The presence of a booster phenomenon among contacts of active pulmonary tuberculosis cases: a retrospective cohort

Abstract Background Assuming a higher risk of latent tuberculosis (TB) infection in the population of Rio de Janeiro, Brazil, in October of 1998 the TB Control Program of Clementino Fraga Filho Hospital (CFFH) routinely started to recommend a two-step tuberculin skin test (TST) in contacts of pulmonary TB cases in order to distinguish a boosting reaction due to a recall of delayed hypersensitivity previously established by infection with Mycobacterium tuberculosis (M.tb) or BCG vaccination from a tuberculin conversion. The aim of this study was to assess the prevalence of boosted tuberculin skin tests among contacts of individuals with active pulmonary tuberculosis (TB). Methods Retrospective cohort of TB contacts ≥ 12 years old who were evaluated between October 1st, 1998 and October 31st 2001. Contacts with an initial TST ≤ 4 mm were considered negative and had a second TST applied after 7–14 days. Boosting reaction was defined as a second TST ≥ 10 mm with an increase in induration ≥ 6 mm related to the first TST. All contacts with either a positive initial or repeat TST had a chest x-ray to rule out active TB disease, and initially positive contacts were offered isoniazid preventive therapy. Contacts that boosted did not receive treatment for latent TB infection and were followed for 24 months to monitor the development of TB. Statistical analysis of dichotomous variables was performed using Chi-square test. Differences were considered significant at a p < 0.05. Results Fifty four percent (572/1060) of contacts had an initial negative TST and 79% of them (455/572) had a second TST. Boosting was identified in 6% (28/455). The mean age of contacts with a boosting reaction was 42.3 ± 21.1 and with no boosting was 28.7 ± 21.7 (p = 0.01). Fifty percent (14/28) of individuals whose test boosted met criteria for TST conversion on the second TST (increase in induration ≥ 10 mm). None of the 28 contacts whose reaction boosted developed TB disease within two years following the TST. Conclusion The low number of contacts with boosting and the difficulty in distinguishing boosting from TST conversion in the second TST suggests that the strategy of two-step TST testing among contacts of active TB cases may not be useful. However, this conclusion must be taken with caution because of the small number of subjects followed.

Clinical, radiographic and histologic analysis of the effects of pulp capping materials used in pulpotomies of human primary teeth

Aim: To compare the clinical, radiographic and histological responses of the pulp to mineral trioxide aggregate (MTA), calcium hydroxide (CH) and Portland cement (PC) when used as a pulpotomy agent in human primary teeth. Study design: Forty-five mandibular primary molar teeth were randomly assigned to CH, MTA or PC groups and treated by pulpotomy technique. Methods: The teeth were treated by conventional pulpotomy technique, differing only in the capping material for each group. Clinical and radiographic evaluations were recorded at 6-, 12- and 24-month follow-up. Teeth in the regular exfoliation period were further processed for histologic analysis. Statistics: The teeth were treated by conventional pulpotomy technique, differing only in the capping material for each group. Clinical and radiographic evaluations were recorded at 6-, 12- and 24-month follow-up. Teeth in the regular exfoliation period were further processed for histologic analysis. Statistics: Clinically and radiographically, the MTA and PC groups showed 100 % success rates at 6, 12 and 24 months. In CH group, several teeth presented clinical and radiographic failures detected throughout the follow-up period, and internal resorption was a frequent radiographic finding. Histologic analysis revealed the presence of dentine-like mineralised material deposition obliterating the root canal in the PC and MTA groups. CH group presented, in most of the sections, necrotic areas in the root canals. Conclusions: MTA and PC may serve as effective materials for pulpotomies of primary teeth as compared to CH. Although our results are very encouraging, further studies and longer follow-up assessments are needed in order to determine the safe clinical indication of Portland cement.

Reproductive biology of the sea cucumber Holothuria sanctori (Echinodermata: Holothuroidea)

[EN] The reproductive biology of the sea cucumber Holothuria sanctori was studied over 24 months (February 2009 to January 2011) at Gran Canaria through the gonad index and a combination of macro- and microscopic analysis of the gonads. Holothuria sanctori showed a 1:1 sex ratio and a seasonal reproductive cycle with a summer spawning: the mean gonad index showed a maximum (3.99±0.02) in summer (June-July) and a minimum (0.05±0.04) between late autumn (November) and early spring (March). Females had significantly wider gonad tubules than males. First maturity occurred at a size of 201 to 210 mm, a gutted body weight of 101 to 110 g and a total weight of 176 to 200 g. Holothuria sanctori shows a typical temperate species reproduction pattern. These results could be useful for managing current extractions of H. sanctori in the Mediterranean and in case a specific fishery is started in the eastern Atlantic region.

