objectives: To evaluate the epidemiological profile of patients with psoriasis, focusing on the risk factors for CVDs and inflammation. ; Materials & Methods: Patients with a diagnosis of psoriasis who were attended at the dermatology outpatient clinic of a university hospital were evaluated. ; Results: 229 adult patients of mean age 50 years, among whom 52% were male, were evaluated. Twenty patients (8.7%) were concomitantly affected by psoriatic arthritis. From analysis on laboratory tests from 177 patients, we saw that 111 (62.7%) were dyslipidemic and that among these, only 9 (8%) were undergoing treatment. 35.6% presented abnormal glycemia tests, but 22% were not having any treatment for the glycemic alteration observed. We analyzed possible associations of the severity of psoriasis and length of time with the disease with lipid disorders, glycemic disorders and systemic arterial hypertension, but did not find any significant associations. ; Conclusion: The findings observed in this study corroborate previous findings in similar studies, thus demonstrating that the prevalence of risk factors for CVDs among patients with psoriasis is greater than in the general population, but that a large proportion of such patients do not undergo treatment for this. We did not find any possible association between the inflammatory process and the genesis of risk factors for CVDs, although the magnitude of this evidence is not strong. These findings serve to alert dermatologists to remain attentive to these factors, among patients with psoriasis.

Unlike other developing states in the 1980s, 1990s and 2000s, Iraq did not participate in the proliferation of bilateral investment treaties and the widespread adoption of arbitration for the resolution of disputes falling within their scope. As a consequence, in the years since the fall of Saddam Hussein and the end of the U.S.-led occupation, Iraq has had to consider how and on what terms it will participate in this global regime. This paper examines the development of international arbitration as an institution in Iraq with reference to both Iraq’s domestic law and its international commitments.

Gorlin-Goltz syndrome is mainly characterised by the development of numerous multicentric and relapsing cutaneous basal cell carcinomas (BCCs). A major problem for patients with Gorlin-Goltz syndrome is the large amount of BCCs that can invade the deep underlying structures, especially the face. Here, we describe the case of a 23-year-old male affected by Gorlin-Goltz syndrome. He had recurrent BCCs on a hairless scalp and dorsum since he was 17 years old and underwent four surgical procedures to excise BCCs, including a reconstruction with anteromedial thigh perforator flap. For each of the surgical procedures, a phenotypic study on peripheral blood mononuclear cells using flow cytometry was performed on the same day of surgery, and on days 7, 14 and 21 after surgery. The role of the tumour-specific cytolytic immune response as a potential future treatment of syndromic BCCs and its trend in relation to surgical ablation of large portions of tumour tissue was examined, and the cosmetic and therapeutic results are shown.

We report on a paleomagnetic study of the southern sector of the Olevano-Antrodoco-Sibillini (OAS) thrust front, which corresponds to the southern limb of the Northern Apennines (Italy) orogenic salient. A lively debate has developed regarding the oroclinal/progressive-arc versus non-rotational nature of the OAS, which has been alternatively interpreted as a dextral strike-slip fault, dextral transpressive fault, or frontal to oblique ramp that reactivated pre-existing Jurassic normal faults. Here, we document the paleomagnetism, integrated with biostratigraphic and structural data, of 52 new sites from both the OAS hanging wall and footwall. On the basis of 39 retained sites, we find a peculiar pattern of tectonic rotations along the OAS thrust that evidences four rotational domains. The thrust footwall is characterized by a southern domain that undergoes an approximately 30° counterclockwise rotation with respect to the stable foreland, and an approximately non-rotated domain. The data from the hanging wall indicate the occurrence of a dextral strike-slip component along the southern sector of the OAS thrust supported by a strong clockwise rotation close to the NE-SW lateral ramp, which rapidly fades 1?km from the thrust front. A slight but significant CW rotation observed in the remaining sites from the hanging wall confirms the progressive nature of the OAS, and its structural position as the southern limb of the Northern Apennines salient. Our detailed paleomagnetic study is crucial in discriminating between progressive-arc- and strike-slip-related components in the main curved orogenic front of the Northern Apennines. We report on a paleomagnetic study from the curved Northern Apennines beltWe document a peculiar pattern of tectonic rotations (four domains)We discriminate arc-related and strike-slip related rotations in curved belts

