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The concentration of nitrogen in must is critical to yeast fermentation efficiency and wine aroma profile. The present work determined the effect of the amount of yeast assimilable nitrogen (YAN) on fermentation kinetics, aroma production, and gene expression patterns of the wine yeast Saccharomyces cerevisiae. Fermentations were performed under two different YAN concentrations of must. Acetate esters, linalool, and nerol appeared to be clearly affected by the different YAN levels. Real-time-PCR results revealed that the genes involved in ethyl and acetate esters production recorded, in general, higher transcript levels under high nitrogen supplementation. In addition, an up-regulation of the BGL2and EXG1genes, which are related to terpenes production, was observed in the case of high nitrogen content and it is well corresponded to the terpenol concentration found. Our study revealed the impact of nitrogen supplementation on yeast metabolism and its importance to adjust wine’s aromatic composition and sensory profile.

Human immunodeficiency virus (HIV) infection represents a major cardiovascular risk factor, and the cumulative cardiovascular disease (CVD) burden among aging people living with HIV (PLWH) constitutes a leading cause of morbidity and mortality. To date, CVD risk assessment in PLWH remains challenging. Therefore, it is necessary to evaluate and stratify the cardiovascular risk in PLWH with appropriate screening and risk assessment tools and protocols to correctly identify which patients are at a higher risk for CVD and will benefit most from prevention measures and timely management. This review aims to accumulate the current evidence on the association between HIV infection and CVD, as well as the risk factors contributing to CVD in PLWH. Furthermore, considering the need for cardiovascular risk assessment in daily clinical practice, the purpose of this review is also to report the current practices and novel perspectives in cardiovascular risk assessment of PLWH and provide further insights into the development and implementation of appropriate CVD risk stratification and treatment strategies, particularly in countries with high HIV burden and limited resources.

Context:Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected.Objective:The objective was to determine whether the overall and site-specific incidence of cancer is comparable to that of the general population.Design and Setting:Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed.Main Outcome Measure:Standard incidence ratios (SIRs) were calculated as compared to the general population.Results:Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P= .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges <1, 1–2.5, and ≥2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P= .94). There was not a significant dependence on normal vs elevated IGF-1 (P= .87), radiation therapy (P= .45), disease duration (P= .96), age at diagnosis (P= .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P= .41).Conclusions:Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer.

Context:We have recently reported somatic mutations in the ubiquitin-specific protease USP8gene in a small series of adenomas of patients with Cushing's disease.Objective:To determine the prevalence of USP8mutations and the genotype-phenotype correlation in a large series of patients diagnosed with Cushing's disease.Design:We performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph adenomas using Sanger sequencing. Biochemical and clinical features were collected and examined within the context of the mutational status of USP8, and new mutations were characterized by functional studies.Patients:A total of 145 patients who underwent surgery for an ACTH-producing pituitary adenoma.Main Outcomes Measures:Mutational status of USP8. Biochemical and clinical features included sex, age at diagnosis, tumor size, preoperative and postoperative hormonal levels, and comorbidities.Results:We found somatic mutations in USP8in 48 (36%) pituitary adenomas from patients with Cushing's disease but in none of 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases (41 vs 17%) and in females than in males (43 vs 17%). Adults having USP8-mutated adenomas were diagnosed at an earlier age than those with wild-type lesions (36 vs 44 y). Mutations were primarily found in adenomas of 10 ± 7 mm and were inversely associated with the development of postoperative adrenal insufficiency. All the mutations affected the residues Ser718 or Pro720, including five new identified alterations. Mutations reduced the interaction between USP8 and 14-3-3 and enhanced USP8 activity. USP8 mutants diminished epidermal growth factor receptor ubiquitination and induced Pomcpromoter activity in immortalized AtT-20 corticotropinoma cells.Conclusions:USP8is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.

Cardiopulmonary resuscitation (CPR) is an emergency life-saving endeavor, performed either in the hospital or outpatient settings, that significantly improves outcome and survival rates when performed timely. As with any other medical procedure, CPR can bare potential risks not only for the patient but also for the rescuers.

