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Introduction: Proton beam therapy has been utilised for the treatment of uveal melanoma in the UK for over 30 years, undertaken under a single centre. In the UK, all ocular tumours are treated at one of four centres. We aimed to understand the variation in referral patterns to the UK proton service, capturing all uveal melanoma patients treated with this modality. Methods: Retrospective analysis of data regarding all patients treated at the Clatterbridge Proton service between January 2004 and December 2014. Results: A total of 1084 patients with uveal melanoma were treated. The mean age was 57 years (range 9–90 years), basal diameter of 11.5 mm (range 2.0–23.4 mm) and tumour thickness of 3.9 mm (range 0.1–15.4 mm). The majority were TNM stage I (39%) or II (36%). The distance to the optic nerve varied from 0 to 24.5 mm with 148 (14%) of patients having ciliary body involvement. There were variations in the phenotypic characteristic of the tumours treated with protons from different centres, with London referring predominantly small tumours at the posterior pole, Glasgow referring large tumours often at the ciliary body and Liverpool sending a mix of these groups. Discussion: In the UK, common indications for the use of proton treatment in uveal melanoma include small tumours in the posterior pole poorly accessible for plaque treatment (adjacent to the disc), tumours at the posterior pole affecting the fovea and large anterior tumours traditionally too large for brachytherapy. This is the first UK-wide audit enabling the capture of all patients treated at the single proton centre.

Flowering time is one of the most important traits affecting cultivar adaptation and remains of great interest for breeders. Early flowering genetic stocks have been selected and utilized as models for scientific, breeding, and educational purposes. In this study, Gaspé Flint 1.1.1 (GF111; Reg. no. GS‐11, PI 698804), a new rapid cycle, diminutive maize (Zea maysL.) inbred line, is described. GF111 was developed by repeated selfing (eight cycles) and selection starting from an open‐pollinated accession of the Canadian landrace Gaspé Flint. GF111 can be grown in 1‐L pots and is characterized by short stature (0.4–0.8 m), small number of leaves (8.1–9.7), two ears per plant with only one being fertilized, from zero to one tillers, early flowering (41–50 d after sowing and as little as 357 growing degree units), and very limited protandry. High‐density molecular marker analysis showed a high level of homozygosity (>96%) and an approximately 30‐Mb‐long region shared with the maize reference line B73 on chromosome 10. Because of its high homozygosity, rapid generation cycle, easy hand‐based pollination, good fertility, and limited growing requirements as to space and resources, GF111 has great potential to be used in genetic and gene functional studies, in phenotypic screenings on phenomics platforms, and for teaching activities in plant biology and breeding. Gaspé Flint 1.1.1 is a new maize line with rapid cycle, small size, and simple shoot architecture.Gaspé Flint 1.1.1 grows in 1‐L pots and flowers in 42 d or 360 growing degree units.Gaspé Flint 1.1.1 is proposed as maize genetic model and teaching tool.

Background/aims: Optic nerve sheath fenestration (ONSF) is a surgical intervention in the management of idiopathic intracranial hypertension (IIH) infrequently performed in the United Kingdom. Numerous surgical approaches have been described, including medial transconjunctival, lateral and endoscopic. We describe our outcomes and complications from ONSF via a supero-medial eyelid skin crease incision in patients with IIH. Methods: We performed a retrospective review of consecutive patients undergoing ONSF for IIH between January 2011 and December 2017 by a single surgeon. Results: Thirty patients were included in the analysis with a median follow-up of 14.5 months. Bilateral ONSFs were undertaken in 27 (90%). The data from one eye per patient were analysed. The mean kinetic perimetry score in mean radial degrees of the I4e isopter improved from 27.3° to 35.7°, p= 0.04. After removing cases with optic atrophy, the median modified Frisén grade of papilloedema improved from 2.5 to 1.0, p= 0.007. A total of 5/30 (17%) patients had complications: two (7%) had recurrence/late failure (one managed medically and one with cerebrospinal fluid [CSF] diversion surgery), one had transient cotton wool spots post-operatively, one had transient retinal haemorrhages and one patient had a transiently oval pupil. No patients had repeat ONSF, but CSF diversion surgery was subsequently carried out in 4/30 (13%) patients. Conclusions: ONSF via a supero-medial eyelid skin crease approach is effective at improving visual function in patients with IIH. The complication rates are low when compared with CSF diversion surgery and other surgical approaches for ONSF.