Sistema nervoso enterico e scrapie sperimentale in ovini di razza sarda con diversa suscettibilità genetica nei confronti della malattia

Sebbene il sistema nervoso enterico (“enteric nervous system”, ENS) svolga un ruolo cruciale nella patogenesi della Scrapie ovina, non esistono tuttavia in letteratura dati sulle popolazioni cellulari progressivamente coinvolte nel corso dell’infezione, né sugli eventuali danni morfo-funzionali da esse subiti. Il presente studio è stato condotto sui plessi mienterici e sottomucosi dell’ileo di 46 pecore di razza Sarda, recanti diversi polimorfismi del gene Prnp (ARQ/ARQ, ARQ/AHQ, ARQ/ARR, ARR/ARR). I suddetti animali, infettati per os all’età di 8 mesi con un ceppo di Scrapie precedentemente caratterizzato nel topo, sono stati sacrificati mediante eutanasia a determinati intervalli di tempo post-infezione (p.i.). E’ stata quindi valutata, tramite immunoistochimica ed immunofluorescenza indiretta su sezioni tissutali e su preparati “wholemount”, l’immunoreattività (IR) nei confronti della PrPSc, del “marker” panneuronale Hu C/D, dell’ossido-nitrico sintetasi (nNOS), della calbindina (CALB) e della proteina fibrillare acida gliale (GFAP). In 8 pecore con genotipo ARQ/ARQ, clinicamente sane e sacrificate a 12-24 mesi p.i., nonché in 5 ovini clinicamente affetti (2 con genotipo ARQ/ARQ, 3 con genotipo ARQ/AHQ), questi ultimi sacrificati rispettivamente a 24, 36 e 40 mesi p.i., le indagini immunoistochimiche hanno consentito di dimostrare la presenza di PrPSc a livello sia dell’encefalo (obex), sia dell’ENS, in particolar modo nei plessi mienterici. In tali distretti il deposito della PrPSc risultava pienamente compatibile con un interessamento delle cellule enterogliali (“enteroglial cells”, EGCs), mentre occasionalmente si notava un contestuale coinvolgimento della componente neuronale ivi residente. In conclusione, i dati della presente indagine consentono di ipotizzare un verosimile coinvolgimento delle EGCs e dei neuroni residenti a livello dei plessi dell’ENS nella patogenesi della Scrapie sperimentale realizzata per os in ovini di razza Sarda.

Study of silicon-on-insulator multiple-gate MOS structures including band-gap engineering and self heating effects