3D space registration and visualization has become an imperative need in order to optimally reflect all complex cases of rapid urbanization of property rights and restrictions. Besides, current technological advances as well as the availability of sophisticated software packages (proprietary or open source) call for 3D modeling especially in the GIS domain. Within this context, GIS community's present demands concerning the third dimension are discussed, while a variety of 3D modeling techniques is presented, with special emphasis on procedural modeling. Procedural modeling refers to a variety of techniques for the algorithmic generation of detailed 3D models and composite facade textures from sets of rules which are called grammars. In this paper procedural modeling is employed via CityEngine software focusing on the 3D visualization of the National Technical University of Athens (NTUA) campus' three-dimensional model, rendering a higher detail on the School of Rural and Surveying Engineering (SRSE). This algorithmic modeling concept is based on the principle that all real world buildings are defined by rules, since repetitive patterns and hierarchical components describe their geometry. The detailed geometries of the model derived from the application of CGA (Computer Generated Architecture) shape grammars on selected footprints, and the process resulted in a final 3D model, optimally describing the built environment and proved to be a good practice example of 3D visualization.

ABSTRACTCandida parapsilosisisolates occasionally display resistance in vitroto echinocandins and cause breakthrough infections to echinocandins. The degree of the in vivocross-resistance among echinocandins and the fitness loss associated with caspofungin (CAS) resistance of C. parapsilosisare not well studied. We compared the activities of CAS and anidulafungin (ANF), each given at 2 dosing schedules (high dose or low dose) in a nonneutropenic mouse model of invasive candidiasis (IC) caused by ANF-susceptible isolates of C. parapsilosiswith different degrees of susceptibility to CAS (CAS resistant [CAS-R], MIC, >16 mg/liter; CAS intermediate [CAS-I], MIC, 4 mg/liter; and CAS susceptible [CAS-S], MIC, 2 mg/liter). We analyzed tissue fungal burden, histopathology, and weight loss patterns. Increasing CAS resistance was associated with reduced virulence of C. parapsilosisisolates (mortality rates for CAS-S versus CAS-I versus CAS-R, 100% versus 11.1% versus 0%, respectively; P< 0.001). High doses of either echinocandin were active against infection with the CAS-I isolate when assessed by fungal burden reduction and weight gain. In contrast to CAS-S and CAS-I isolates, there was no reduction in fungal burden in mice infected with the CAS-R isolate following treatment with either echinocandin, each given at a high or low dose. Nevertheless, mice infected with the CAS-R isolate had reduced disease severity following echinocandin treatment, suggesting that echinocandins have activity in vivo, even against echinocandin-resistant strains. A complex interplay of residual echinocandin activity, decreased virulence, and/or fitness of isolates with altered cell wall and possible immunomodulatory effects can be encountered in vivoduring infection with CAS-resistant C. parapsilosisisolates.

Abstract Pulmonary endothelium is a major metabolic organ affecting pulmonary and systemic vascular homeostasis. Brain death (BD)-induced physiologic and metabolic derangements in donors’ lungs, in the absence of overt lung pathology, may cause pulmonary dysfunction and compromise post-transplant graft function. To explore the impact of BD on pulmonary endothelium, we estimated pulmonary capillary endothelium-bound (PCEB)-angiotensin converting enzyme (ACE) activity, a direct and quantifiable index of pulmonary endothelial function, in eight brain-dead patients and ten brain-injured mechanically ventilated controls. No subject suffered from acute lung injury or any other overt lung pathology. Applying indicator-dilution type techniques, we measured single-pass transpulmonary percent metabolism (%M) and hydrolysis (v) of the synthetic, biologically inactive, and highly specific for ACE substrate 3H-benzoyl-Phe-Ala-Pro, under first order reaction conditions, and calculated lung functional capillary surface area (FCSA). Substrate %M (35 ± 6.8%) and v (0.49 ± 0.13) in BD patients were decreased as compared to controls (55.9 ± 4.9, P = 0.033 and 0.9 ± 0.15, P = 0.033, respectively), denoting decreased pulmonary endothelial enzyme activity at the capillary level; FCSA, a reflection of endothelial enzyme activity per vascular bed, was also decreased (BD patients: 1,563 ± 562 mL/min vs 4,235 ± 559 in controls; P = 0.003). We conclude that BD is associated with subtle pulmonary endothelial injury, expressed by decreased PCEB-ACE activity. The applied indicator-dilution type technique provides direct and quantifiable indices of pulmonary endothelial function at the bedside that may reveal the existence of preclinical lung pathology in potential lung donors.

