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Craniomaxillofacial surgery has been experiencing a deep conceptual change in surgical planning over the last decade, with virtual reality technologies becoming widely adopted. The high demand has led to an exponential increase in available software. The aim of this review was to outline the current literature and provide evidence on the most used software for virtual surgical planning (VSP), and also to define contemporary knowledge on which procedures are more ready candidates for VSP. A search was performed in the major databases, and screening of the results according to the PRISMA statement identified 535 articles reporting the implementation of preoperative VSP during the years 2010-2020. A total of 77 different software programs were identified. The surgical procedures were assigned a standardized nomenclature and further simplified into 10 categories for analysis: temporomandibular joint (TMJ), implants (IMPL), malformations (MALF), reconstruction (REC), oncology (ONCO), oral surgery (ORAL), orthognathic surgery (ORTH), cranial surgery (CRANIO), trauma (TRAUMA), miscellaneous (OTHER). The journals they were reported in and the sample size of each study were also investigated. The results showed that the Materialise suite was the most widespread tool for VSP, with a prevalence of 36.3%, followed by the Geomagic family. Several packages were found to be associated with a specific type of surgical procedure. This review offers a synopsis of the array of VSP software reported in the literature and sets the basis for an informed, evidence-based use of this software in craniomaxillofacial surgery.

Supplemental Table 1. Multivariate analysis of late relapse, transplant-related mortality, overall survival after HCT for each disease (AML, ALL, CML, MDS)

Purpose: Malignancy relapse remains a major obstacle for successful allogeneic hematopoietic cell transplantation (HCT). Chronic graft-versus-host disease (cGVHD) is associated with fewer relapses. However, when studying effects of cGVHD on relapse, it is difficult to separate from acute GVHD effects as most cases of cGVHD occur within the first year after transplant at the time when acute GVHD is still active.Experimental Design: This study based on CIBMTR registry data investigated cGVHD and its association with the incidence of late relapse and survival in 7,489 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS), who were leukemia free at 12 months after myeloablative allogeneic HCT.Results: Forty-seven percent of the study population was diagnosed with cGVHD at 12 months after transplant. The protective effect of cGVHD on late relapse was present only in patients with CML [RR, 0.47; 95% confidence interval (CI), 0.37–0.59; P < 0.0001). cGVHD was significantly associated with higher risk of treatment-related mortality (TRM; RR, 2.43; 95% CI, 2.09–2.82; P < 0.0001) and inferior overall survival (RR, 1.56; 95% CI, 1.41–1.73; P < 0.0001) for all diseases. In patients with CML, all organ sites and presentation types of cGVHD were equally associated with lower risk of late relapse.Conclusions: These results indicate that clinically relevant antileukemia effects of cGVHD on late relapses are present only in CML but not in AML, ALL, or MDS. Chronic GVHD in patients who are 1-year survivors after myeloablative allogeneic HCT is primarily associated with higher TRM and inferior survival. Clin Cancer Res; 21(9); 2020–8. ©2014 AACR.See related commentary by Gill, p. 1981

Supplemental Table 4. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival, overall survival in patients with AML, ALL, MDS who developed cGVHD

Supplemental Table 2. Multivariate analysis showing impact of cGVHD characteristics in CML patients on relapse

Supplemental Table 3. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival and overall survival in patients with CML who developed cGVHD

Supplemental Figure 1. Cumulative incidence of cGVHD, relapse and death in patients with AML, ALL, CML, MDS

The characterization of the mechanical behavior of shape memory thin film alloys is essential for their application as microactuators. Depending on the particular application, different elements have been considered for the fabrication of ternary NiTi-based alloys in order to shift the martensitic transformation toward a lower or a higher temperature range. This work presents the design and implementation of a specific device to perform thermal cycles at constant stress on film-like samples over a wide temperature range, between −130 and 300 °C. The uniaxial stress application, the elongations and contractions measurements associated with the martensitic transformations, and the cooling and heating methods are detailed in the present work. The fabrication and operation features of this relatively low cost device facilitate and promote the study of shape memory thin films.

BACKGROUND Readiness for mechanical ventilation (MecV) weaning and extubation is usually assessed clinically with the use of a spontaneous breathing trial (SBT), but its accuracy is limited, and the pathophysiology of weaning failure not completely elucidated. The purpose of the present study was to describe the physiological behavior of electrical impedance tomography parameters during SBT and to propose additional variables that could be helpful in defining weaning/extubation outcome. METHODS From December 2015 to January 2017, all subjects who remained under MecV with an orotracheal tube for more than 24 hours and who were submitted to SBT both in pressure-support ventilation (PSV) or T-tube were included in the study. Both clinical and impedance parameters were collected immediately before as well as during SBT. RESULTS Forty-two subjects were included in the final analysis. For subjects submitted to SBT in PSV, none of the impedance parameters added significant information regarding weaning outcomes. For subjects submitted to a T-tube SBT, a significant and progressive decrease in end-expiratory lung impedance (dEELI) was observed, which was more prominent in subjects who clinically failed the SBT. These subjects had a significant rapid shallow breathing index at the end of SBT. CONCLUSIONS dEELI was a potentially useful parameter in the evaluation of MecV weaning outcome when abrupt lung depressurization was induced during SBT in our study. The degree of dEELI decrease was probably related to the magnitude of lung derecruitment, which seems to play a key role in the MecV weaning outcome.