The progresses of electron devices integration have proceeded for more than 40 years following the well–known Moore’s law, which states that the transistors density on chip doubles every 24 months. This trend has been possible due to the downsizing of the MOSFET dimensions (scaling); however, new issues and new challenges are arising, and the conventional ”bulk” architecture is becoming inadequate in order to face them. In order to overcome the limitations related to conventional structures, the researchers community is preparing different solutions, that need to be assessed. Possible solutions currently under scrutiny are represented by: • devices incorporating materials with properties different from those of silicon, for the channel and the source/drain regions; • new architectures as Silicon–On–Insulator (SOI) transistors: the body thickness of Ultra-Thin-Body SOI devices is a new design parameter, and it permits to keep under control Short–Channel–Effects without adopting high doping level in the channel. Among the solutions proposed in order to overcome the difficulties related to scaling, we can highlight heterojunctions at the channel edge, obtained by adopting for the source/drain regions materials with band–gap different from that of the channel material. This solution allows to increase the injection velocity of the particles travelling from the source into the channel, and therefore increase the performance of the transistor in terms of provided drain current. The first part of this thesis work addresses the use of heterojunctions in SOI transistors: chapter 3 outlines the basics of the heterojunctions theory and the adoption of such approach in older technologies as the heterojunction–bipolar–transistors; moreover the modifications introduced in the Monte Carlo code in order to simulate conduction band discontinuities are described, and the simulations performed on unidimensional simplified structures in order to validate them as well. Chapter 4 presents the results obtained from the Monte Carlo simulations performed on double–gate SOI transistors featuring conduction band offsets between the source and drain regions and the channel. In particular, attention has been focused on the drain current and to internal quantities as inversion charge, potential energy and carrier velocities. Both graded and abrupt discontinuities have been considered. The scaling of devices dimensions and the adoption of innovative architectures have consequences on the power dissipation as well. In SOI technologies the channel is thermally insulated from the underlying substrate by a SiO2 buried–oxide layer; this SiO2 layer features a thermal conductivity that is two orders of magnitude lower than the silicon one, and it impedes the dissipation of the heat generated in the active region. Moreover, the thermal conductivity of thin semiconductor films is much lower than that of silicon bulk, due to phonon confinement and boundary scattering. All these aspects cause severe self–heating effects, that detrimentally impact the carrier mobility and therefore the saturation drive current for high–performance transistors; as a consequence, thermal device design is becoming a fundamental part of integrated circuit engineering. The second part of this thesis discusses the problem of self–heating in SOI transistors. Chapter 5 describes the causes of heat generation and dissipation in SOI devices, and it provides a brief overview on the methods that have been proposed in order to model these phenomena. In order to understand how this problem impacts the performance of different SOI architectures, three–dimensional electro–thermal simulations have been applied to the analysis of SHE in planar single and double–gate SOI transistors as well as FinFET, featuring the same isothermal electrical characteristics. In chapter 6 the same simulation approach is extensively employed to study the impact of SHE on the performance of a FinFET representative of the high–performance transistor of the 45 nm technology node. Its effects on the ON–current, the maximum temperatures reached inside the device and the thermal resistance associated to the device itself, as well as the dependence of SHE on the main geometrical parameters have been analyzed. Furthermore, the consequences on self–heating of technological solutions such as raised S/D extensions regions or reduction of fin height are explored as well. Finally, conclusions are drawn in chapter 7.

Il Nilotinib nella terapia di prima linea della leucemia mieloide cronica

Background: Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy nilotinib vs imatinib, with higher and faster molecular responses. After 24 months, the rates of progression to accelerated-blastic phase (ABP) were 0.7% and 1.1% with nilotinib 300mg and 400mg BID, respectively, significantly lower compared to imatinib (4.2%). Nilotinib has been approved for the frontline treatment of Ph+ CML. With imatinib 400mg (IRIS trial), the rate of any event and of progression to ABP were higher during the first 3 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely important. Aims: To evaluate the response and the outcome of patients treated for 3 years with nilotinib 400mg BID as frontline therapy. Methods: A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Minimum 36-month follow-up data for all patients will be presented. Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio <0,1%IS; Complete Molecular Response (CMR): undetectable transcript levels with ≥10,000 ABL transcripts; failures: according to the revised ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Results: 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR at 12 months was 100%. CCgR at each milestone: 78%, 96%, 96%, 95%, 92% at 3, 6, 12, 18 and 24 months, respectively. The overall estimated probability of MMR was 97%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The overall estimated probability of CMR was 79%, while the rates of CMR at 12 and 24 months were 12% and 27%, respectively. No patient achieving a MMR progressed to AP. Only one patient progressed at 6 months to ABP and subsequently died (high Sokal risk, T315I mutation). Adverse events were mostly grade 1 or 2 and manageable with appropriate dose adaptations. During the first 12 months, the mean daily dose was 600-800mg in 74% of patients. The nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%), 6 permanent discontinuations. Detail of discontinuation: 1 patient progressed to ABP; 3 patients had recurrent episodes of amylase and/or lipase increase (no pancreatitis); 1 patient had atrial fibrillation (unrelated to study drug) and 1 patient died after 32 months of mental deterioration and starvation (unrelated to study drug). Two patients are currently on imatinib second-line and 2 on dasatinib third-line. With a median follow-up of 39 months, the estimated probability of overall survival, progression-free survival and failure-free survival was 97%, the estimated probability of event-free survival was 91%. Conclusions: The rate of failures was very low during the first 3 years. Responses remain stable. The high rates of responses achieved during the first 12 months are being translated into optimal outcome for most of patients.