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6–7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37–1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10–2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34–1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21–1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00–1.82 and OR = 0.94, 95% CI = 0.69–1.28, respectively). At ages 13–14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51–1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33–1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84–3.59 and OR = 2.38, 95% CI = 1.52–3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27–1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07–1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.

Purpose: To determine the safety and effectiveness of orbital decompression for thyroid eye disease (TED) in our unit. To put this in the context of previously published literature. Patients and methods: A retrospective case review of all patients undergoing orbital decompression for TED under the care of one orbital surgeon (SMS) between January 2009 and December 2015. A systematic literature review of orbital decompression for TED. Results: Within the reviewed period, 93 orbits of 55 patients underwent decompression surgery for TED. There were 61 lateral (single) wall decompressions, 17 medial one-and-a-half wall, 11 two-and-a-half wall, 2 balanced two wall, and 2 orbital fat only decompressions. For the lateral (single) wall decompressions, mean reduction in exophthalmometry (95% confidence interval (CI) was 4.2 mm (3.7–4.8), for the medial one-and-a-half walls it was 2.9 mm (2.1–3.7), and for the two-and-a-half walls it was 7.6 mm (5.8–9.4). The most common complications were temporary postoperative numbness (29% of lateral decompressions, 17% of other bony decompressions, OR 0.50, 95% CI 0.12–2.11) and new postoperative diplopia (9% of lateral decompressions, 39% of other bony decompressions, OR 6.8, 95% CI 1. 5–30.9). Systematic literature searching showed reduction in exophthalmometry for lateral wall surgery of 3.6–4.8 mm, with new diplopia 0–38% and postoperative numbness 12–50%. For other bony decompressions, reduction in exophthalmometry was 2.5–8.0 mm with new diplopia 0–45% and postoperative numbness up to 52%. Conclusion: Differing approaches to orbital decompression exist. If the correct type of surgery is chosen, then safe, adequate surgical outcomes can be achieved.

Les sténoses ou thromboses de la veine cave supérieure (VCS) sont actuellement fréquemment observées au décours de cathétérismes veineux qui peuvent être un cathéter d’hémodialyse, une sonde de stimulation endocavitaire ou la mise en place d’une chambre implantable (CI). Les lésions de la veine cave supérieure secondaires à la mise en place d’une CI sont plus souvent symptomatiques, liées à la sévérité des lésions et à la toxicité de la chimiothérapie. Nous rapportons notre expérience de six patients traités entre 2007 et 2012, par voie endovasculaire (5 cas) ou par abord chirurgical direct (1 cas). Tous les malades présentaient un syndrome cave cliniquement symptomatique. Chez trois malades, le cathéter était en place lorsque les manifestations cliniques sont survenues. Les explorations morphologiques ont comporté une exploration hémodynamique et morphologique, par échotomographie Doppler et angioscanner. Les lésions étaient : une sténose isolée de la VCS (deux cas) ; une sténose de la VCS associée à une sténose du tronc de Pirogoff droit (un cas) ; une sténose de la VCS associée à une thrombose du tronc veineux innominé gauche et une sténose du confluent de Pirogoff (un) ; une thrombose de la VCS (deux cas). Chez une de ces malades, le thrombus débordait dans l’oreillette droite. Dans ces deux cas, le retour veineux azygos était concerné. Cinq malades ont été traités par voie endovasculaire, par un abord jugulaire droit (deux cas), par un abord bijugulaire (trois cas). Une angioplastie de la VCS avec mise en place d’un stent cave a été réalisée dans deux cas. Une angioplastie cave avec stent et angioplastie du tronc veineux droit ont été réalisées dans un cas. Une angioplastie en kissing, après thrombolyse des deux troncs veineux innominés et de la VCS, avec mise en place d’un stent cave a été réalisée dans un cas. Une angioplastie simple a été réalisée dans un cas, en raison de l’obtention d’un résultat incomplet, avec une lumière résiduelle inférieure à 8mm. Une malade présentait une thrombose complète de la VCS, avec extension du thrombus dans l’oreillette droite. Elle a été traitée par un abord chirurgical par sternotomie médiane verticale, contrôle des deux troncs veineux innominés et clampage latéral de l’oreillette droite. Une thrombo-intimectomie a permis l’extraction du thrombus avec fermeture par une angioplastie en péricarde. Les suites postopératoires ont été satisfaisantes chez cinq patients. Un patient a présenté une tamponnade postopératoire qui a nécessité un drainage péricardique. Le contrôle scanographique a montré un bon résultat morphologique dans cinq cas, un résultat incomplet dans un cas. Les malades ont été suivis cliniquement et par échotomographie Doppler annuel. Le suivi va de deux à six ans. Une malade a présenté une resténose au 7emois, nécessitant une nouvelle angioplastie, réalisée par voie fémorale et mise en place d’une nouvelle chambre implantable par voie cervicale. Les quatre autres malades ont conservé un résultat hémodynamique correct. Deux malades ont présenté une évolutivité métastatique entraînant le décès au 8eet 36emois. En conclusion, le traitement des lésions de la VCS après mise en place d’une chambre implantable est actuellement souvent possible par voie endovasculaire. La chirurgie conventionnelle conserve des indications, lorsque les lésions sont très étendues ou débordent dans l’oreillette droite.

Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitroand impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitroand in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

We investigate a large geodetic data set of interferometric synthetic aperture radar (InSAR) and GPS measurements to determine the source parameters for the three main shocks of the 2016 Central Italy earthquake sequence on 24 August and 26 and 30 October (Mw6.1, 5.9, and 6.5, respectively). Our preferred model is consistent with the activation of four main coseismic asperities belonging to the SW dipping normal fault system associated with the Mount Gorzano‐Mount Vettore‐Mount Bove alignment. Additional slip, equivalent to a Mw~ 6.1–6.2 earthquake, on a secondary (1) NE dipping antithetic fault and/or (2) on a WNW dipping low‐angle fault in the hanging wall of the main system is required to better reproduce the complex deformation pattern associated with the greatest seismic event (the Mw6.5 earthquake). The recognition of ancillary faults involved in the sequence suggests a complex interaction in the activated crustal volume between the main normal faults and the secondary structures and a partitioning of strain release. Coseismic ground deformation of the 2016 Central Italy earthquake sequence measured with InSAR and GPS dataAt least four main normal fault segments played an active role in the sequenceAntithetic faults and/or preexisting compressional structures may have been reactivated during the sequence with extensional kinematics

PurposeSuspicious neoplastic conjunctival lesions often require wide excision with tumour-free margins, leaving significant conjunctival defects requiring reconstruction. In this study we report the results of using fresh frozen amniotic membrane grafts (AMG) after wide excision of potentially malignant lesions.MethodsRetrospective review of 53 patients; between January 2011 and April 2014. Conjunctival lesions were excised with a non-touch technique (2 mm margin) and sent for histopathological analysis. The surgical margins were treated with cryotherapy and a fresh frozen AMG was used to cover the defect. The main features examined were for any signs of recurrence, the conjunctivalisation of the AMG, complications and cosmetic appearance.ResultsFifty-three patients; 35 males and 18 females. Mean age was 54.9 (range 19–88). The mean follow up to January 2015 for all lesions was 21.4 months (range 8–48 months). The most common lesions were invasive malignant melanoma. There were no local surgical complications in 77.3% of patients; minimal scarring (11.3%), symblepharon (11.3%), and granuloma (7.5%). Five patients with conjunctival melanoma developed in-transit metastasis and orbital extension, none of it was at the site of the AMG.ConclusionOur case series is the largest reported to date, with the largest number of melanomas. The use of fresh frozen AMG has improved the local surgical outcomes by improving healing and reducing scarring as well as allowing for a wider surgical margin.

PurposeTo share our initial experience in the use of intralesional interferon alpha-2a at primary presentation in ocular surface tumours as a method of immunoreduction prior to definitive surgical management.MethodsCase series of patients referred to Sheffield Ocular Oncology Service with rapidly growing ocular surface tumours, treated with intralesional interferon alpha-2a at first presentation prior to definitive surgical management.ResultsAll three patients, two with conjunctival melanoma and one with ocular surface squamous neoplasia (OSSN) demonstrated immunoreduction of tumour without any adverse side effects.ConclusionsInterferon alpha-2a is effective in conjunctival melanoma and OSSN. Intralesional interferon at first presentation may be used for immunoreduction prior to definitive surgical management. This may improve surgical and long-term outcomes, improve patient experience, and help meet cancer treatment targets.