BackgroundGlucocorticoids (GCs) are still the mainstay of treatment of Giant Cell Arteritis (GCA), while Tocilizumab (TCZ) has been licensed as the first biologic treatment for GCA. Although GCs are highly effective in GCA, it is well documented the high burden of toxicity of GCs as well as the disease relapse during GC tapering. Therefore, patients with GCA may benefit from GC-sparing treatments[1].ObjectivesThe aim is to compare the efficacy as steroid-sparing agents of Tocilizumab (TCZ) or Methotrexate (MTX) in GCA.MethodsA single-center retrospective study included 39 patients with newly diagnosed GCA confirmed by temporal artery biopsy, temporal artery ultrasound, or TC-PET. Patients were collected from December 2010 to December 2020. The inclusion criterion was the initiation of treatment with MTX or TCZ as GC-sparing agent within the first year of disease, whereas the exclusion criterion was previous treatment with other immunosuppressive agents.Results11 patients received TCZ (162mg/week), while 28 patients MTX (up to 20mg/week) as a GC-sparing agent. Baseline characteristics were reported in Table 1.Table 1.Baseline characteristics of 39 newly diagnosed GCA patients.Median (IQR) or n (%)TCZ (n=11)MTX (n=28)All (n=39)P valueAge, years66 (57-77)72 (66-76)71 (65-76)0.125Female9 (81.8)20 (71.4)29 (74.4)0.504ESR, mm/h89.5 (71-116)51.5 (39.5-88.5)72 (46-92)0.026CRP, mg/L102 (79-169)43.9 (20.8-68)54 (27-102)0.006Fibrinogen, mg/dL605 (381-897)680 (539-800)680 (492-808)0.760≥3 ACR criteria5 (45.5)10 (35.7)15 (38.5)0.718AION3 (27.3)0 (0)3 (0.8)0.018Fever8 (72.7)13 (46.4)21 (53.8)0.138Extra-cranial symptoms7 (63.6)17 (60.7)24 (61.5)1.000TAB positive6 (54.5)13 (46.4)19 (48.7)1.000Halo sign positive5 (45.5)6 (21.4)11 (28.2)0.234TC-PET positive6 (54.5)12 (42.9)18 (46.2)0.676Comorbidities*5 (45.5)15 (53.6)20 (51.3)0.648*Presence of at least one among diabetes mellitus, hypertension, ischaemic heart disease, obesity, or osteoporosis.The follow-up time between groups was 20 (IQR 18.5-24.5) months vs 36 (IQR 24-60.5) months, respectively. At the last medical examination, all patients were in sustained remission, 6/11 (54.5%) and 17/28 (60.7%) had discontinued GCs. The prednisone equivalent dosage of 5 mg/day was achieved at 5 (IQR 2.75-5.5) and 7 (IQR 5-10) months (p-value 0.078), respectively, while discontinuation of GCs was achieved at 7.5 (IQR 6.25-11) and 19 (IQR 14-24) months (p-value 0.015), respectively. No differences were observed as concerns GC-related adverse events at 1 year after the onset of GCA (1 event in 11 patients [9.1%] vs 3 events in 28 patients [10.7%]). In details, GC-related adverse events were development of diabetes (2/4), hypertension (1/4), or osteoporosis (1/4). Two patients in the first group (18.2%) and 9 in the second one (32.1%) experienced at least one relapse (median time to relapse was 6.5 [IQR 5.75-7.25] and 18 [IQR 12-24] months). Relapses required the association of MTX with TCZ (1/11 [9.1%]) or start of TCZ (1/11 [9.1%] in the former group, while they required an increase in steroid dosage (7/11 [63.6%]), switch from MTX to TCZ (1/11 [9.1%]), or reinstatement of MTX therapy after its discontinuation (1/11 [9.1%]) in the latter.Overall, both drugs were well tolerated. 1/11 (9.1%) and 5/28 (17.9%) had discontinued TCZ and MTX, respectively, due to mild and reversible drug-related adverse events (4/6 general malaise or discomfort, 1/6 gastrointestinal symptoms, or 1/6 abnormal liver function tests). No serious infections were observed.ConclusionTCZ showed a faster steroid-sparing effect than MTX. Both immunosuppressants are safe, effective and allow the discontinuation of GCs.References[1]Quartuccio, L.; Isola, M.; Bruno, D.; Treppo, E.; Gigante, L.; Angelotti, F. et al. Treatment Strategy Introducing Immunosuppressive Drugs with Glucocorticoids Ab Initio or Very Early in Giant Cell Arteritis: A Multicenter Retrospective Controlled Study. J. Transl. Autoimmun.2020, 3, 100072, doi:10.1016/j.jtauto.2020.100072.Disclosure of InterestsNone declared

BackgroundThe ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire is a 29-item disease-specific PRO measure for AAV[1]. The Italian version of the AAV-PRO questionnaire (AAV-PRO_ita) was translated in collaboration with Oxford and Bristol University (UK) and was preliminarily tested on a single-center Italian cohort[2].ObjectivesThe main objective of this multicentric study was to assess the internal consistency, feasibility, and reliability of the AAV-PRO_ita in a large cohort of Italian AAV patients. The secondary objective was to investigate the clinical characteristics of AAV patients associated with AAV-PRO_ita domains.MethodsThe AAV-PRO_ita is describes the following disease domains: (1) organ-specific and systemic symptoms and signs (SSS); (2) physical function (PF); (3) social and emotional impact (SEI). In this study, Italian-speaking AAV patients were recruited from Italian Centres (N=13) with a large experience in the diagnosis and treatment of systemic vasculitis, belonging to the Vasculitis Study Group of the Italian Society of Rheumatology. Inclusion criteria were: a confirmed diagnosis of GPA, MPA, or EGPA; ANCA positivity in at least once occasion or biopsy-proven AAV; and age ≥18 years old. Participants completed the AAV-PRO_ita at three different time-points: baseline, after 5-7 days, and at month 3.Results229 AAV-patients (56.3% women) with a median age of 61 (IQR 51-72) were recruited and completed the questionnaires. The subtype of AAV was mainly GPA (131, 57.2%), followed by EGPA (58, 25.3%), and MPA (40, 17.5%). Median BVASv3 at baseline was 0 (IQR 0-3), whereas the median BVASv3 at the onset of disease was 14 (IQR 9-20). Participants had a median duration of disease of 67 (IQR 24-126) months. Patients who experienced at least one relapse, one hospitalization, and one severe infection were 40.2%, 53.3%, and 24%, respectively. 83% of the patients were on immunosuppressant therapy and 71.6% were still receiving glucocorticoids (GC).AAV-PRO_ita questionnaire had good internal consistency (Cronbach’s Alpha range 0.81-0.93) and good test-retest reliability (ICCs range 0.93-0.96). Item response rates were high overall (maximum 0.87% missing data), supporting the feasibility of the questionnaire.Concerning the domains of the questionnaire, female AAV patients scored higher (i.e. worse) in all three domains, especially in the SEI domain (p-value0.3, p-valueConclusionThe AAV-PRO_ita questionnaire is a new 29-item, disease-specific PRO measure for use in AAV in the Italian language. It is a self-administered Italian questionnaire with good internal consistency, feasibility, and reliability. AAV-PRO_ita proved to be a useful tool to explore the AAV patient’s perception of quality of life, and it could become an important way of measuring the unmet needs of AAV patients.References[1]Robson, J.C. et al. Validation of the ANCA-Associated Vasculitis Patient-Reported Outcomes (AAV-PRO) Questionnaire. Ann. Rheum. Dis.2018, 77, 1157–1164, doi:10.1136/annrheumdis-2017-212713.[2]Treppo, E.; Palese, A.; Vita, S.D.; Quartuccio, L. AB0392 PRELIMINARY VALIDATION OF THE ITALIAN VERSION OF ANCA-ASSOCIATED VASCULITIS PATIENT-REPORTED OUTCOME (AAV-PRO_ita) QUESTIONNAIRE: FATIGUE AND CHRONIC PAIN AS UNMET NEEDS BY CURRENT TREATMENTS. Ann. Rheum. Dis.2021, 80, 1224–1224, doi:10.1136/annrheumdis-2021-eular.2123.AcknowledgementsWe thank the Italian Study Group on Systemic Vasculitis.Disclosure of InterestsNone declared