Valutazione dell’impiego dei test per la genotipizzazione di HPV e l’espressione degli oncogeni virali nel follow-up di donne conizzate per lesioni cervicali di alto grado nello screening del cervico-carcinoma della Regione Emilia-Romagna

Obiettivi: Valutare la prevalenza dei diversi genotipi di HPV in pazienti con diagnosi di CIN2/3 nella Regione Emilia-Romagna, la persistenza genotipo-specifica di HPV e l’espressione degli oncogeni virali E6/E7 nel follow-up post-trattamento come fattori di rischio di recidiva/persistenza o progressione di malattia; verificare l’applicabilità di nuovi test diagnostici biomolecolari nello screening del cervicocarcinoma. Metodi: Sono state incluse pazienti con citologia di screening anormale, sottoposte a trattamento escissionale (T0) per diagnosi di CIN2/3 su biopsia mirata. Al T0 e durante il follow-up a 6, 12, 18 e 24 mesi, oltre al Pap test e alla colposcopia, sono state effettuate la ricerca e la genotipizzazione dell'HPV DNA di 28 genotipi. In caso di positività al DNA dei 5 genotipi 16, 18, 31, 33 e/o 45, si è proceduto alla ricerca dell'HPV mRNA di E6/E7. Risultati preliminari: Il 95.8% delle 168 pazienti selezionate è risultato HPV DNA positivo al T0. Nel 60.9% dei casi le infezioni erano singole (prevalentemente da HPV 16 e 31), nel 39.1% erano multiple. L'HPV 16 è stato il genotipo maggiormente rilevato (57%). Il 94.3% (117/124) delle pazienti positive per i 5 genotipi di HPV DNA sono risultate mRNA positive. Abbiamo avuto un drop-out di 38/168 pazienti. A 18 mesi (95% delle pazienti) la persistenza dell'HPV DNA di qualsiasi genotipo era del 46%, quella dell'HPV DNA dei 5 genotipi era del 39%, con espressione di mRNA nel 21%. Abbiamo avuto recidiva di malattia (CIN2+) nel 10.8% (14/130) a 18 mesi. Il pap test era negativo in 4/14 casi, l'HPV DNA test era positivo in tutti i casi, l'mRNA test in 11/12 casi. Conclusioni: L'HR-HPV DNA test è più sensibile della citologia, l'mRNA test è più specifico nell'individuare una recidiva. I dati definitivi saranno disponibili al termine del follow-up programmato.

Efficacia e complicanze durante la curva di apprendimento della Thulep: risultati a breve e medio termine delle prime 48 procedure

MATERIALI E METODI: Tra il 2012 e il 2013, abbiamo analizzato in uno studio prospettico i dati di 48 pazienti sottoposti a ThuLEP con approccio autodidatta. I pazienti sono stati rivalutati a 3, 6, 12 e 24 mesi con la valutazione del PSA, il residuo post-minzionale (RPM), l'uroflussometria (Qmax), l'ecografia transrettale e questionari validati (IPSS: international prostate symptom score e QoL: quality of life) RISULTATI: Il volume medio della prostata è di 63 ± 5,3 ml. Il tempo operatorio medio è stato di 127,58 ± 28.50 minuti. Il peso medio del tessuto asportato è stato di 30,40 ± 13,90 gr. A 6 mesi dopo l'intervento l'RPM medio è diminuito da 165,13 ± 80,15 ml a 7,78 ± 29.19 ml, mentre il Qmax medio è aumentato da 5.75 ± 1.67ml / s a 18.1 ± 5.27 ml / s. I valori medi dei IPSS e QoL hanno dimostrato un progressivo miglioramento: da 19.15 (IQR: 2-31) e 4 (IQR: 1-6) nel preoperatorio a 6.04 (IQR: 1-20) e 1.13 (IQR: 1-4), rispettivamente. Durante la curva di apprendimento si è assistito ad un progressivo aumento del peso del tessuto enucleato e ad una progressiva riduzione del tempo di ospedalizzazione e di cateterismo. Tra le principali complicanze ricordiamo un tasso di incontinenza transitoria del 12,5% a 3 mesi e del 2.1% a 12 mesi. CONCLUSIONI: ThuLEP rappresenta una tecnica chirurgica efficace, sicura e riproducibile indipendentemente dalle dimensioni della prostata. I nostri dati suggeriscono che la ThuLEP offre un miglioramento significativo dei parametri funzionali comparabili con le tecniche tradizionali, nonostante una lunga curva di apprendimento.