ABSTRACTCryoglobulin characteristics in chronic hepatitis C (CHC) might be of importance for knowing more about the pathogenesis and treatment of the disease. We aimed to investigate the relationship between cryoglobulin types and their specificity against hepatitis C virus (HCV) antigenic epitopes in CHC patients. We analyzed samples from 43 patients with HCV-associated cryoglobulinemia, of whom 4 had concomitant lymphoma. Cryoglobulins were measured, purified, typed by immunofixation electrophoresis, and tested for IgG and IgM anti-HCV antibodies by immunoblot analysis and an enzyme-linked immunosorbent assay (ELISA). Clinical and other laboratory data were recorded. The median cryocrit level of the tested samples was 6%. Type I cryoglobulins were detected in 9.3% (4/43) of the cryoprecipitates, and type II cryoglobulins were detected in 48.8% (21/43) of the cryoprecipitates. IgM monoclonal protein, mainly IgM(?), was found in 92% (23/25) of type I and II cryoprecipitates. Type III cryoglobulins were identified in 41.9% (18/43) of the patients and were associated with high blood serum IgG levels. In 81.3% (13/16) of type II and 92.3% (12/13) of type III cryoglobulins, there was IgG reactivity against the viral core region. Ninety-two percent and 32% of IgG anti-HCV core-positive cryoprecipitates had additional specificities against the NS3 and NS4 regions, respectively. Also, IgM anti-HCV antibodies were detected in 31% of the cryoprecipitates. In conclusion, all types of cryoglobulins were found in patients with HCV-associated cryoglobulinemia, with type II being the most frequently identified. Type III cryoglobulins were common and were associated with high serum IgG levels. HCV-related cryoglobulins demonstrated IgM, and particularly IgG, anti-HCV specificities, mainly against the core and NS3 epitopes.

We report a case of NMT lymphadenitis in a previously healthy 4-year-old girl caused by Mycobacterium marseillense, a newly recognized strain belonging to Mycobacterium avium complex.

Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed to describe the kinetics of MD-derived metabolites during the course of critical sepsis, to assess whether these metabolites are useful in grading sepsis severity, and to investigate their prognostic use. To this end, 54 mechanically ventilated septic patients were prospectively studied, out of which 39 had shock. Upon sepsis onset, an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh. Dialysate samples were analyzed for glucose, pyruvate, lactate, and glycerol. Sampling was performed six times per day for a maximum of 6 days. The daily mean values of MD measurements were calculated for each patient. Arterial blood was analyzed for glucose, lactate, and glycerol concomitantly with dialysate sampling. Blood glucose and tissue glucose levels along with lactate levels were high during the entire study period. Tissue pyruvate and glycerol were also raised, whereas the lactate-pyruvate ratio was preserved. At study entry, patients with septic shock had higher tissue lactate (3.3 vs. 1.9 mmol/L, P= 0.01) and glycerol (340 vs. 169 mol/L, P= 0.04) levels compared with those without shock. Nonsurvivors had higher tissue lactate (P= 0.008), glycerol (P= 0.004), and pyruvate (P= 0.002) levels than survivors during the whole observation period. Logistic regression analysis showed that age (odds ratio OR, 1.075; 95% confidence interval CI, 1.004-1.150; P= 0.03), Sequential Organ Failure Assessment score on day 1 (OR, 1.550; 95% CI, 1.043-2.312; P= 0.03), and tissue glycerol on day 1 (OR, 1.007; 95% CI, 1.001-1.012; P= 0.01) predicted mortality independently. In conclusion, critical sepsis is characterized by high tissue lactate and pyruvate levels and a preserved lactate-pyruvate ratio, suggesting a nonischemic mechanism for raised blood lactate levels. Septic shock is associated with higher tissue lactate and glycerol levels compared with sepsis without shock. Elevated tissue lactate, pyruvate, and glycerol levels are related to poor clinical outcome, with the latter constituting an independent predictor.

