998 resultados para Graf, Urs, approximately 1485-approximately 1527.


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A recent modelling study has shown that precipitation and runoff over land would increase when the reflectivity of marine clouds is increased to counter global warming. This implies that large scale albedo enhancement over land could lead to a decrease in runoff over land. In this study, we perform simulations using NCAR CAM3.1 that have implications for Solar Radiation Management geoengineering schemes that increase the albedo over land. We find that an increase in reflectivity over land that mitigates the global mean warming from a doubling of CO2 leads to a large residual warming in the southern hemisphere and cooling in the northern hemisphere since most of the land is located in northern hemisphere. Precipitation and runoff over land decrease by 13.4 and 22.3%, respectively, because of a large residual sinking motion over land triggered by albedo enhancement over land. Soil water content also declines when albedo over land is enhanced. The simulated magnitude of hydrological changes over land are much larger when compared to changes over oceans in the recent marine cloud albedo enhancement study since the radiative forcing over land needed (-8.2 W m(-2)) to counter global mean radiative forcing from a doubling of CO2 (3.3 W m(-2)) is approximately twice the forcing needed over the oceans (-4.2 W m(-2)). Our results imply that albedo enhancement over oceans produce climates closer to the unperturbed climate state than do albedo changes on land when the consequences on land hydrology are considered. Our study also has important implications for any intentional or unintentional large scale changes in land surface albedo such as deforestation/afforestation/reforestation, air pollution, and desert and urban albedo modification.

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Double beam modulation is widely used in atomic collision experiments in the case where the noise arising froth each of the beams exceeds the measured signal. A method for minimizing the statistical uncertainty in a measured signal in a given time period is discussed, and a flexible modulation and counting system based on a low cost PIC microcontroller is described. This device is capable of modifying the acquisition parameters in real time during the course of an experimental run. It is shown that typical savings in data acquisition time of approximately 30% can be achieved using this optimized modulation scheme.

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Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. CONCLUSION: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.

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PURPOSE: Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS: Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS: A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION: Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.

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Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow- up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.

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When modeling real-world decision-theoretic planning problems in the Markov Decision Process (MDP) framework, it is often impossible to obtain a completely accurate estimate of transition probabilities. For example, natural uncertainty arises in the transition specification due to elicitation of MOP transition models from an expert or estimation from data, or non-stationary transition distributions arising from insufficient state knowledge. In the interest of obtaining the most robust policy under transition uncertainty, the Markov Decision Process with Imprecise Transition Probabilities (MDP-IPs) has been introduced to model such scenarios. Unfortunately, while various solution algorithms exist for MDP-IPs, they often require external calls to optimization routines and thus can be extremely time-consuming in practice. To address this deficiency, we introduce the factored MDP-IP and propose efficient dynamic programming methods to exploit its structure. Noting that the key computational bottleneck in the solution of factored MDP-IPs is the need to repeatedly solve nonlinear constrained optimization problems, we show how to target approximation techniques to drastically reduce the computational overhead of the nonlinear solver while producing bounded, approximately optimal solutions. Our results show up to two orders of magnitude speedup in comparison to traditional ""flat"" dynamic programming approaches and up to an order of magnitude speedup over the extension of factored MDP approximate value iteration techniques to MDP-IPs while producing the lowest error of any approximation algorithm evaluated. (C) 2011 Elsevier B.V. All rights reserved.