Funktionelle Analyse der Plasmamembran-Ca 2+-ATPase 2 -PMCA2- in Modellen der Neurodegeneration

Calcium (Ca2+) ist ein ubiquitär vorkommendes Signalmolekül, das an der Regulation zahlreicher zellulärer Prozesse, von der Proliferation bis zum programmierten Zelltod, beteiligt ist. Daher müssen die intrazellulären Ca2+-Spiegel streng kontrolliert werden. Veränderungen der Ca2+-Homöostase während der altersassoziierten Neurodegeneration können dazu beitragen, dass Neuronen vulnerabler sind. So wurden erhöhte Ca2+-Konzentrationen in gealterten Neuronen, begleitet von einer erhöhten Vulnerabilität, beobachtet (Hajieva et al., 2009a). Weiterhin wird angenommen, dass der selektive Untergang von dopaminergen Neuronen bei der Parkinson Erkrankung auf eine erhöhte Ca2+-Last zurückzuführen sein könnte, da diese Neuronen einem ständigen Ca2+-Influx,rnaufgrund einer besonderen Isoform (CaV 1.3) spannungsgesteuerter Ca2+-Kanäle des L-Typs, ausgesetzt sind (Chan et al., 2007). Bislang wurden die molekularen Mechanismen, die einem Ca2+-Anstieg zu Grunde liegen und dessen Auswirkung jedoch nicht vollständig aufgeklärt und daher in der vorliegenden Arbeit untersucht. Um Veränderungen der Ca2+-Homöostase während der altersassoziiertenrnNeurodegeneration zu analysieren wurden primäre Mittelhirnzellen aus Rattenembryonen und SH-SY5Y-Neuroblastomazellen mit dem Neurotoxin 1-Methyl-4-Phenyl-Pyridin (MPP+), das bei der Etablierung von Modellen der Parkinson-Erkrankung breite Anwendung findet, behandelt. Veränderungen der intrazellulären Ca2+-Konzentration wurden mit einem auf dem grün fluoreszierenden Protein (GFP)-basierten Ca2+-Indikator,rn„Cameleon cpYC 3.6“ (Nagai et al., 2004), ermittelt. Dabei wurde in dieser Arbeit gezeigt, dass MPP+ die Abregulation der neuronenspezifischen ATP-abhängigen Ca2+-Pumpe der Plasmamembran (PMCA2) induziert, die mit der Ca2+-ATPase des endoplasmatischen Retikulums (SERCA) und dem Na+/Ca2+-Austauscher (NCX) das zelluläre Ca2+-Effluxsystem bildet, was zu einer erhöhten zytosolischen Ca2+-Konzentration führt. Die PMCA2-Abnahme wurde sowohl auf Transkriptionsebene als auch auf Proteinebene demonstriert, während keine signifikanten Veränderungen der SERCA- und NCX-Proteinmengen festgestellt wurden. Als Ursache der Reduktion der PMCA2-Expression wurde eine Abnahme des Transkriptionsfaktors Phospho-CREB ermittelt, dessen Phosphorylierungsstatus abhängig von der Proteinkinase A (PKA) war. Dieser Mechanismus wurde einerseits unter MPP+-Einfluss und andererseits vermittelt durch endogene molekulare Modulatoren gezeigt. Interessanterweise konnten die durch MPP+ induzierte PMCA2-Abregulation und der zytosolische Ca2+-Anstieg durch die Aktivierung der PKA verhindert werden. Parallel dazu wurde eine MPP+-abhängige verringerte mitochondriale Ca2+-Konzentration nachgewiesen, welche mit einer Abnahme des mitochondrialen Membranpotentials korrelierte. Darüber hinaus kam es als Folge der PMCA2-Abnahme zu einem verminderten neuronalen Überleben.rnVeränderungen der Ca2+-Homöostase wurden auch während der normalen Alterung inrnprimären Fibroblasten und bei Mäusen nachgewiesen. Dabei wurden verringerte PMCA und SERCA-Proteinmengen in gealterten Fibroblasten, einhergehend mit einem Anstieg der zytosolischen Ca2+-Konzentration demonstriert. Weiterhin wurden verringerte PMCA2-Proteinmengen im Mittelhirn von gealterten Mäusen (C57B/6) detektiert.rnDer zelluläre Ca2+-Efflux ist somit sowohl im Zuge der physiologischen Alterung als auch in einem altersbezogenen Krankheitsmodell beeinträchtigt, was das neuronale Überleben beeinflussen kann. In zukünftige Studien soll aufgeklärt werden, welche Auswirkungen einer PMCA2-Reduktion genau zu dem Verlust von Neuronen führen bzw. ob durch eine PMCA2-Überexpression neurodegenerative Prozesse verhindert werden können.