The aim of this ex vivo study was to test a novel three-dimensional (3D) automated computer-aided design (CAD) method (aCAD) for the computation of femoral angles in dogs from 3D reconstructions of computed tomography (CT) images. The repeatability and reproducibility of three manual radiography, manual CT reconstructions and the aCAD method for the measurement of three femoral angles were evaluated: (1) anatomical lateral distal femoral angle (aLDFA); (2) femoral neck angle (FNA); and (3) femoral torsion angle (FTA). Femoral angles of 22 femurs obtained from 16 cadavers were measured by three blinded observers. Measurements were repeated three times by each observer for each diagnostic technique. Femoral angle measurements were analysed using a mixed effects linear model for repeated measures to determine the levels of intra-observer agreement (repeatability) and inter-observer agreement (reproducibility). Repeatability and reproducibility of measurements using the aCAD method were excellent (intra-class coefficients, ICCs≥0.98) for all three angles assessed. Manual radiography and CT exhibited excellent agreement for the aLDFA measurement (ICCs≥0.90). However, FNA repeatability and reproducibility were poor (ICCs

Ifosfamide has been shown to be associated with encephalopathy in 10-40% of patients. Although it is a well-documented toxicity associated with ifosfamide therapy, an anecdotal upsurge in its occurrence at our institution prompted us to review ifosfamide usage. A 1-year single-center retrospective study was performed to assess the incidence of and potential risk factors for ifosfamide-induced encephalopathy (IIE). A total of 28 inpatients received ifosfamide-based chemotherapy over 47 separate treatment sessions. During those treatment sessions, seven cases of IIE (14.9%) were observed, which presented a significant increase compared with historical data from our institution (≤3.3%). On the basis of these data, we switched from the ifosfamide product made from Sicor's liquid formulation for injection to that made from a different manufacturer's powder formulation for injection in 2010. Since this switch in the ifosfamide formulation was made, we have observed a reduction in the rate and severity of IIE at our institution. It is noteworthy that the infusions associated with encephalopathy showed a significantly higher degree of post-treatment leukopenia compared with those that did not. In the absence of chromatography analysis and/or potency analysis, we could not definitely attribute the high rate of IIE observed in our study to the liquid ifosfamide formulation; nevertheless, practitioners should be more vigilant about unexpected rates of chemotherapy adverse events when switching to a different manufacturer's product. We have also observed an association between severe post-treatment leukopenia and the development of IIE, which has not been reported previously.

Hemophilia A is an X-linked bleeding disorder caused by defects in the gene encoding factor VIII (FVIII). Routine prophylaxis with exogenous FVIII requires frequent intravenous injections. One of the most challenging issues in the treatment of hemophilia A is the development of alloantibodies against infused FVIII. Presence of inhibitors results in an ineffective factor replacement therapy and increases the risk of morbidity and mortality in these patients. Therefore, there is growing interest in the development of new strategies for the prophylaxis and prevention of bleeding in patients with hemophilia to circumvent these drawbacks. Emicizumab (ACE-910; Roche, Genentech and Chugai Pharmaceutical) is a recombinant humanized bispecific antibody that restores the function of missing FVIII by bridging activated FIX and FX, simulating the cofactor function of FVIII.

The nature of chemical defenses in poison frogs has been explored in a variety of species, and most studies focus on the types of chemical defenses and their sources. The defensive compounds of frogs are stored in dermal granular glands that have been described for several species that are chemically protected from predators and/or microorganisms. Gland ultrastructure is known for some species of dendrobatoid frogs, but the relationship between body size and chemical defense has heretofore not been explored. It might be expected that the capacity for defensive protection increases as a function of body size, especially given the fact that juvenile poison frogs are known to have smaller quantities of alkaloids than adults. We examined poison glands histologically in a sample of the poison frog Oophaga pumilio to determine if the physical basis of the defensive system changes as a function of body size. We measured average gland size, estimated the number of glands, and calculated the density and percentage of skin area occupied by glands in a patch of dorsal skin for 25 individuals. For males and females, the size, number and percentage of skin area occupied by poison glands increased allometrically as a function of body size, whereas poison gland density decreased with body size. Adults have a larger capacity to store alkaloids and more of their dorsal skin is associated with poison glands as compared with juveniles, which may translate into greater protection from predators in adults and could explain why adults are more apparent (active above the leaf litter) than juveniles at our study site in north-eastern Costa Rica. Furthermore, juveniles and subadults may benefit from automimicry because they resemble adults in appearance.