Atenolol is the most used drug in Brazil to hypertension treatment. Two crystal structures are known for this molecule: a racemic form (R,S)-atenolol and a pure form S-atenolol. The racemic form is found in commercial tablets. X-ray powder diffraction (XRD) is an adequate tool to study crystalline structures including drugs. Using the Rietveld Method with XRD data it is possible to quantify the crystalline structures existing in the raw material. Other methods like Le Bail and Pawley can be used to the profile fit and phases identification. For this work we analyzed three tablets of atenolol, two generics and the reference (materials were purchased from a drugstore at the city of Araraquara). These tablets were analyzed by Rietveld, Le Bail and Pawley methods. All tablets exhibited the racemic mixture API (R,S)-atenolol. Some crystalline excipients could be characterized: magnesium carbonate hydrate, lactose monohydrate and talc. The conclusion is that the three methods can be efficiently used to characterize the three atenolol tablets.

[Os5C(CO)14]^2- was synthesized on the surface of MgO by reductive carbonylation of adsorbed Os3(CO)12 at 548 K and 1 bar. The supported species were characterized by infrared (IR), ¹³C NMR, and extended X-ray absorption fine structure (EXAFS) spectroscopies. The IR and EXAFS data are consistent with the presence of [Os5C(CO)14]^2-, formed in a yield of about 65%, along with smaller osmium carbonyl clusters. As the supported clusters were decarbonylated in flowing He or H2, they were characterized by IR and EXAFS spectroscopies, which indicate that the decarbonylation was complete after each treatment at 573 K. The EXAFS data characterizing the sample treated in He determine an Os−Os first-shell coordination number of 3.4, matching that of [Os5C(CO)14]^2- and indicating that the Os5C frame was retained after decarbonylation in He. Treatment of MgO-supported [Os5C(CO)14]^2- in H2 at 573 K resulted in the formation of aggregated osmium clusters larger than Os5C. The catalytic activity of Os5C for toluene hydrogenation was found to be an order of magnitude less than that of the aggregated osmium clusters, which are metallic in character.

[Os5C(CO)14]^2- was synthesized in 65% yield on the surface of MgO by treatment of adsorbed [Os3(CO)12] in CO. High-resolution transmission electron microscopy (HRTEM) indicated that the nanoclusters were nearly monodisperse and in the size range consistent with [Os5C(CO)14]^2-. The supported [Os5C(CO)14]^2- was decarbonylated in helium, giving supported nanoclusters that are well approximated as Os5C, as shown by HRTEM and EXAFS data. Decarbonylation in H2 gave larger clusters of osmium, as shown by HRTEM.

The peptide derived from the melanoma-associated protein Melan-A (Melan-A(26-35)/HLA-A2) is an attractive candidate for tumor immunotherapy but little is known about the intracellular processing of this antigen. Here we show that Melan-A is a single-pass membrane protein with an NH(2) terminus exposed to the lumen of the exocytic compartment. In transfected melanoma cells, Melan-A accumulates in the Golgi region. Inversion of the membrane topology leads to the retention of Melan-A in the endoplasmic reticulum. Most strikingly, melanoma cells expressing this form of Melan-A are more effectively recognized by specific CTL than those expressing either Melan-A in its native membrane orientation or Melan-A artificially localized in the cytosol. Our data are compatible with the notion that proteins retained in the endoplasmic reticulum are more efficiently degraded and produce more antigenic peptides.

The authors report the clinical and molecular findings in eight patients with hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome. The most consistent neurologic finding was spastic paraparesis, seen in five of the eight patients. However, all showed signs of pyramidal tract involvement. A broad spectrum of pathogenetic mutations (including missense, nonsense, splice site, insertion, and deletions) were identified in the ORNT1gene.