The article discusses the significant aspects of Digital Smile Design (DSD) for treatment planning and communication in aesthetic dentistry. It provides an overview about DSD, which allows for careful analysis of the patient's facial and dental characteristics along with any critical factors. It also tackles several areas were DSD protocol has the advantages including aesthetic diagnosis, patient management and education.

Non-alcoholic fatty liver disease (NAFLD) is found in individuals who do not drink or abuse alcohol and represents a significant health burden for the general community. NAFLD is often associated with one or more features of the metabolic syndrome and has potential for evolution towards non-alcoholic steatohepatitis (NASH), the necro-inflammatory form of liver steatosis. The most worrisome evolutive events in a subgroup of NASH patients include advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. Pathophysiology of NAFLD/NASH is complex, but studies point to a pre-eminent role of oxidative stress and lipid peroxidation in the liver, including early mitochondrial dysfunction. Changes follow an insulin resistance status with a background of a chronic pro-inflammatory status due to an excess of visceral adiposity. Although no established therapy exists for NAFLD/NASH, potential therapeutic approaches are discussed in this review.

The recent identification of aquaporin-8 (AQP8), an aquaporin (AQP) channel permeable to water and ammonia, in the inner membrane (IMM) of rat liver mitochondria suggested a role for such AQP in the hydration state and the metabolic function of mitochondria. Since thyroid hormone triiodothyronine (T3) is known to modulate both the shape and the metabolic activities of liver mitochondria, it was interesting to investigate the expression and distribution of AQP8 as well as the osmotic water permeability of the IMM in liver mitochondria from rats in different thyroid states. By semi-quantitative reverse transcriptase (RT)-PCR, when compared with the euthyroid counterpart, the levels of hepatic AQP8 mRNA significantly increased in the hypothyroid state, whereas they were strongly decreased after administration of T3. A similar pattern was seen at the protein level by immunoblotting mitochondrial membranes. The upregulation of mitochondrial AQP8 in the hypothyroid liver was confirmed by immunogold electron microscopy. Stopped-flow light scattering with IMM vesicles showed no significant differences in terms of osmotic water permeability among the IMMs in the various thyroid states. Overall, our data indicate that the T3 modulation of the AQP8gene is a rapid downregulation of transcription. Modulation of hepatic AQP8 expression may be relevant to the regulation of mitochondrial metabolism by thyroid hormones.

C57L mice are susceptible and AKR mice are resistant to gallstone formation. We studied in male mice of both strains gallbladder histopathology, cholecystokinin-induced emptying, and concentrating function at 0, 14, 28, and 56 days on a lithogenic diet. Gallbladder wall thickness increased on the diet, with stromal granulocyte infiltration, progressive fibrosis, edema, and epithelial cell indentation, particularly in C57L. Strong basal cholecystokinin octapeptide-induced gallbladder emptying (70% of fasting volumes) occurred in both strains, but fasting gallbladder volumes were significantly larger in C57L (14.8 ± 2.2 µl vs. 8.8 ± 1.0 µl). On the diet, fasting volumes increased exclusively in C57L (28.6 ± 2.9 µl on day 56), with progressively decreased emptying (27% of fasting volumes on day 56). Gallbladder emptying remained normal in AKR. Gallbladder concentrating function decreased on the lithogenic diet (especially in C57L), coinciding with decreased aquaporin-1 (AQP1) and AQP8 expression at the mRNA and protein levels. In additional experiments, similar downregulation of AQP1 and AQP8 mRNA expression occurred in farnesoid X receptor (FXR)-deficient mice after 1 week on the lithogenic diet, without any difference from corresponding wild-type mice. In conclusion, during murine lithogenesis, altered gallbladder histology is associated with impaired motility, reduced concentrating function, and decreased AQP1 and AQP8 expression, the latter without the involvement of the FXR.