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Over the last few decades, informal caregivers of patients with chronic diseases have received more attention, and there is a growing volume of studies demonstrating high rates of burden, stress, and mental disorders in this group of individuals. The objective of this study was to evaluate the burden, stress, and psychosocial characteristics of informal caregivers of liver transplantation candidates. Participants were assessed by individual evaluations with the following instruments: a semi-structured interview, the Caregiver Burden Scale, the Inventario de Sintomas de Stress para Adultos de Lipp, and the Beck Depression Inventory. The Mann-Whitney test was used for statistical analysis with a significance level of 0.05. The characteristics of the study group (n = 61) were similar to those of groups in other studies with respect to gender (82% were women), kinship (64% were spouses), and age (the mean age was 47.6 years). The main stressors identified by the participants were as follows: doubts about ways to react in a crisis or in emergency situations (42.6%), mood swings of the patient (29.5%), and care involving food and medications (27.9%). Approximately 25% of the caregivers reported that they felt unprepared to adequately perform their roles. Data analysis indicated a greater burden overall on caregivers when the patient`s Model for End-Stage Liver Disease score was greater than or equal to 15 points (P = 0.041). Furthermore, caregivers of patients with alcoholic liver disease showed higher depression (P = 0.034) and overall burden scores (P = 0.031) versus caregivers of patients with liver disease due to other etiologies. In conclusion, the participants showed significantly high levels of burden, stress, and depression. Support measures and caregiver preparation should be implemented by health care providers. Liver Transpl 16: 1164-1168, 2010. (C) 2010 AASLD.

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Approximately 25% of acute myeloid leukemias (AMLs) carry internal tandem duplications (ITD) of various lengths within the gene encoding the FMS-like tyrosine kinase receptor 3 (FLT3). Although varying duplication sites exist, most of these length mutations affect the protein´s juxtamembrane domain. FLT3-ITDs support leukemic transformation by constitutive phosphorylation resulting in uncontrolled activation, and their presence is associated with worse prognosis. As known form previous work, they represent leukemia- and patient-specific neoantigens that can be recognized by autologous AML-reactive CD8+ T cells (Graf et al., 2007; Graf et al., unpublished). Herein, in patient FL, diagnosed with FLT3-ITD+ AML and in first complete remission after induction chemotherapy, T cells against her leukemia´s individual FLT3-ITD were detected at a frequency up to 1.7x10-3 among peripheral blood CD8+ T lymphocytes. This rather high frequency suggested, that FLT3-ITD-reactive T cells had been expanded in vivo due to the induction of an anti-leukemia response.rnrnCell material from AML patients is limited, and the patients´ anti-leukemia T-cell repertoire might be skewed, e.g. due to complex previous leukemia-host interactions and chemotherapy. Therefore, allogeneic sources, i.e. buffy coats (BCs) from health donors and umbilical cord blood (UCB) donations, were exploited for the presence and the expansion of FLT3-ITD-reactive T-cell populations. BC- and UCB-derived CD8+ T cells, were distributed at 105 cells per well on microtiter plates and, were stimulated with antigen-presenting cells (APCs) transfected with in vitro-transcribed mRNA (IVT-mRNA) encoding selected FTL3-ITDs. APCs were autologous CD8- blood mononuclear cells, monocytes or FastDCs.rnrnBuffy coat lymphocytes from 19 healthy individuals were analyzed for CD8+ T-cell reactivity against three immunogenic FLT3-ITDs previously identified in patients VE, IN and QQ and designated as VE_, IN_ and QQ_FLT3-ITD, respectively. These healthy donors carried at least one of the HLA I alleles known to present an ITD-derived peptide from one of these FLT3-ITDs. Reactivities against single ITDs were observed in 8/19 donors. In 4 donors the frequencies of ITD-reactive T cells were determined and were estimated to be in the range of 1.25x10-6 to 2.83x10-7 CD8+ T cells. These frequencies were 1,000- to 10,000-fold lower than the frequency of autologous FLT3-ITD-reactive T cells observed in patient FL. Restricting HLA I molecules were identified in two donors. In one of them, the recognition of VE_FLT3-ITD was found to be restricted by HLA-C*07:02, which is different from the HLA allele restricting the anti-ITD T cells of patient VE. In another donor, the recognition of IN_FLT3-ITD was restricted by HLA-B*35:01, which also had been observed in patient IN (Graf et al., unpublished). By gradual 3´-fragmentation of the IN_FLT3-ITD cDNA, the 10-mer peptide CPSDNEYFYV was identified as the target of allogeneic T cells against IN_FLT3-ITD. rnLymphocytes in umbilical cord blood predominantly exhibit a naïve phenotype. Seven UCB donations were analyzed for T-cell responses against the FLT3-ITDs of patients VE, IN, QQ, JC and FL irrespective of their HLA phenotype. ITD-reactive responses against all stimulatory FLT3-ITDs were observed in 5/7 UCB donations. The frequencies of T cells against single FLT3-ITDs in CD8+ lymphocytes were estimated to be in the range of 1.8x10-5 to 3.6x10-6, which is nearly 15-fold higher than the frequencies observed in BCs. Restricting HLA I molecules were identified in 4 of these 5 positive UCB donations. They were mostly different from those observed in the respective patients. But in one UCB donation T cells against the JC_FLT3-ITD had exactly the same peptide specificity and HLA restriction as seen before in patient JC (Graf et al., 2007). Analyses of UCB responder lymphocytes led to the identification of the 10-mer peptide YESDNEYFYV, encoded by FL_FLT3-ITD, that was recognized in association with the frequent allele HLA-A*02:01. This peptide was able to stimulate and enrich ITD-reactive T cells from UCB lymphocytes in vitro. Peptide responders not only recognized the peptide, but also COS-7 cells co-transfected with FL_FLT3-ITD and HLA-A*02:01.rnrnIn conclusion, T cells against AML- and individual-specific FLT3-ITDs were successfully generated not only from patient-derived blood, but also from allogeneic sources. Thereby, ITD-reactive T cells were detected more readily and at higher frequencies in umbilical cord blood than in buffy coat lymphocytes. It occurred that peptide specificity and HLA restriction of allogeneic, ITD-reactive T cells were identical to autologous patient-derived T cells. As shown herein, allogeneic, FLT3-ITD-reactive T cells can be used for the identification of FLT3-ITD-encoded peptides, e.g. for future therapeutic vaccination studies. In addition, these T cells or their receptors can be applied to adoptive transfer.