El objetivo de este trabajo fue describir el proceso de limitación de los esfuerzos terapéuticos (LET) en los pacientes internados en una sala general. Para ello se realizó un estudio prospectivo descriptivo, desarrollado en la sala de internación general de un hospital universitario. Fueron evaluados pacientes que tuviesen alguna LET, asistidos por el servicio de clínica médica en un período de 60 días consecutivos. Durante el mismo se hospitalizaron 402 pacientes, 62 (15%) tuvieron algún tipo de LET. Este último grupo estaba compuesto por un 66% de mujeres, la mediana de edad fue de 86 años (78-90) y de la duración de hospitalización de 12 días (8-18). La mala calidad de vida fue la causa más frecuente de LET (69%). Se brindó información acerca de las limitaciones a 43 familias (69%) y 8 pacientes (13%). En la decisión participaron el médico de cabecera (50%), médicos de planta (50%), residentes (40%), la familia (42%) y los propios pacientes (11%). En 7 casos hubo constancia en la historia clínica (11%). Diecisiete pacientes (27%) con LET fallecieron durante la internación, mientras que 44 (71%) fueron dados de alta. En conclusión, la limitación de esfuerzos terapéuticos en nuestros pacientes constituyó un hecho frecuente. No se logró identificar un proceso uniforme o sistematizado para la toma de la decisión de LET. Resulta innegable la necesidad de normativas que guíen al equipo de salud en la toma de decisiones, tranquilicen a familiares y acompañen a los pacientes en sus reales necesidades.The purpose of this study is to describe the limiting life-sustaining treatment process of patients admitted to a general ward. A prospective descriptive study was designed. The setting was the general ward of universitary hospital. Study participants were patients assisted by the internal medicine department during a 60- consecutive days period who had limitations of life sustaining treatments. During the study period, 402 patients were hospitalized, 62 (15%) of them had limitations of life support care. The median patient age of the last group was 86 years (78-90), 66% were women and the length of stay was 12 days (8-18). A low quality of life was the most frequent cause of limitation (69%). Information about the limitations was provided to 43 families (69%) and 8 patients (13%). The primary care physician participated in the decision in 50% of the cases, while the attending physician, the resident in charge, patient's family and patients themselves participated in 50%, 40%, 42% and 11% of the cases respectively. The decision of limiting life-sustaining treatments was recorded in seven patient's charts (11%). Seventeen (27%) patients with limitations died during the hospital stay while 44 (71%) were discharged. In conclusion, we found a frequent life sustaining treatment limitation in our patients. These decisions did not follow a uniform or systemized process. The need of guidelines to sort the medical and ethical challenges imposed to the medical team is undeniable.

Our recent ultrastructural study of human parotid glands revealed that the melatonin receptors, MT1 and MT2, are localised in the plasma cell membranes of acinar and ductal cells but also, and intriguingly, predominantly in acinar secretory granules, giving rise to the working hypothesis that secretory granules are a part of a transcytotic transport system for melatonin. To put this hypothesis to the test in rat parotid glands, anaesthetised animals were exposed to a high melatonin dose (3 mg/kg per hour), infused intravenously over two hours and aiming to stimulate a glandular melatonin-receptor-dependent intracellular transport system, if any. Thirty minutes later, the right parotids were removed. Pre-stimulation, left parotid gland tissue was removed to serve as (untreated) controls. Gland tissues were processed for the gold post-embedding technique and for western blot analysis. In untreated glands, on transmission electron microscope images, melatonin receptors displayed a distribution pattern similar to that in human parotids, i.e. here, too, the receptors were principally associated with the acinar secretory granules. In melatonin- treated glands, the number of granules associated with the MT1 receptor was twice that in untreated glands, despite the same total granule number in the two glands. Moreover, the density of gold particles showing MT1-receptor immunoreactivity associated with granules in melatonin-treated glands was 2.5 times that in untreated glands. The number of MT1 receptors associated with the granule membrane was about three times higher in melatonin-treated glands than in untreated glands, while the number of MT1 receptors inside the granules was about twice that in untreated glands. The immunoblotting of membrane-enriched samples showed that the MT1-receptor expression was about three times that of untreated glands. When it came to the MT2 receptor, no changes were observed. Melatonin itself thus exerts dynamic effects on its MT1 receptor, which may reflect an adaptive receptor-linked carrier system for melatonin, delivering - upon gland stimulation - melatonin to the saliva by exocytosis.

In vivo animal studies show that pentagastrin, cholecystokinin and melatonin cause the secretion and synthesis of salivary proteins. Melatonin occurs in large amounts in the gut and is released into the blood on food intake. In vitro experiments suggest that pentagastrin exerts secretory activity in human salivary glands, as judged by ultrastructural changes, reflecting secretion, and an actual protein output. Currently, it is hypothesised that melatonin induces secretory exocytotic events in the human parotid gland. Human parotid tissues were exposed to a high single concentration of melatonin in vitro, processed for high resolution scanning electron microscopy and then assessed morphometrically with the emphasis on the membrane of the intercellular canaliculi, a site of protein secretion. Compared with controls and in terms of density, the melatonin-exposed parotid tissues displayed increases in protrusions (signalling anchored granules) and microbuds (signalling membrane recycling and/or vesicle secretion) and decreases in microvilli (signalling cytoskeletal re-arrangement related to exocytosis), phenomena abolished or very largely reduced by the melatonin receptor blocker, luzindole. In conclusion, acinar serous cells of parotid tissue displayed in vitro exocytotic activity to melatonin, signalling protein secretion. Whether, under physiological conditions, melatonin influences the secretion of human parotid glands remains to be explored, however.