In this study we analyse coseismic GPS displacements and DInSAR data to constrain a dislocation model for the three largest earthquakes of the 1997 Umbria-Marche seismic sequence. The first two events, which occurred on September 26 at 00:33 GMT (Mw 5.7) and 09:40 GMT (Mw 6.0) respectively, are investigated using both GPS displacements and DInSAR interferograms. We discuss and compare the results of previous studies which separately modeled a smaller subset of geodetic data. We provide a dislocation model for these two earthquakes which fits well both GPS and DInSAR data and agrees with the results of seismological and geological investigations. The first event consists of a unilateral rupture towards the southeast with a uniform dislocation. The strike, rake and dip angles are those resulting from the CMT solution. The second event consists of an unilateral rupture towards the northwest and a variable slip distribution on the fault plane. The strike and the rake are consistent with the CMT solution, but the dip angle has been slightly modified to improve the simultaneous fit of GPS and DInSAR data. While the second rupture (09:40 GMT) arrived very close to the surface, the fit to geodetic data shows that the first rupture (00:33 GMT) is deeper (2 km), despite the more evident surface geological effects. The analysis of new SAR interferograms allows the identification of a 5–6 cm additional displacement caused by the October 3 (Mw 5.2) and 6 (Mw 5.4) seismic events.We use data from a new DInSAR interferogram to model the displacement field of the Sellano earthquake of October 14, 1997. For this event significant GPS measurements were not available. We tested two different fault plane geometries: a blind, planar fault (top depth = 2.4 km), and a curved (listric) fault reaching the surface. The two models provide a generally similar fit to the data, and show that most of the slip was released at depths greater than 2.4 km along a gently dipping (40°–45°) fault surface. They also show that a unilateral rupture does not allow fitting the interferometric fringes since there is evident surface deformation to the northwest of the hypocenter. Moreover, we suggest that the concentration of high residuals in the southern part of our uniform slip model may in fact indicate a certain slip variability in this area.We conclude that, despite the moderate magnitudes and the lack of significant surface faulting, the space geodetic data allowed to constrain dislocation models giving new insights in the rupture process of the three largest events of the sequence.

A priority task for correct environmental planningis to evaluate Natural Hazards, especially inhighly populated areas. In particular, thoroughinvestigations based on different Earth Sciencetechniques must be addressed for the Seismic HazardAssessment (SHA) in tectonically active areas. Notonly the management but also the multidisciplinaryanalysis of all the SHA-related data sets is bestperformed using a Geographic Information System. In this paper we show how a research-oriented GIS isbuilt and used in a practical case. The GeochemicalGeographic Information System (G2IS) wasdeveloped and applied to the Gargano promontory(southern Italy) in the framework of an EC researchproject, the Geochemical Seismic Zonation(GSZ)Project. This multidisciplinary – multiscalingpowerful tool is described in its structure, updatingprocedures and manipulation techniques. Preliminaryresults are presented on the detection of geochemically active fault zonesand theircorrelation with remote sensing data and otherevidences of seismogenic structures.

Abstract:  Abscisic acid (ABA) concentration in leaves of drought-stressed plants is a quantitatively inherited trait. In order to identify quantitative trait loci (QTLs) controlling leaf ABA concentration (L-ABA) in maize, leaf samples were collected from 80 F3:4 families of the cross Os420 (high L-ABA)�IABO78 (low L-ABA) tested under drought conditions in field trials conducted over 2 years. In each year, leaf samples were collected at stem elongation and near anthesis. The genetic map obtained with 106 restriction fragment length polymorphism (RFLP) loci covered 1370 cM, which represented approximately 85% of the UMC maize map. Sixteen different QTLs with a LOD>2.0 were revealed in at least one sampling. Across samplings, only four QTLs significantly influenced L-ABA, accounting for 66% of the phenotypic variation and 76% of the genetic variation among families. At these QTLs, the alleles which increased L-ABA were contributed by Os420. The two most important QTLs were mapped on chromosome 2 near csu133 and csu109a. The effects associated with the QTL near csu133 were more pronounced near anthesis. The support intervals of the four primary QTLs for L-ABA did not overlap the presumed map position of mutants impaired in ABA biosynthesis.

In this prospective study we looked for possible epidemiological and etiological factors in “autonomous” nonspecific duodenitis. Of 136 dyspeptic patients who entered the study, duodenitis was found in 25.6 (94.4 chronic duodenitis and 5.6 isolated active duodenitis). Men predominated with a significant prevalance of 74; 49 of them had white-collar jobs, but age, psychological factors, and the season of the year played no role. We found that smoking and alcohol and coffee intake bore no relation to duodenitis. Helicobacter pylori(HP) was present in only 17.1 of patients with duodenitis, little different from the 10 prevalence in dyspeptic patients without duodenitis. HP was always associated with gastric metaplasia and inflammatory activity.