The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile, cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of cholesterol molecules into sub microscopic nuclei occurs from these super saturated vesicles. This crucial step is followed by precipitation and agglomeration of cholesterol crystals which then become visible at light microscopy. Here we describe the mechanism of cholesterol crystallization and its modulation in vivo and in vitro. Recent advances on the role of ursodeoxycholate as an agent preventing the precipitation of cholesterol crystals in bile will be highligthed.

The function of the gallbladder is not only to store bile, but also to concentrate it during the interdigestive phase by means of salt-dependent water reabsorption. On the contrary, secretions of water and salt take place during the digestive phase. Dysregulation of ion absorption or secretion are common in many gallbladder diseases, such as colelithiasis. Transepithelial absorptions are determined by the Na +/K+ pump on the basolateral membrane, and by several apical membrane Na+-coupled transporters. Among these, some isoforms of Na+/H+ and Cl-/HCO3 - exchangers have been studied. The presence of a Na+-Cl- simport has been molecularly and functionally characterized in some animal species. The ion transepithelial secretion is mainly dependent on an apical chloride transport attributable to a CFTR-like cAMPactivated channel with high permeability to HCO3 -. The apical membrane electrical potential is one of the factors influencing anion secretion and is maintained by the activity of cAMP-dependent K+ channels. The regulation of the activity of these channels is complex, because of their sensitivity to voltage, and to intracellular calcium and pH. The coordinated interplay underlying the regulation of transporters and channels needs to be clarified yet, as well as the interactions between transporters, channels and aquaporins.

Formation of bile and generation of bile flow are driven by the active secretion of bile salts (BS), lipids and electrolytes into the canalicular and bile duct lumens followed by the osmotic movement of water. Although the transporting proteins involved in solute secretion have been cloned and their coordinated interplay defined both in health and disease, boosted by the discovery of the aquaporin water channels, only recently has considerable attention been addressed to the mechanism by which water, the major component of bile ( 95%), moves across the hepatobiliary epithelia. This review summarizes the novel acquisitions in liver membrane water transport and functional participation of aquaporin water channels in multiple aspects of hepatobiliary fluid balance. Emerging evidences suggesting involvement of aquaporins in the metabolic homeostasis of the hepatobiliary tract are also discussed.

The primum movens in cholesterol gallstone formation is hypersecretion of hepatic cholesterol, chronic surpersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles. Associated events include biochemical defects (increased biliary mucin, and increased proportions of hydrophobic bile salts in the intestine and gallbladder), motility defects (gallbladder smooth muscle hypocontractility in vitro and gallbladder stasis in vivo, sluggish intestinal transit), and an abnormal genetic background. The study of physical-chemical factors and pathways leading to cholesterol crystallization in bile has clinical relevance and the task can be carried out in different ways. The lithogenicity of bile is investigated in artificial model biles made by three biliary lipids - cholesterol, bile salts and phospholipids - variably combined in systems plotting within the equilibrium ternary phase diagram; also, crystallization propensity of ex vivo incubated human bile is studied by biochemical analysis of precipitated crystals, polarizing quantitative light microscopy and turbidimetric methods. The present review will focus on the recent advances in the field of pathobiology of cholesterol gallstones, by underscoring the role of early events like water transport, lipid transport, crystallization phenomena - including a genetic background - in gallstone pathogenesis. Agents delaying or preventing precipitation of cholesterol crystals and gallstone formation in bile will also be discussed.