The current FDA-approved time interval between plerixafor dosing and apheresis initiation is approximately 11 hours, but this time interval is impractical for most care providers. Few studies have examined mobilization kinetics beyond 11 hours in multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) patients. Therefore, this study's intent was to analyze an interval of 17 to 18 hours between plerixafor dosing and apheresis initiation.In 11 patients with MM or NHL, 240 μg/kg plerixafor was administered at 5 p.m. on Day 4 of granulocyte-colony-stimulating factor (G-CSF) mobilization. Peripheral blood (PB) CD34+ and CD34+CD38- concentrations were enumerated every 2 hours until 7 a.m. and immediately before apheresis on Day 5, for a total interval time of 17 to 18 hours after plerixafor. Data were analyzed using mixed-model analysis of repeated measures and paired t testing.Ten of the 11 subjects achieved a CD34+ product count of more than 2 × 10(6) /kg with a single leukapheresis procedure. All 10 had a preplerixafor PB CD34+ concentration ([CD34+]) of at least 10/μL. PB [CD34+] was not different between 10 and 18 hours after plerixafor (p = 0.8). In contrast, PB CD34+CD38- concentrations significantly increased from 10 to 18 hours after plerixafor (p = 0.03).In MM and NHL patients with adequate preplerixafor [CD34+], leukapheresis initiated 14 to 18 hours after plerixafor and G-CSF mobilization may not impair adequate CD34+ collection and may increase more primitive CD34+CD38- collection. In this subset of patients, late-afternoon dosing of plerixafor at 5 p.m. with initiation of next-day apheresis as late as 11 a.m. appears feasible without loss of efficacy.

To study the health-related quality of life (HRQOL) in severe cryoglobulinaemic vasculitis (CV) associated with hepatitis C virus infection (HCV) and to describe the effect of rituximab on HRQOL.HRQOL was evaluated with the Medical Outcomes Study Short Form 36 (SF-36). Health Survey questionnaire was submitted to 15 patients with severe CV. SF-36 questionnaire was evaluated at baseline and after rituximab. Physical Health Composite Summary (PCS) and Mental Health Composite Summary (MCS) scores were calculated according to standard protocols, and normalised to healthy controls. SF-36 summary scores were compared with those of HCV positive patients without CV, and other vasculitis published in the literature. European Quality of Life-5 dimensions (EQ5D) scores were also derived.Physical and mental domain scores were all reduced if compared with those of the healthy population, with physical domains being greatly affected. HRQOL of CV was comparable with HRQOL reported for the other small vessel vasculitis. The development of CV in HCV positive patients worsened PCS rather than MCS score. Birmingham Vasculitis Activity Score (BVAS) did not correlate with HRQOL, while the presence of peripheral neuropathy was associated with a worse HRQOL. Early rituximab treatment improved both PCS and MCS scores, with long-term effects.PCS rather than MCS was affected in HCV positive patients when CV is present. Rituximab improved both physical and mental domains, thus supporting its use before antiviral therapy in severe HCV-related CV. The cost/benefits ratio of a sequential therapy may be supported.

To explore linguistic abilities in schizophrenia and bipolar disorder. Specifically, the aims of this study were to: i) investigate microlinguistic (lexicon, morphology, syntax) and macrolinguistic (discourse coherence, pragmatics) dimensions of speech production and ii) evaluate syntactic comprehension skills in both schizophrenia and bipolar disorder.Linguistic performance of 30 Italian-speaking patients with schizophrenia, 30 participants with bipolar disorder and 30 healthy controls comparable for age and educational level has been assessed using a story-telling task and a computer-based test of syntactic comprehension.In narrative production, compared with healthy participants, those with schizophrenia had slight problems in speech rate and deficits at both local and global discourse coherence, whereas patients with bipolar disorder showed reduced mean length of utterance. As regards syntactic comprehension, both groups of patients collected more grammatical errors than controls, but they differed with regard to the number and kind of grammatical construction they missed.Linguistic deficits have been detected in both groups of patients, being, however, more severe and generalized in schizophrenia than in bipolar disorder. Such results help us in improving our understanding of the potential psychopathological overlapping between these disorders.

Alteration of salivary gland secretion is one of the consequences of diabetes. In a recent study on the submandibular gland of diabetic subjects, we found changed expression of statherin, a salivary protein of fundamental importance in preserving tooth integrity, whose reduction was related with the high incidence of oral diseases in patients with diabetes. The goal of this report is to extend the study to human parotid gland and to compare the effects of diabetes on statherin expression with those previously described in submandibular gland.Fragments of parotid glands obtained from diabetic and non-diabetic patients were fixed, dehydrated, embedded in Epon Resin and processed for the immunogold histochemistry. The staining density was expressed as number of gold particles per μm(2) and statistically evaluated.In all samples, statherin reactivity was specifically localized in secretory granules of acinar cells. The statistical analysis showed that labelling density was significantly lower in diabetic than in non-diabetic parotid glands and that diabetes affects protein expression at identical extent in parotid and submandibular glands. The results strengthen the hypothesis that a reduced statherin secretion may be responsible for the higher incidence of oral disorders in diabetic subjects.

Salivary statherin, which plays a special role in the defense of tooth integrity, is secreted by both major and minor salivary glands. A significantly reduced expression of this was recently found in human major salivary glands removed from diabetic subjects and was correlated with the high incidence of dental diseases occurring in patients with diabetes. In this study, we measured the density of gold particles indicating statherin immunoreactivity in labial glands to reveal a significant difference between diabetic and non-diabetic patients.Surgical samples of labial glands obtained from both diabetic and non-diabetic patients were fixed with a glutaraldehyde and paraformaldehyde mixture, embedded in Epon, and treated for immunogold histochemistry using a polyclonal antibody specific for statherin.Statherin immunoreactivity was detected onto small vesicles diffused throughout the cytoplasm of serous cells. Statistical analysis revealed that the number of stained particles was significantly lower in the samples from diabetic subjects than from non-diabetic subjects.The results indicate that diabetes affects statherin secretion in labial glands and support the hypothesis that the increased susceptibility to oral diseases associated with diabetes could be related with a reduced statherin secretion.