Reactivation of Epstein-Barr virus (EBV) infection and posttransplant lymphoproliferative disorder (PTLD) pose a significant risk after T-cell-depleted (TCD) allogeneic hematopoietic stem-cell transplantation (HSCT). The pattern of EBV reactivation in patients receiving allogeneic HSCT, incorporating in vivo or in vitro alemtuzumab as the method of TCD, is not known.

Clostridium difficile infection is an emerging and often difficult-to-treat iatrogenic complication. Recent data suggest that tigecycline, a novel antibiotic with broad-spectrum antibacterial activity, can be used successfully to treat patients with severe Clostridium difficile infection. We report a 70-year-old man who developed severe Clostridium difficile infection, was admitted to the intensive care unit and eventually succumbed to complications of his illness despite receiving tigecycline for approximately three weeks in combination with vancomycin, metronidazole and intravenous immunoglobulin. Additionally, we discuss the unique challenges that emerged during tigecycline treatment, such as the development of Proteus mirabilis bacteraemia and of colonisation with Acinetobacter baumannii resistant to tigecycline. Finally, we review data on other cases reported in the medical literature. Even though tigecycline looks promising for the treatment of Clostridium difficile infection, we urge caution against its indiscriminate use for off label indications.

The mechanisms of the N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) release in intensive care unit (ICU) patients with preserved ejection fraction (EF) are unclear. We investigated whether left ventricular (LV) dysfunction, as assessed by tissue Doppler imaging (TDI), is related to NT-pro-BNP levels in ICU patients with preserved EF and has a complementary value to NT-pro-BNP in the determination of in-hospital mortality. We examined 58 mechanically ventilated patients with no history of heart failure (age, 60 ± 18 years; EF, 63% ± 7%). The systolic (S) and early diastolic (E) velocity of the mitral annulus by TDI and the E/E as well as NT-pro-BNP, troponin, lactate acid, blood oxygen (PO2/FiO2), sepsis, and ICU mortality were assessed. Systolic, E, and E/E correlated with age, PO2/FiO2, lactate acid, NT-pro-BNP, troponin, history of arterial hypertension, and diabetes (P< 0.05). By multivariate analysis, the determinants of NT-pro-BNP were S (P= 0.024), E/E (P= 0.017), and sepsis (P= 0.015). An NT-pro-BNP greater than 941 pg/mL was a reliable predictor of LV diastolic dysfunction defined as a composite of E less than or equal to 8 cm/s and/or mean E/E greater than or equal to 13 (area under the curve, 75%; P= 0.03). Patients with combined NT-pro-BNP greater than 941 pg/mL and abnormal TDI markers had increased creatinine levels and a lower MAP, PO2/FiO2, and survival rate than those with abnormal TDI or NT-pro-BNP alone or patients with normal TDI markers and NT-pro-BNP (25%, 60%, 70%, and 84%, respectively; P< 0.05). The addition of abnormal TDI in a model including NT-pro-BNP and sepsis increased the model's value for in-hospital mortality (Pfor change = 0.01). In ICU patients with preserved EF, LV diastolic dysfunction and sepsis determine NT-pro-BNP levels. Tissue Doppler imaging markers and NT-pro-BNP have a complementary value for in-hospital mortality.