Among 251 eyes successfully operated on for retinal detachment, the postoperative visual acuity was better in those without preoperative macular detachment (72 eyes) than in those with macular detachment (179 eyes). In eyes with macular detachment, the level of visual acuity obtained postoperatively was not statistically correlated with the duration of detachment for up to eight weeks. After eight weeks, the prognosis for recovery of macular function was reduced significantly according to the duration of detachment.

Pervovskites, Ba[B 1/3Nb2/3]O3 where B = Mn, Fe and Cu have been synthesised by high temperature solid-state reaction. The X-ray diffraction technique indicates that they are single phase cubic disordered structure (a = 4A°) having ordering in c direction (c=9A° At room temperature these materials give high dielectric constant around 2500 to 5000 at 400 Hz. Their room temperature relaxtion spectra in the frequency from 1Hz to 1Mhz indicates the presence of “interfacial polarization”. However, these spectra are characterised by strong conductivity term and relaxtion time constant < 2γsec obtained from Debye's relaxtion equation. Also, the temperature variation of permittivity at 400Hz has been investigated in the range from 300 to 800°K. These curves show a rather slow, steady rise of permittvity from room temperature till a maximum in the range from 500 to 800°K is obtained. These facts implies the presence “diffused phase”. The properties of these materials have been compared with some well-known relaxors.

To determine whether T-cell-receptor (TCR) usage by T cells recognizing a defined human tumor antigen in the context of the same HLA molecule is conserved, we analyzed the TCR diversity of autologous HLA-A2-restricted cytotoxic T-lymphocyte (CTL) clones derived from five patients with metastatic melanoma and specific for the common melanoma antigen Melan-A/MART-1. These clones were first identified among HLA-A2-restricted anti-melanoma CTL clones by their ability to specifically release tumor necrosis factor in response to HLA-A2.1+ COS-7 cells expressing this tumor antigen. A PCR with variable (V)-region gene subfamily-specific primers was performed on cDNA from each clone followed by DNA sequencing. TCRAV2S1 was the predominant alpha-chain V region, being transcribed in 6 out of 9 Melan-A/MART-1-specific CTL clones obtained from the five patients. beta-chain V-region usage was also restricted, with either TCRBV14 or TCRBV7 expressed by all but one clone. In addition, a conserved TCRAV2S1/TCRBV14 combination was expressed in four CTL clones from three patients. None of these V-region genes was found in a group of four HLA-A2-restricted CTL clones recognizing different antigens (e.g., tyrosinase) on the autologous tumor. TCR joining regions were heterogeneous, although conserved structural features were observed in the complementarity-determining region 3 sequences. These results indicate that a selective repertoire of TCR genes is used in anti-melanoma responses when the response is narrowed to major histocompatibility complex-restricted antigen-specific interactions.

The major limitation implicit in the endovascular procedures for aortic prosthetic substitution is that they cannot be used in those tracts of the aorta where important collateral branches originate (aortic arch, thoraco-abdominal tract, upper abdominal), that would be occluded by the prosthesis. In order to overcome this limitation we hypothesized the endovascular positioning of a prosthesis in the form of a wide mesh network that would be gradually and spontaneously covered by new intima and included in the aortic wall. The fabric framework linked to the aortic wall would then condition its significant, regular and uniform mechanical strengthening that fractionates and partially absorbs the centrifuge pulsatile stress of the bloodstream. The purpose of this paper is to report the results of the insertion of a braided Prolene net prosthesis in the first 7 cm of the descending aorta of ten swine. The animals were killed after 6 weeks, the substituted segment removed and aortic wall compliance measured under standardized conditions. The prosthesis was found entirely covered by new intima, well embodied in the aortic wall. The intercostal collateral included in the substituted segment was patent, as proved by bubble formation during underwater insufflation. Compliance of the prosthesis segment was significantly lower than that of the adjacent descending aorta. Histology showed a regular net prosthesis inclusion deep in the neo-intima layer. Present results indicate the technical feasibility of the procedure, achieving significant aortic wall strengthening without affecting the collateral (intercostal) circulation.