The involvement of soluble N-ethylmaleimide sensitive factor-attachment protein receptor (SNARE) proteins in the cAMP-induced exocytosis of aquaporin 2 (AQP2)-containing vesicles was investigated in AQP2-transfected renal CD8 cells. RT-PCR and western blot analysis confirmed the presence of the SNARE homologs VAMP/synaptobrevin-2, syntaxin-1, syntaxin-4 and SNAP-23 in CD8 cells. Tetanus neurotoxin (TeNT) was efficient in cleaving synaptobrevin-like protein both in vitro and in intact CD8 cells incubated with the toxin. TeNT treatment in intact CD8 cells completely abolished cAMP-stimulated AQP2 targeting to the plasma membrane, as assessed by quantification of cell-surface immunoreactivity to an anti-AQP2 antibody raised against a peptide reproducing the extracellular AQP2 C-loop. These results represent the first evidence for the functional involvement of VAMP-2 in cAMP-induced AQP2 exocytosis in renal cells.

The involvement of soluble N-ethylmaleimide sensitive factor-attachment protein receptor (SNARE) proteins in the cAMP-induced exocytosis of aquaporin 2 (AQP2)-containing vesicles was investigated in AQP2-transfected renal CD8 cells. RT-PCR and western blot analysis confirmed the presence of the SNARE homologs VAMP/synaptobrevin-2, syntaxin-1, syntaxin-4 and SNAP-23 in CD8 cells. Tetanus neurotoxin (TeNT) was efficient in cleaving synaptobrevin-like protein both in vitro and in intact CD8 cells incubated with the toxin. TeNT treatment in intact CD8 cells completely abolished cAMP-stimulated AQP2 targeting to the plasma membrane, as assessed by quantification of cell-surface immunoreactivity to an anti-AQP2 antibody raised against a peptide reproducing the extracellular AQP2 C-loop. These results represent the first evidence for the functional involvement of VAMP-2 in cAMP-induced AQP2 exocytosis in renal cells.

Fluid secretion and reabsorption are of central importance in male reproductive (MR) physiology. However, the related molecular mechanisms are poorly known. Here, potential roles for AQP7 and AQP8, two aquaporin water channels abundantly expressed in the MR tract, were investigated by studying their expression and distribution in the developing testis of the Wistar rat. By semiquantitative RT-PCR and immunoblotting, first expression of AQP7 was noted at postnatal day 45 (P45), with levels increasing substantially at P90 and remaining at high levels thereafter. AQP8 began to be expressed at P15, rapidly increased until P20, and remained fairly stable thereafter. Immunohistochemical analyses demonstrated AQP7 in elongated spermatids, testicular spermatozoa, and residual bodies at P45 with increased signal intensity thereafter. AQP8 was observed in primary spermatocytes from P20 to P30 and, in elongated spermatids, residual bodies and Sertoli cells at P30 and thereafter. The ontogeny and distribution of AQP7 and AQP8 in rat testis suggest involvement in major physiologic changes in testis development and spermatogenesis.

Spermatogenesis and sperm maturation and storage are accompanied by significant movements of water, and multiple aquaporin transmembrane water channels (AQPs) have been recognized in the male reproductive tract. Nevertheless, the involvement of aquaporins in male reproductive physiology is mostly unknown. Here the expression and localization of AQP8 in rat spermatogenesis is defined and compared to that of AQP7, another aquaporin expressed in male germ cells. AQP8mRNA was found in testis but not in epididymis, whereas the AQP7transcript was present in both locations. By immunoblotting, the AQP8 protein was detected as a 25-kDa band and a 32- to 40-kDa diffuse component corresponding to the core and glycosylated protein, respectively. Membrane fractionation revealed AQP8 both in microsomal and plasma membrane-enriched fractions of rat testis while no apparent bands were detected in epididymis. AQP7 appeared as a 23- to 24-kDa band and was found both in testis and epididymis. By immunofluorescence, AQP8 labeling was found intracellularly as well as over the plasma membrane of germ cells throughout spermatogenesis. AQP7 was present in spermatids and spermatozoa and was predominant over the plasma membrane. AQP8 may be involved in the cytoplasmic condensation occurring during differentiation of spermatids into spermatozoa and in the generation of seminiferous tubule fluid.