ABSTRACTColistin penetration into the cerebrospinal fluid (CSF) was studied in five critically ill adult patients receiving colistin methanesulfonate for infections by multiresistant gram-negative bacilli. Colistin concentrations were determined in paired serum and CSF samples, with the latter taken by lumbar puncture, with the exception of one patient with an external ventriculostomy. CSF-to-serum ratios (0.051 to 0.057) for all study patients coincided at all sampling times. The low level (5%) of penetration suggests inadequate bactericidal colistin concentrations in the CSF.

The present study aimed to determine whether amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) predicts intensive care unit (ICU) mortality in a cohort of general, noncardiac, critically ill patients. To this end, a total of 233 consecutive mechanically ventilated patients (109 men) having a median age of 60 years and a wide range in admitting diagnoses, including medical (n = 118), surgical (n = 83), and multiple trauma (n = 32) cases were prospectively studied. Median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores on ICU admission were 16 and 9, respectively. The study end point was ICU outcome. Blood samples were drawn on admission in the ICU and on postadmission days 1 and 2 to determine NT-pro-BNP levels. In a subgroup (n = 77), admission proinflammatory and anti-inflammatory cytokine levels, including TNF-, IL-6, and IL-10, were also measured. Nonsurvivors (n = 98) had significantly higher NT-pro-BNP levels than survivors (n = 135) on admission in the ICU (2,074 vs. 283 pg/mL; P< 0.001), on day 1 (2,197 vs. 221 pg/mL; P< 0.001), and on day 2 (2,726 vs. 139 pg/mL; P< 0.001). Median values for TNF-, IL-6, and IL-10 were 3.70, 131.57, and 111.88 pg/mL, respectively. Receiver operating characteristic analysis showed that the area under the receiver operating characteristic curve in predicting ICU mortality was 0.70 for APACHE II and 0.77 for admission NT-pro-BNP (P= 0.08). The cutoff in admission NT-pro-BNP that best predicted outcome was 941 pg/mL. Multiple logistic regression analysis revealed that APACHE II score (odds ratio, 1.06; P= 0.007) and the best cutoff point in admission NT-pro-BNP (odds ratio, 7.74; P< 0.001) independently predicted ICU mortality, even if cytokines were entered in the analysis. In conclusion, plasma NT-pro-BNP is frequently raised in noncardiac, mixed, critically ill patients, and nonsurvivors have consistently higher levels than survivors. Elevated admission NT-pro-BNP represents an independent predictor for poor ICU outcome in the presence of clinical severity scores.

Single ionization of helium by 102 eV electron impact has been studied by measuring the momentum vectors of all final-state particles, i.e., two electrons and the He+ion, with an advanced reaction microscope. Fully differential cross sections for asymmetric scattering geometry, which have been normalized to an absolute scale, have been obtained covering a large range of emission angles for the emitted low-energy (E? 15 eV) electron and different scattering angles for the fast electron. Strong electron emission out of the projectile scattering plane is confirmed for electron impact, as was observed before for heavy-ion impact ionization. The data are compared with theoretical predictions from a three-Coulomb wavefunction model, first-order and second-order distorted-wave approaches, as well as a convergent close-coupling calculation.

A better understanding of the biology and pathogenesis of hematological malignancies has led to the development of immunotherapeutic and immunoregulatory drugs. Many of these agents have revolutionized the current treatment modalities, while others are under investigation. Rituximab (anti-CD20 antibody) has been established as the gold standard of treatment for aggressive B-cell lymphomas in combination with CHOP and has shown significant activity as monotherapy in the treatment of indolent B-cell lymphomas. In follicular lymphomas the combination of Rituximab with chemotherapy improves the outcome compared to chemotherapy alone. CD 20-based radioimmunotherapy, with the advantage of the bystander effect, represents an additional therapeutic alternative in B-cell lymphomas and may produce tumor regression in Rituximab resistant patients. The anti-CD52 monoclonal antibody, alemtuzumab, further expands the armamentarium against lymphoid malignancies producing high response rates in these entities. Antibody-targeted chemotherapy such as gemtuzumab ozogamicin, consisting of an anti-CD33 antibody combined to calicheamicin, has shown efficacy in the treatment of refractory acute myeloid leukemia; exact indications, timing and dosing schedule for optimized efficacy remain to be determined. Interferons have proven significant activity in cutaneous lymphomas, hairy cell leukemia and chronic myelogenous leukemia by mechanisms that are not fully elucidated. Thalidomide, by acting as an immunomodulatory and antiangiogenic agent can modulate neoplastic cells microenvironment and lead to disease control in multiple myeloma as well as in numerous other hematological malignancies. Bortezomib, a proteasome inhibitor, displays significant anti-tumor activity, especially in multiple myeloma and lymphoproliferative disorders. The addition of these agents in therapeutic regimens has improved considerably the treatment of hematological malignancies.