HLA-A2-restricted, CD3+, CD8+, alpha/beta+ cytotoxic T cell (CTL) clones were isolated from peripheral blood (PBL) or tumor infiltrating lymphocytes (TIL) of two HLA-A2+ melanoma patients (9742 and 5810), to evaluate the possible recognition of autologous melanoma and of allogeneic HLA-A2-matched normal melanocytes. These CTL clones lysed not only fresh and cultured autologous melanoma cells, but also allogeneic HLA-A2+, but not HLA-A2-, normal melanocytes. The lysis of autologous neoplastic cells and of melanocytes could be inhibited by an anti-HLA-A2 monoclonal antibody (mAb). Lysis of the normal melanocytes was not dependent on the presence of human or fetal calf serum in the culture medium. HLA-A2-restricted CTL clones recognized not only proliferating melanocytes cultured in complete melanocyte medium, but also melanocytes made quiescent by culture for up to 6 d in a basal medium devoid of exogenous factors such as phorbol ester (O-tetradecanoyl phorbol 13-acetate [TPA]), epidermal growth factor, insulin, and pituitary extracts. Analysis of specificity of four CTL clones (A75, A83, A94, and 119) from patient 9742, performed on a panel of 39 targets, indicated that the three HLA-A2-restricted CTL (A75, A83, and A94) lysed all but one of nine allogeneic melanomas expressing the HLA-A2 molecule with no reactivity on nine HLA-A2- allogeneic melanomas. Only a few instances of borderline reactivity were seen by the same effectors on 21 targets of nonmelanocyte lineage, including 12 carcinomas of different histology, four Epstein-Barr virus-transformed B cells (lymphoblastoid cell lines [LCL]), including the autologous LCL, four lines of normal fibroblasts, and normal kidney cells. Lack of reactivity on allogeneic targets of nonmelanocyte lineage occurred in spite of expression of HLA-A2 on 14 of these targets as determined by conventional tissue typing and cytofluorimetric analysis with four different anti-HLA-A2 mAb. These data indicate that tissue-related antigens can be expressed on normal and neoplastic cells of the melanocyte lineage and can be recognized in association with HLA-A2 by CTL clones from melanoma patients.

HLA-A2+ melanomas express common melanoma-associated antigens (Ags) recognized in vitro by autologous cytotoxic T lymphocytes (CTL). However, it is not known whether tumor Ags can drive in vivo a selective accumulation/expansion of Ag-specific, tumor-infiltrating T lymphocytes (TIL). Therefore, to evaluate this possibility, 39 CTL clones isolated from several independent mixed lymphocyte tumor cultures (MLTC) of TIL and peripheral blood lymphocytes (PBL) of an HLA-A2+ melanoma patient and selected for T cell receptor (TCR)-dependent, HLA-restricted tumor lysis, were used for analysis of TCR alpha and beta chain structure by the cDNA polymerase chain reaction (PCR) technique with variable gene-specific primers followed by sequencing. Despite absence of oligoclonality in fresh TIL and PBL, as well as in T cells of day 28 MLTC (day of cloning), sequence analysis of TCR alpha and beta chains of TIL clones revealed a dominance of a major category of melanoma-specific, HLA-A2-restricted T cells expressing a V alpha 8.2/J alpha AP511/C alpha and V beta 2.1/D beta 1/J beta 1.1/C beta 1 TCR. The same TCR was also found in 2 out of 14 PBL clones. The other PBL clones employed a V alpha 2.1 gene segment associated with either V beta 13.2, 14, or w22. Clones A81 (V alpha 2.1/J alpha IGRJ alpha 04/C alpha and V beta 14/D beta 1/J beta 1.2/C beta 1) and A21 (V alpha 8.2/J alpha AP511/C alpha and V beta 2.1/D beta 1/J beta 1.1/C beta 1), representative of the two most frequent TCR of PBL and TIL, respectively, expressed different lytic patterns, but both were HLA-A2 restricted and lysed only HLA-A2+ melanomas and normal melanocytes, thus indicating recognition of two distinct HLA-A2-associated and tissue-related Ags. Finally, by the inverse PCR technique, the specific TCR beta chain (V beta 2.1/D beta 1/J beta 1.1/C beta 1) expressed by the dominant TIL clone was found to represent 19 and 18.4% of all V beta 2 sequences expressed in the fresh tumor sample and in the purified TIL, respectively, but < 0.19% of V beta 2+ sequences expressed in PBL. These results are consistent with the hypothesis that a clonal expansion/accumulation of a melanocyte-lineage-specific and HLA-A2-restricted T cell clone occurred in vivo at the site of tumor growth.