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Das Enterobakterium Escherichia coli sowie das Bodenbakterium Bacillus subtilis können C4-Dicarbonsäuren als aerobe Kohlenstoffquelle zur Energiekonservierung nutzen. Die Regulation des C4-Dicarboxylatstoffwechsels erfolgt in E. coli und B. subtilis durch das Zweikomponentensystem DcuSREc bzw. DctSRBs, bestehend aus einer Sensorkinase und einem Responseregulator. Diese kontrollieren die Expression des C4-Dicarboxylat-Transporters DctA. Der Sensor DcuSEc benötigt für seine Funktion im aeroben Stoffwechsel den Transporter DctA als Cosensor. Für das DctSRBs-System gibt es Hinweise aus genetischen Untersuchungen, dass DctSBs das Bindeprotein DctBBs und möglicherweise auch DctABs als Cosensoren für seine Funktion benötigt. In dieser Arbeit sollte ein direkter Nachweis geführt werden, ob DctBBs und DctABs gemeinsam oder nur jeweils eine der Komponenten als Cosensoren für DctSBs fungieren. Sowohl für DctBBs als auch für DctABs wurde eine direkte Protein-Protein-Interaktion mit DctSBs durch zwei in vivo Interaktionsmethoden nachgewiesen. Beide Methoden beruhen auf der Co-Reinigung der Interaktionspartner mittels Affinitätschromatographie und werden je nach Affinitätssäule als mSPINE oder mHPINE (Membrane Strep/His-Protein INteraction Experiment) bezeichnet. Die Interaktion von DctSBs mit DctBBs wurde zusätzlich über ein bakterielles Two-Hybrid System nachgewiesen. Nach Coexpression mit DctSBs interagieren DctABs und DctBBs in mSPINE-Tests gleichzeitig mit der Sensorkinase. DctSBs bildet somit eine sensorische DctS/DctA/DctB-Einheit in B. subtilis und das Bindeprotein DctBBs agiert nur als Cosensor, nicht aber als Transport-Bindeprotein. Eine direkte Interaktion zwischen dem Transporter DctABs und dem Bindeprotein DctBBs besteht nicht. Transportmessungen belegen, dass der DctA-vermittelte Transport von [14C]-Succinat unabhängig ist von DctBBs. Außerdem wurde untersucht, ob Zweikomponentensysteme aus anderen Bakteriengruppen nach einem ähnlichen Schema wie DcuSREc bzw. DctSRBs aufgebaut sind. Das thermophile Bakterium Geobacillus kaustophilus verfügt über ein DctSR-System, welches auf genetischer Ebene mit einem Transporter des DctA-Typs und einem DctB-Bindeprotein geclustert vorliegt. Die Sensorkinase DctSGk wurde in E. coli heterolog exprimiert und gereinigt. Diese zeigt in einer E. coli DcuS-Insertionsmutanten Komplementation der DcuS-Funktion und besitzt dabei Spezifität für die C4-Dicarbonsäuren Malat, Fumarat, L-Tartrat und Succinat sowie für die C6-Tricarbonsäure Citrat. In Liposomen rekonstituiertes DctSGk zeigt Autokinase-Aktivität nach Zugabe von [γ-33P]-ATP. Der KD-Wert für [γ-33P]-ATP der Kinasedomäne von DctSGk liegt bei 43 μM, die Affinität für ATP ist damit etwa 10-fach höher als in DcuSEc.