Vergleichende, prospektive Untersuchung der Arzneimittelcompliance, Funktionskapazität und Lebensqualität bei Patienten mit Rheuma, die mit Methotrexat peroral oder subkutan behandelt werden

Um einen positiven Einfluss auf den Krankheitsverlauf bei Patienten mit Rheumatoider Arthritis zu nehmen, ist die Compliance mit dem Basistherapeutikum Methotrexat unerlässlich. Therapietreue mit Methotrexat kann die Krankheitsprogression verhindern und irreversiblen Knochenerosionen vorbeugen. Methotrexat wird sowohl in subkutaner als auch in peroraler Applikationsform verordnet. Im Rahmen der vorliegenden Arbeit wurde die Compliance mit der Anwendung von Methotrexat Fertigspritzen und Tabletten mit einer elektronischen Messmethode (MEMS™) bestimmt. Hauptziel der Studie war die Bestimmung der Taking Compliance mit Methotrexat. Untersucht wurde hinsichtlich eines Unterschieds zwischen der Applikationsform und der Erkrankungsdauer. Daneben wurde die Dosing Compliance mit peroralem Methotrexat erfasst, sowie Einschätzungen der Patienten bezüglich der Compliance, Funktionskapazität, Lebensqualität und Zufriedenheit erhoben. Die Compliancestudie erfolgte in Kooperation mit dem Netzwerk ADAPTHERA. 74 Studienpatienten wurden 3 Gruppen zugeteilt: Gruppe 1 Methotrexat p.o.; Gruppe 2 Methotrexat s.c. und Erkrankungsdauer <24 Monate; Gruppe 3 Methotrexat s.c. und Erkrankungsdauer >24 Monate. Die Beobachtungsdauer betrug bei peroraler Applikationsform 9 Monate und bei subkutaner 6 Monate. Im Median wurde eine Taking und Dosing Compliance von 100% gemessen. Anhand der subjektiven Einschätzung der Patienten zur Funktionskapazität konnten geringe Einschränkungen für die Patienten im Alltag verzeichnet werden. 25% des Studienkollektivs litt unter einem reduzierten Wohlbefinden. Die Studie konnte zeigen, dass Patienten von einer frühzeitigen Therapie und einer hohen Compliancerate profitieren.

Early loading after 21 days of healing of nonsubmerged titanium implants with a chemically modified sandblasted and acid-etched surface: two-year results of a prospective two-center study

PURPOSE: The aim of this two-center study was to evaluate screw-type titanium implants with a chemically modified, sandblasted and acid-etched surface when placed in the posterior maxilla or mandible, and loaded 21 days after placement. MATERIAL AND METHODS: All 56 patients met strict inclusion criteria and provided informed consent. Each patient displayed either a single-tooth gap, an extended edentulous space, or a distal extension situation in the posterior mandible or maxilla. Eighty-nine dental implants (SLActive, Institut Straumann AG, Basel, Switzerland) were inserted according to an established nonsubmerged protocol and underwent undisturbed healing for a period of 21 days. Where appropriate, the implants were loaded after 21 days of healing with provisional restorations in full occlusion. Definitive metal ceramic restorations were fabricated and positioned on each implant after 6 months of healing. Clinical measurements regarding soft tissue parameters and radiographs were obtained at different time points up to 24 months after implant placement. RESULTS: Of the 89 inserted implants, two (2.2%) implants failed to integrate and were removed during healing, and two (2.2%) additional implants required a prolonged healing time. A total of 85 (95.6%) implants were therefore loaded without incident after 21 days of healing. No additional implant was lost throughout the study period, whereas one implant was lost to follow-up and therefore left unaccounted for further analysis. The remaining 86 implants all exhibited favorable radiographic and clinical findings. Based on strict success criteria, these implants were considered successfully integrated 2 years after insertion, resulting in a 2-year success rate of 97.7%. CONCLUSION: The results of this prospective two-center study demonstrate that titanium implants with a modified SLA surface can predictably achieve successful tissue integration when loaded in full occlusion 21 days after placement. Integration could be maintained without incident for at least 2 years of follow-up.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi

Objective  Malnutrition is common in HIV-infected children in Africa and an indication for antiretroviral treatment (ART). We examined anthropometric status and response to ART in children treated at a large public-sector clinic in Malawi. Methods  All children aged <15 years who started ART between January 2001 and December 2006 were included and followed until March 2008. Weight and height were measured at regular intervals from 1 year before to 2 years after the start of ART. Sex- and age-standardized z-scores were calculated for weight-for-age (WAZ) and height-for-age (HAZ). Predictors of growth were identified in multivariable mixed-effect models. Results  A total of 497 children started ART and were followed for 972 person-years. Median age (interquartile range; IQR) was 8 years (4–11 years). Most children were underweight (52% of children), stunted (69%), in advanced clinical stages (94% in WHO stages 3 or 4) and had severe immunodeficiency (77%). After starting ART, median (IQR) WAZ and HAZ increased from −2.1 (−2.7 to −1.3) and −2.6 (−3.6 to −1.8) to −1.4 (−2.1 to −0.8) and −1.8 (−2.4 to −1.1) at 24 months, respectively (P < 0.001). In multivariable models, baseline WAZ and HAZ scores were the most important determinants of growth trajectories on ART. Conclusions  Despite a sustained growth response to ART among children remaining on therapy, normal values were not reached. Interventions leading to earlier HIV diagnosis and initiation of treatment could improve growth response.

Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy associated with defective regulation of the alternative complement pathway. The prognosis for patients with aHUS is poor, and plasma exchange represents the first-line therapy. Eculizumab is a humanized monoclonal anti-C5 antibody that prevents the activation of the terminal complement pathway. Here, we report the case of a 9-year-old girl with frequent relapsing aHUS due to heterozygous factor H mutation who was initially treated with plasma exchange three times per week with 150% plasma exchange volume. This treatment frequently caused allergic reactions and school absences. Because any reduction in the frequency of plasma exchange immediately induced relapses of the aHUS, treatment with eculizumab, 600 mg every 2 weeks, was started and plasma exchange completely stopped. On this drug regimen the patient showed no evidence of disease activity during a period of more than 24 months. Renal function improved, proteinuria disappeared, the number of antihypertensive medications could be decreased, and the quality of life increased substantially. The inhibition of the terminal complement pathway by eculizumab was also confirmed by renal biopsy, which showed the absence of thrombotic microangiopathy 2 months after the initiation of eculizumab therapy. This case illustrates the long-term favorable outcome of aHUS with eculizumab treatment.

Prediction of Psychosis by Mismatch Negativity

BACKGROUND: To develop risk-adapted prevention of psychosis, an accurate estimation of the individual risk of psychosis at a given time is needed. Inclusion of biological parameters into multilevel prediction models is thought to improve predictive accuracy of models on the basis of clinical variables. To this aim, mismatch negativity (MMN) was investigated in a sample clinically at high risk, comparing individuals with and without subsequent conversion to psychosis. METHODS: At baseline, an auditory oddball paradigm was used in 62 subjects meeting criteria of a late risk at-state who remained antipsychotic-naive throughout the study. Median follow-up period was 32 months (minimum of 24 months in nonconverters, n = 37). Repeated-measures analysis of covariance was employed to analyze the MMN recorded at frontocentral electrodes; additional comparisons with healthy controls (HC, n = 67) and first-episode schizophrenia patients (FES, n = 33) were performed. Predictive value was evaluated by a Cox regression model. RESULTS: Compared with nonconverters, duration MMN in converters (n = 25) showed significantly reduced amplitudes across the six frontocentral electrodes; the same applied in comparison with HC, but not FES, whereas the duration MMN in in nonconverters was comparable to HC and larger than in FES. A prognostic score was calculated based on a Cox regression model and stratified into two risk classes, which showed significantly different survival curves. CONCLUSIONS: Our findings demonstrate the duration MMN is significantly reduced in at-risk subjects converting to first-episode psychosis compared with nonconverters and may contribute not only to the prediction of conversion but also to a more individualized risk estimation and thus risk-adapted prevention.