Most complications of descending aorta prosthetic substitution seem mainly to be related directly (ischemia to distal organs, i.e. liver, kidney, spinal cord) or indirectly (extracorporeal circulation or shunts and systemic heparinization complications) to the duration of blood flow interruption. the purpose of this study is to report the results of animal experimentation of a new device for sutureless prosthetic substitution of the descending thoracic aorta, with a very short cross-clamping phase.

Elderly patients are becoming a greater proportion of the hypertensive population. In addition, they may respond differently to drugs, both pharmacodynamically and pharmacokinetically. Therefore, approximately 25 of the patients treated with lacidipine in early studies were over 65 years old. In three double-blind, parallel-group comparative trials, 118 elderly hypertensive patients were treated with lacidipine or comparators, either atenolol, nifedipine SR, or hydrochlorothiazide (HCTZ). Lacidipine was at least as effective in lowering blood pressure as the comparators, as well tolerated as nifedipine SR (but with a significantly lower incidence of edema) and HCTZ, and better tolerated than atenolol. In a double-blind, placebo-controlled, parallel-group, dose—response study of 131 elderly hypertensive patients randomized to receive either lacidipine or placebo, lacidipine significantly reduced the diastolic blood pressure compared with placebo. In the long-term evaluation, more patients required titration with 2 mg of lacidipine than with 4 mg. These results suggest that 4 mg once daily is an effective and well-tolerated antihypertensive treatment in the elderly and, as with the general adult population, represents the optimal long-term maintenance dose.

Elderly patients are becoming a greater proportion of the hypertensive population. In addition, they may respond differently to drugs, both pharmacodynam-ically and pharmacokinetically. Therefore, approximately 25 of the patients treated with lacidipine in early studies were over 65 years old. In three double-blind, parallel-group comparative trials. 118 elderly hypertensive patients were treated with lacidipine or comparators, either atenolol, nifedipine SR, or hydrochlorothiazide (HCTZ). Lacidipine was at least as effective in lowering blood pressure as the comparators, as well tolerated as nifedipine SR (but with a significantly lower incidence of edema) and HCTZ, and better tolerated than atenolol. In a double-blind, placebo-controlled, parallel-group, dose-response study of 131 elderly hypertensive patients randomized to receive either lacidipine or placebo, lacidipine significantly reduced the diastolic blood pressure compared with placebo. In the long-term evaluation, more patients required titration with 2 mg of lacidipine than with 4 mg. These results suggest that 4 mg once daily is an effective and well-tolerated antihypertensive treatment in the elderly and, as with the general adult population, represents the optimal long-term maintenance dose.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

Mutations in the epsilon-sarcoglycangene (SGCE) are associated with familial myoclonus dystonia, but the full spectrum of the phenotype may not be fully defined. We screened 58 individuals with a range of myoclonic/dystonic syndromes for SGCEmutations. We found mutations (four of them novel) in six (21%) of the 29 patients with essential myoclonus and myoclonic dystonia, but did not find mutations in the 29 patients with other phenotypes.

Concomitant pneumonectomy and coronary artery bypass grafting (CABG) carry a high morbidity and mortality rate. We present the case of a patient operated on for left pneumonectomy and off pump CABG through a left thoracotomy incision in a one-stage procedure with a 1-year disease-free follow-up. To the best of our knowledge, simultaneous surgical management as presented in this patient has not been previously reported.

A new technique for bilateral apical bullectomy and pleurectomy via axillary minithoracotomy and transmediastinal access to the contralateral side, was used in 13 patients with bilateral apical blebs and/or pneumothorax. The contralateral space is reached at the posterior superior mediastinum, passing between the first thoracic vertebral bodies (T1-T4) and the oesophagus. The contralateral lung apex is then pulled into the thoracotomy side and apical bullectomy carried out by linear stapler. The obvious advantages of avoiding a second thoracotomy while providing complete solution to the clinical problem are particularly important in young patients with spontaneous pneumothorax caused by bilateral apical blebs.