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In Switzerland, approximately 350,000 people aged 70 years or older own a valid driving license. By law, these drivers are medically assessed every other year, most commonly by their general practitioner, to exclude that a medical condition is interfering with their driving skills. A prerequisite for driving is the integration of high-level cognitive functions with perception and motor function. Ageing, per se, does not necessarily impair driving or increase the crash risk. However, medical conditions, such as cognitive impairment and dementia, become more prevalent with advancing age and may contribute to poor driving and an increased crash risk. The extent to which driving skills are impaired depends on the cause of dementia, disease severity, other co-morbidities and individual compensation strategies. Dementia often remains undiagnosed and therefore general practitioners (GPs) can find themselves in the difficult situation to disclose a suspicion about cognitive impairment and queries about medical fitness to drive, at the same time. In addition, the literature suggests that cognitive screening tests, most commonly used by GPs, have a limited role in judging whether an older person remains fit to drive. Further specialist assessment, for example in a memory clinic or on the road testing (ORT), may be helpful when the diagnosis or its implication for driving remain unclear. Here, we review the literature about cognition and driving, for GPs who advise older drivers who wish to continue driving.

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Radiofrequency neurotomy is a recognized treatment for cervical zygapophysial joint pain. In several studies, the method has provided complete pain relief in 60-70% of the patients for approximately 9 months. The validated technique has the disadvantage of procedural times of 2-4 hours because several lesions are performed to take into account the variable nerve course. We tested the hypothesis that ultrasound localization of the nerves would enable us to reduce the number of lesions performed, while reaching the benchmark of at least 80% pain relief in 80% of patients with a median duration of 35 weeks, as achieved by a previous investigation using the standard method.

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L-type calcium channels are composed of a pore, alpha1c (Ca(V)1.2), and accessory beta- and alpha2delta-subunits. The beta-subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five beta2-subunits isoforms expressed in human heart (beta(2a-e)) on the single L-type calcium channel current. These splice variants differ only by amino-terminal length and amino acid composition. Single-channel modulation by beta2-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All beta2-subunits increased open probability, availability, and peak current with a highly consistent rank order (beta2a approximately = beta2b > beta2e approximately = beta2c > beta2d). We show graded modulation of some transition rates within and between deep-closed and inactivated states. The extent of modulation correlates strongly with the length of amino-terminal domains. Two mutant beta2-subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.