Statherin is a salivary protein involved in the formation of enamel pellicle and in regulation of calcium homeostasis. Diabetes and other pathologies affect both salivary flow and protein secretion by salivary glands, causing increased susceptibility to mucosal infections, tooth demineralization, and caries. The purpose of this study was to compare the statherin expression in submandibular glands of healthy and diabetic subjects. Fragments of submandibular glands obtained from diabetic and non diabetic patients were fixed, dehydrated, embedded in Epon Resin and processed for the immunogold histochemistry. The results were statistically evaluated. Specific statherin labeling was demonstrated in secretory granules of acinar cells in both diabetic and normal samples. The staining was much more intense in the latter compared to those of diabetics. The labeling density was quantified by evaluating the number and spatial distribution of gold particles within the granules. The number of gold particles was significantly lower in glands from diabetics than in control glands. The results obtained suggest that a reduced statherin secretion by salivary glands might be partly responsible for a less effective protection of the oral tissues, resulting in an higher incidence of caries and oral infections associated with diabetes.

The purpose of this study is to describe the limiting life-sustaining treatment process of patients admitted to a general ward. A prospective descriptive study was designed. The setting was the general ward of universitary hospital. Study participants were patients assisted by the internal medicine department during a 60-consecutive days period who had limitations of life sustaining treatments. During the study period, 402 patients were hospitalized, 62 (15%) of them had limitations of life support care. The median patient age of the last group was 86 years (78-90), 66% were women and the length of stay was 12 days (8-18). A low quality of life was the most frequent cause of limitation (69%). Information about the limitations was provided to 43 families (69%) and 8 patients (13%). The primary care physician participated in the decision in 50% of the cases, while the attending physician, the resident in charge, patient's family and patients themselves participated in 50%, 40%, 42% and 11% of the cases respectively. The decision of limiting life-sustaining treatments was recorded in seven patient's charts (11%). Seventeen (27%) patients with limitations died during the hospital stay while 44 (71%) were discharged. In conclusion, we found a frequent life sustaining treatment limitation in our patients. These decisions did not follow a uniform or systemized process. The need of guidelines to sort the medical and ethical challenges imposed to the medical team is undeniable.

Background Individualization of mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) therapeutic drug monitoring may minimize the risk of organ transplant rejection. The MPA area under the 12-hour concentration–time curve (MPA-AUC0–12h) is a more powerful predictor of rejection than are MPA trough levels. Measurement of MPA-AUC0–12h, however, is difficult and clinically impractical. The limited sampling strategy (LLS) has been proposed to overcome this problem. Objective To validate the predictive performance of MPA LSS algorithms previously published for heart transplant (HTx) recipients (initial group) when applied to a new independent group of 29 HTx recipients (validation group) during the first year after transplantation. Patients and Methods In a previous study, we established 2 algorithms using a LSS in HTx recipients: (1) 5.568 + 0.902 × C1.25 + 2.022 × C2 + 4.594 × C6 and (2) 3.8 + 1.025 · C1.25 + 1.819 × C2 + 1.566 × C4 + 3.479 × C6. Agreement between abbreviated AUC and the full AUC0–12h was tested using the Bland-Altman method. The validation group was used to test and assess bias and precision. Results The 2 LSS algorithms used predicted the corresponding MPA-AUC0–12h with a mean bias of −4.85% and −3.6% and mean precision of 15.9% and 14%, respectively. Conclusions The MPA-AUC0–12h obtained using the LSS may be useful to guide clinical management and dosing. This study prospectively validates 2 algorithms for calculation of MPA-AUC0–12h using an LSS calculated in HTx recipients. Bias and precision values suggest that our algorithms could be used for MPA therapeutic drug monitoring predictions in HTx recipients who share the same characteristics.

We present here findings obtained on a large number of human tissues over a period of more than ten years, by our modification of the Osmium maceration method for high resolution scanning electron microscopy (HRSEM). Data are documented by original pictures which illustrate both some 3-D intracellular features not previously shown in human tissues, and results obtained in our current studies on mitochondrial morphology and on the secretory process of salivary glands. We have demonstrated that mitochondria of cells of practically all human tissues and organs have usually tubular cristae, and that even the cristae that look lamellar are joined to the inner mitochondrial membrane by tubular connexions similar to the crista junctions later seen by electron tomography. Concerning salivary glands an important result is the development of a morphometric method that allows the quantitative evaluation of the secretory events.

Cytochalasin D (CD) is a fungal toxin which binds to the faster growing end of actin microfilament and inhibits actin polymerization. By an in vitro incubation system of slices of human submandibular glands obtained at surgery, we investigated by light microscope (LM), transmission electron microscope (TEM), and high resolution scanning electron microscope (HRSEM) the morphological changes caused by CD on serous cells. We studied the effects of the drug on secretory events induced by isoproterenol (I) and carbachol (C). With LM, following CD incubation, canaliculi were enlarged and prominent vacuoles were seen throughout the cytoplasm. By TEM, the vacuoles, which in many cases were in continuity with the lumen, represented the distinctive feature of secretory cells. With HRSEM, intercellular canaliculi, seen from their cytoplasmic side, exhibited many small spherical bulges, corresponding to the coated pits seen with TEM and indicating that the retrieval of plasma membrane was arrested at an early phase by the disruption of the actin cytoskeleton. In specimens treated with secretagogues and CD, a consequence reported here for the first time was the presence of dense granules within the vacuoles. The protrusions seen by HRSEM on the cytoplasmic side of intercellular canaliculi, following secretagogues stimulations, appeared peculiar to each stimulants, even if combined with CD, suggesting that besides actin filaments, other components, unaffected by CD, also are involved in the process of exocytosis and related phenomena.