Understanding the selectivity of aquaporin water channels will require structural and functional studies of wild-type and modified proteins; however, expression systems have not previously yielded aquaporins in the necessary milligram quantities. Here we report expression of a histidine-tagged form of Escherichia coli aquaporin-Z (AqpZ) in its homologous expression system. 10-His-AqpZ is solubilized and purified to near homogeneity in a single step with a final yield of ∼2.5 mg/l of culture. The histidine tag is removed by trypsin, yielding the native protein with the addition of three N-terminal residues, as confirmed by microsequencing. Sucrose gradient sedimentation analysis showed that the native, solubilized AqpZ protein is a trypsin-resistant tetramer. Unlike other known aquaporins, AqpZ tetramers are not readily dissociated by 1 % SDS at neutral pH. Hydrophilic reducing agents have a limited effect on the stability of the tetramer in 1 % SDS, whereas incubations for more than 24 hours, pH values below 5.6, or exposure to the hydrophobic reducing agent ethanedithiol cause dissociation into monomers. Cys20, but not Cys9, is necessary for the stability of the AqpZ tetramer in SDS. Upon reconstitution into proteoliposomes, AqpZ displays very high osmotic water permeability (pf  10 × 10−14 cm3 s−1 subunit−1) and low Arrhenius activation energy (Ea = 3.7 kcal/mol), similar to mammalian aquaporin-1 (AQP1). No permeation by glycerol, urea or sorbitol was detected. Expression of native and modified AqpZ in milligram quantities has permitted biophysical characterization of this remarkably stable aquaporin tetramer, which is being utilized for high-resolution structural studies.

The Marche‐Abruzzi thrust system is part of the Central Apennine fold‐and‐thrust belt of mainland Italy. Our study area covers the SE portion of the Umbria‐Marche‐Abruzzi region and the northern part of the Gran Sasso Mountains. A thick pile of turbidites is exposed in this area; they were deposited within a Messinian foredeep in front of the evolving fold‐and‐thrust belt. We have used regional structural interpretations together with unpublished well‐log and seismic data to construct a cross‐section across the external portion of the thrust system.

The Umbria-Marche belt constitutes the most southern and external portion of the Northern Apennine Arc. typically convex to the northeast. Within this, the central part (the Umbria-Marche-Sabina Apennines) is the most elevated and is characterized by a locally more pronounced curvature.

The study of the anatomical variations of the external ear is important for the ear surgeon who assesses the middle ear in this way. Furthermore, the design of insert earmoulds for use with either hearing aids or portable radios requires a better knowledge of the shape of the external ear. We studied the external ear structures and the drumhead in 140 cadavers with no previous history of ear pathology. A silicone resin was used, employing a dental impression technique. These permanent impressions were analysed by means of an operating microscope. Different parameters were studied, to determine the average dimensions of the structures. The clinical significance of these results is discussed.

The aquaporin family of molecular water channels is widely expressed throughout the plant and animal kingdoms. No bacterial aquaporins are known; however, sequence-related bacterial genes have been identified that encode glycerol facilitators (glpF). By homology cloning, a novel aquaporin-related DNA (aqpZ) was identified that contained no surface N-glycosylation consensus. The aqpZ RNA was not identified in mammalian mRNA by Northern analysis and exhibited bacterial codon usage preferences. Southern analysis failed to demonstrate aqpZ in mammalian genomic DNA, whereas a strongly reactive DNA was present in chromosomal DNA from Escherichia coli and other bacterial species and did not correspond to glpF. The aqpZ DNA isolated from E. coli contained a 693-base pair open reading frame encoding a polypeptide 28-38% identical to known aquaporins. When compared with other aquaporins, aqpZ encodes a 10-residue insert preceding exofacial loop C, truncated NH2 and COOH termini, and no cysteines at known mercury-sensitive sites. Expression of aqpZ cRNA conferred Xenopus oocytes with a 15-fold increase in osmotic water permeability, which was maximal after 5 days of expression, was not inhibited with HgCl2, exhibited a low activation energy (Ea = 3.8 kcal/mol), and failed to transport nonionic solutes such as urea and glycerol. In contrast, oocytes expressing glpF transported glycerol but exhibited limited osmotic water permeability. Phylogenetic comparison of aquaporins and homologs revealed a large separation between aqpZ and glpF, consistent with an ancient gene divergence.