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OBJECTIVE: EORTC trial 30891 compared immediate versus deferred androgen-deprivation therapy (ADT) in T0-4 N0-2 M0 prostate cancer (PCa). Many patients randomly assigned to deferred ADT did not require ADT because they died before becoming symptomatic. The question arises whether serum prostate-specific antigen (PSA) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment. METHODS: PSA data at baseline, PSA doubling time (PSADT) in patients receiving no ADT, and time to PSA relapse (>2 ng/ml) in patients whose PSA declined to <2 ng/ml within the first year after immediate ADT were analyzed in 939 eligible patients randomly assigned to immediate (n=468) or deferred ADT (n=471). RESULTS: In both arms, patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSAapproximately 7.5-fold higher in patients with PSADT<12 mo than in patients with PSADT>12 mo. Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. CONCLUSIONS: Patients with a baseline PSA>50 ng/ml and/or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT, whereas patients with a baseline PSA<50 ng/ml and a slow PSADT (>12 mo) were likely to die of causes unrelated to PCa, and thus could be spared the burden of immediate ADT.

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OBJECTIVES: To map the primary prostatic lymphatic landing sites using a multimodality technique. METHODS: Thirty-four patients with organ-confined prostate cancer (cT1-cT2; cN0) underwent single-photon emission computed tomography fused with data from computed tomography (SPECT/CT) (n=33) or magnetic resonance imaging (SPECT/MRI) (n=1) 1h after ultrasound-guided intraprostatic injection of technecium (Tc-99m) nanocolloid. The presence of lymph nodes (LNs) containing Tc-99m was confirmed intraoperatively with a gamma probe. A backup extended pelvic lymphadenectomy (PLND) was performed to preclude missed primary lymphatic landing sites. The SPECT/CT/MRI data sets were used to generate a three-dimensional projection of each LN site. RESULTS: A total of 317 LNs (median, 10 per patient; range, 3-19) were detected by SPECT/CT/MRI, 314 of which were confirmed by gamma probe. With an "extended" PLND, two thirds of all primary prostatic lymphatic landing sites are resected compared with only one third with a "limited" PLND. CONCLUSIONS: The multimodality technique presented here enables precise mapping of the primary prostatic lymphatic landing sites. PLND for prostate cancer should include not only the external and obturator regions as well as the portions medial and lateral to the internal iliac vessels, but also the common iliac LNs at least up to the ureteric crossing, thus removing approximately 75% of all nodes potentially harbouring metastasis.

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OBJECTIVES: Various imaging techniques, including conventional radiography and computed tomography, are proposed to localize the mandibular canal prior to implant surgery. The aim of this study is to determine the incidence of altered mental nerve sensation after implant placement in the posterior segment of the mandible when a panoramic radiograph is the only preoperative imaging technique used. MATERIAL AND METHODS: The study included 1527 partially and totally edentulous patients who had consecutively received 2584 implants in the posterior segment of the mandible. Preoperative bone height was evaluated from the top of the alveolar crest to the superior border of the mandibular canal on a standard panoramic radiograph. A graduated implant scale from the implant manufacturer was used and 2 mm were subtracted as a safety margin to determine the length of the implant to be inserted. RESULTS: No permanent sensory disturbances of the inferior alveolar nerve were observed. There were two cases of postoperative paresthesia, representing 2/2584 (0.08%) of implants inserted in the posterior segment of the mandible or 2/1527 (0.13%) of patients. These sensory disturbances were minor, lasted for 3 and 6 weeks and resolved spontaneously. CONCLUSIONS: Panoramic examination can be considered a safe preoperative evaluation procedure for routine posterior mandibular implant placement. Panoramic radiography is a quick, simple, low-cost and low-dose presurgical diagnostic tool. When a safety margin of at least 2 mm above the mandibular canal is respected, panoramic radiography appears to be sufficient to evaluate available bone height prior to insertion of posterior mandibular implants; cross-sectional imaging techniques may not be necessary.