We address the problem of real-time estimation of multifractal parameters of network traffic. The algorithm accuracy is the major concern in the proposed algorithm. From a statistical point of view, the higher the number of samples used in the estimation, the more accurate the results. However, the network traffic in long intervals of time may have a heterogeneous scaling behavior, which would make the estimation results meaningless. We then propose an adaptive strategy that adjusts the length of the estimation interval on the basis of the local traffic features so as to extend the number of samples as much as the traffic behavior is deemed to be stationary. The development of this strategy relies on an analysis of the variability of multifractality over time in real traffic traces. Simulation results show that the proposed algorithm is characterized by a higher accuracy with respect to a fixed approach.

Telecommunication operators frequently evaluate network performance to validate and optimise network designs by simulation. There is a big problem in this context: simulations often require a long run-time to get accurate results. We address this problem, presenting a new traffic scaling approach to reduce the number of events to be simulated. The proposed method is based on the idea of scaling link capacity and input traffic by a common scaling factor in order to speed up simulations. We analyse the accuracy of this technique for a multiservice asynchronous transfer mode (ATM) network technology, even if such an approach can be applied to other transport technologies. Experiments show good accuracy and high speedup values compared to alternative solutions.

Simulations represent a very powerful means for validating network designs that help telecommunication operators to predict network performance. In this context, two important issues have to be carefully considered: a speedup technique has to be used to reduce the long simulation times; the traffic models should be able to reproduce the burstiness observed in real traces. In this paper, we propose a new solution to these problems based on the application of the importance sampling (IS) theory to the power on-power off model, which can accurately reproduce the self-similar nature of the real traffic. The accuracy and efficiency of the technique have been validated by extensive experiments.

Mast cells (MC) have recently been implicated in the processes of tissue homeostasis, remodeling and repair.In this study, the total and tryptase-reactive mast cell populations were quantified in the duodenal mucosa of 27 subjects suffering from chronic inflammatory bowel disorders. Mast cell density was both related to the general villous architecture (normal or defective) and to the microvascular density in the duodenal mucosa.Total mast cell and tryptase-positive mast cell subpopulation densities were found to be significantly reduced in the samples with defective villous architecture in comparison with those exhibiting a normal villous profile. In these last samples, a relevant proportion of mucosal mast cells exhibited ultrastructural features of secretory activity, in particular piecemeal degranulation. Finally, no correlation was established between microvascular density and tryptase activity, as it has been previously demonstrated in other pathological conditions.Overall, these findings indicate a significant correlation between mast cell density and the duodenal mucosal architecture.

Human saliva from a healthy donor was subjected to fractionation by gel chromatography and six pools were collected and analysed by MALDI-TOF-MS and HPLC-ESI-MS. Three peptides, corresponding to 888.3, 687.3, and 524.1 amu and SNYLYDN, YLYDN, and LYDN sequences (determined by automated Edman sequencing), were isolated from pool 4. YLYDN was not previously described in human saliva. The peptides show the common C-terminal sequence of histatin 3 and histatin 1. To exclude the possibility that the three peptides were an artifact of the purification procedure, nine samples of human saliva were collected from healthy donors, immediately acidified with 0.2% TFA, and analysed by RP-HPLC-ESI-MS. The three peptides were detected in all the analyzed samples. SNYLYDN was always found at a concentration higher than that of YLYDN and LYDN. A correlation analysis performed on quantitative data indicated that the three peptides derive only from histatin 3. Other already known histatins also were searched for in the chromatogram. Histatins 1, 2, 3, 5, 6, 7, 8, and 10 were observed, although not in all samples analyzed, whereas other minor histatins were not detected.

In this paper we generate a statistical significance test for a 2-level coherent mixture model of interferometric radar scattering from forested terrain. We test the model against SIR-C L-band data and show that the assumption of a random volume scattering model for vegetation is fully justified for L-band remote sensing of forested areas. This has important implications for the design of future spaceborne radar sensors aimed at forest mapping applications.

The aim was to test a new instrument, the BACES system, an articulated arm connected to a computer, to improve noninvasive examination of the spine and to reduce X-ray examinations. To this aim, four observers performed three series of eight measurements on a dummy and two healthy volunteers. Data on the projection of the spine, any curve detectable on the frontal and sagittal plane, and any rotation at each thoracolumbar level were collected and analysed. To detect the role of the observer, of the procedure and of the object in measurement variability, a two-factor analysis of variance was performed. The results showed measurement errors for kyphosis and scoliosis generally below 3 degrees, whereas the lordosis showed a major variability, especially in volunteers, because of the attitude role. Rotations showed a limited variability too, generally below 2 degrees. In the clinical setting,2 SD may reasonably be considered a clinical change because it has not a great chance of being a measurement error. Thus, the BACES system allowed us to identify with fairly good precision kyphosis, scoliosis and trunk rotations. Even though at the moment no surface measurement method can replace X-rays, the instrument can integrate and limit the use of radiographic evaluations.

The Mobility Air Forces (MAF) have sustained an extraordinary operations tempo for the last 10 years in performing peacekeeping and humanitarian assistance operations, not to mention a plethora of other operations and contingencies.1 Surely-one would assume-there must be a surfeit of documents capturing the experiences, struggles, successes, and lessons learned of MAF war fighters who led the execution of these incredibly complex operations, which were studded with tactical risks and strategic effects speed bumps, especially since they often required miracles from the mere mortals leading them. No such surfeit exists. There are a smattering of articles and reports, such as Col Clifton L. "Cliff' Bray's outstanding, jaw-dropping case study on the 86th Contingency Response Group's (CRG) involvement in Operation Shining Hope in Tirane, Albania, and a few "lessons learned" documents that are mostly from Army institutions. There appears to be little tangible, strategically crosscutting guidance that a MAF leader, whether a tanker-airlift control element commander or a director of mobility forces (DIRMOBFOR), could grab onto as he or she enters into what is one of our most difficult missions.

Temozolomide is a relatively new chemotherapeutic agent frequently associated with selective CD4+ T-lymphocytopenia. Patients with cell-mediated immune defects are at higher risk for acquiring infections with Salmonella species. We describe the first case of disseminated salmonellosis in a patient treated with temozolomide.