Water quality in tropical rivers is changing rapidly. The ongoing boom of dam construction for hydropower is one of the drivers for this change. In particular, the stratification in tropical reservoirs induces oxygen deficits in their deep waters and warmer surface water temperatures, which often translate into altered thermal and oxygen regimes of downstream river systems, with cascading consequences for the entire aquatic ecosystem. Operation rules of reservoirs, involving water intakes at different levels, could mitigate the consequences for downstream water quality. However, optimized water management of deep reservoirs relies on predictive models for water quality, but such predictive capability is often lacking for tropical dams. Here we focus on the Zambezi River Basin (southern Africa) to address this gap. Using the one‐dimensional General Lake Model, we reproduced the internal dynamics of the transboundary Lake Kariba, the world’s largest artificial lake by volume, created by damming the Zambezi River at the border between Zambia and Zimbabwe. Through this modeling approach, we assessed and quantified the thermal and oxygen alteration in the Zambezi River downstream of the reservoir. Results suggest that these alterations depend directly on Kariba’s stratification dynamics, its water level and the transboundary policies for water withdrawal from the reservoir. Scenario calculations indicate a large potential for mitigating downstream water quality alterations by implementing a hypothetical selective withdrawal technology. However, we show that a different and cooperative management of the existing infrastructure of Kariba Dam has the potential to mitigate most of the actual water quality alterations. We reproduced water temperature and dissolved oxygen dynamics in the transboundary hydropower reservoir, Kariba, using a 1‐D modelHydropower operations and lake mixing behavior drive unnatural alterations to downstream river water temperature and dissolved oxygenPotential management strategies to improve downstream water quality include selective withdrawal technology and transboundary cooperation We reproduced water temperature and dissolved oxygen dynamics in the transboundary hydropower reservoir, Kariba, using a 1‐D model Hydropower operations and lake mixing behavior drive unnatural alterations to downstream river water temperature and dissolved oxygen Potential management strategies to improve downstream water quality include selective withdrawal technology and transboundary cooperation

Polyglutamine diseases are accompanied by large-scale alterations of transcription that may be responsible for neurodegeneration. We have monitored early transcriptional alterations in a Drosophilamodel for dentatorubral-pallidoluysian atrophy (DRPLA) and reported the critical downregulation of the fattumor suppressor gene. We show that, besides partially mediating neurodegeneration in the Drosophilamodel for DRPLA, fatand the downstream hippopathway are essential for adult neuronal homeostasis. This function of the Fat/Hippo pathway is independent of the well-established actions on proliferation and cell polarity; rather it has an impact upon autophagy, which is blocked and ineffective in fat/hippomutants. These findings reveal the unexpected role in postmitotic neuronal homeostasis of a tumor suppressor pathway and hint at a new player involved directly or indirectly in the regulation of autophagy.

The article presents an overview of the pink hybrid technique, which is used in dentistry in the predictable reconstruction of hard and soft tissue ridge deformities in fixed partial implant restorations. A discussion of information which dental professionals can use to become more proficient in using the pink hybrid technique is presented.

ABSTRACTFluoroquinolone resistance in tuberculosis may rapidly emerge. Mice infected with high titers of aerosolized Mycobacterium tuberculosisand treated for 8 weeks with four concentrations of moxifloxacin (0.125, 0.25, 0.50, and 1.0%) mixed into the diet had drug concentrations of 2.4, 4.1, 5.3, and 17.9 μg/ml, respectively, in blood. Selection of fluoroquinolone-resistant mutants occurred in all surviving mice.