Emergency diagnostic and treatment units (EDTUs) may provide an alternative to hospitalization for patients with reversible diseases, such as asthma, who fail to adequately respond to emergency department therapy.To evaluate the medical and cost-effectiveness, patient satisfaction, and quality of life of patients receiving EDTU care for acute asthma compared with inpatient care.A prospective, randomized clinical trial performed at 2 urban public hospitals enrolled patients with acute asthma (age range, 18-55 years) not meeting discharge criteria after 3 hours of emergency department therapy. Patients were treated with inhaled adrenergic agonists and steroids in an EDTU for up to 9 hours after randomization or with routine therapy in a hospital ward. Patients were followed up for 8 weeks.Discharge rate from the EDTU, length of stay, relapse rates, days missed from work or school, days incapacitated during waking hours, symptom-free days and nights, nocturnal awakenings, direct medical costs, patients satisfaction, and patient quality of life.The study consisted of 222 patients with asthma. Sixty-five patients (59%) treated in an EDTU were discharged home; the remainder were admitted to the hospital. There were no differences during the follow-up period in relapse rates (P = .74) or in any other morbidities between the EDTU and inpatient groups. There were significant differences in the length of stay, patient satisfaction, and quality of life favoring EDTU care. The mean (+/-SD) cost per patient in the EDTU group was $1202.79 +/- $1343.96, compared with $2247.32 +/- $1110.18 for the control group (P.001).Treatment of selected patients with asthma in an EDTU results in the safe discharge of most such patients. This study suggests that quality gains and cost-effective measures can be achieved by the use of such units.

To evaluate the efficacy of continuous positive airway pressure (CPAP) administered by face mask in patients with acute respiratory failure with indication of mechanical ventilation.Eleven patients (mean age 41.3 years) in acute respiratory failure were admitted in the Respiratory Unit--Hospital São Paulo--Escola Paulista de Medicina. At the admission pH, PaO2, PaCO2, respiratory rate (f), arterial pressure and heart rate were measured. The measurements were repeated with administration of oxygen with a high flow face mask at ambient airway pressure and then with 5 cm H2O of CPAP by face mask.The use of CPAP by face mask significantly improved the arterial blood oxygenation and decreased the respiratory rate (p0.05).These data allow the conclusion that CPAP administered by face mask improves gas exchange and decreases respiratory rate in patients with acute respiratory failure and may reduce the need for invasive mechanical ventilation.

Over the last 12 years, we and others have demonstrated that fatty acid uptake is not simply a passive, diffusive process, but an interesting, facilitated mechanism the regulation of which has specific implications for disease. This work also tells another tale. Our earliest experiments were called "squirt studies" by our technician because they involved "squirting" a bolus of labelled metabolite intravenously into one limb of the subject and drawing blood samples from another. These studies were conducted in patients, and later in intact animals. From these we moved progressively to investigations in isolated perfused organs, isolated cells, and sub-cellular organelles and membrane vesicles; to the chemistry of membrane proteins, and most recently, to studies combining recombinant DNA technology with cellular biologic studies of controlled differentiation in tissue culture (Figure 5). The work has been not only a continuing process of scientific investigation but, for the investigators, an on-going process of self-education.

e20548 Background: This study assessed the safety and efficacy of Aprepitant, a neurokinin 1 receptor antagonist, in the management of DCINV associated with HCT. Methods: Pilot phase I-II RCT, adult patients undergoing ablative HCT. Eligibility Criteria: Presence of DCINV (>1 episode of vomiting/24 hrs or >25 mm on nausea visual analogue scale (VAS) on day 2–14 post- HCT). Control arm: ondansetron + metoclopramide. Aprepitant arm: Same regimen + aprepitant 125 mg on d1 and 80 mg d2–3. Controls with DCINV persisting >72 hours were crossed to treatment arm. Safety endpoints: Primary: myeloid engraftment (ANC>500/μL by d15.) Secondary: platelet engraftment (plts >20,000/μL by d21.) Efficacy endpoints: Primary: no episodes of emesis. Secondary: VAS reduction ≥ 25 mm Results: 12 pts, ages 23–62 yrs, were randomized, 9 to treatment arm. Two of 3 controls crossed over. The study was interrupted prior to completion of accrual to control arm. Results are summarized as median ± SD in the table below. Treatment arm showed no delay in granulocyte and platelet engraftment, less emesis, and little difference in VAS compared to control. No patients in either group developed unexpected grade III-IV toxicities, including VOD or IPS. Conclusions: The use of aprepitant for control of DCINV after myeloablative HCT decreased the frequency of DCINV and had no adverse effect on granulocyte and platelet engraftment. This pilot study supports the safety and efficacy of aprepitant for DCINV in the setting of HCT. [Table: see text] [Table: see text]

In the relatively short period since its development, the technique for the production of transgenic animals by pronuclear microinjection, as established by Gordon et al. (1980), has resulted in studies that have clearly had a profound effect on our basic understanding of mammalian development and genetics, and upon our outlook for genetic engineering. The question now is: What remains to be done? Clearly, a greater understanding of the mechanism of integration could lead to more efficient transfer of genes and lessen the problem of rearrangement of host DNA. A better characterization of enhancers and their mode(s) of action would allow design of molecules with highly specific patterns of gene expression, as well as novel distributions of expression. When these goals are met, it may well become scientifically feasible to transfer genes into the human germline. Whether such an undertaking is advisable or even desirable is an issue requiring open discussion, but it is an issue that is clearly distinct from the question of technical feasibility. The most rational approach to this profound question lies in the continued pursuit of knowledge relating to transgenic technology, rather than self-imposed ignorance. Even if never used as a medical therapy, transfer of genes into the germline will reveal what is certainly one of nature's greatest secrets: the nature of the interaction of genes in the development of a multicellular eukaryotic organism. Through the contributions to this volume and in the years ahead, we will find ourselves in a position to unravel the details of the awesome and fascinating phenomenon that is mammalian development.