Single ionization of CO2by 6 MeV proton impact has been studied by measuring in coincidence the momentum vectors of the emitted electron and the charged nuclear fragment CO+2, CO+or O+, respectively. The experimental data have been compared with the predictions of a state of the art CDW-EIS (continuum distorted wave-eikonal initial state) calculation for molecular orbitals. A good qualitative agreement is observed even though the vibrational motion of the molecule is not taken into account in the model. The low-energy electron spectra show a rich structure which may be attributed to the presence of molecular excitation channels which undergo radiationless decay, via autoionization and also via predissociation. This interpretation is supported by photoionization studies of CO2.

N. Orologas, S.G. Delivopoulos, A. Dimopoulou andI. Tsekos. 2005. Effects of 2,6-dichlorobenzonitrile on plasma membrane cellulose synthesizing complexes and cellulose localization in cells of the red alga Erythrocladia subintegra. Phycologia44: 465–476.The effects of 2,6-dichlorobenzonitrile (DCB), a cellulose biosynthesis inhibitor, on the density (number/μm2), the terminal complex (TC) length, the number of transverse rows of TC subunits of cellulose synthesizing linear TCs, the cellulose microfibril width and the structure and morphology of cell wall and colonies of Erythrocladia subintegrawere investigated. Treatment with 50 μM of DCB caused a partial inhibition of cellulose synthesis, whereas with higher concentrations (75–100 μM) no TCs were observed; this shows that DCB at these concentrations inhibits cellulose synthesis completely. The cellulose synthesis inhibition had a direct impact on the morphology of cells and colonies as well as on the cell wall structure and function. Ultrathin sections of E. subintegrafixed cells, when treated with cellobiohydrolase I (CBH I)–colloidal gold complex (10 nm gold particles), showed significant gold particle labelling on the cellulose microfibrils. In order to better visualize the inhibitory effect of DCB on cellulose synthesis, a combination of DCB and CBH I–gold complex treatment was applied. DCB treatment with increasing concentration (50, 75 and 100 μM) resulted in a gradual decreasing of the enzyme–gold labelling.

Highly differential cross sections have been obtained for dissociative single ionization of H2 by 6 MeV proton impact by measuring the momentum vectors of the electron and the H+ fragment in coincidence. The investigation of the momentum balance of the fragments along the projectile beam provided detailed insight into the four-particle dynamics, even though the H atom is not detected. Within the axial recoil approximation, molecular-frame angular distributions of emitted electrons have been determined for molecules oriented perpendicular to the projectile beam. They are compared with the predictions of a CDW-EIS calculation.

We present the results of a systematic experimental study of dissociation and Coulomb explosion of molecular hydrogen induced by intense ultrashort (7-25 fs) laser pulses. Using coincident recoil-ion momentum spectroscopy we can distinguish the contributions from dissociation and double ionization even if they result in the same kinetic energies of the fragments. The dynamics of all fragmentation channels drastically depends on the pulse duration, and for 7 fs pulses becomes extremely sensitive to the pulse shape.

Highly differential cross sections have been obtained for dissociative single ionization of H2by 6 MeV proton impact by measuring the momentum vectors of the electron and the H+fragment in coincidence. The investigation of the momentum balance of the fragments along the projectile beam provided detailed insight into the four-particle dynamics, even though the H atom is not detected. Within the axial recoil approximation, molecular-frame angular distributions of emitted electrons have been determined for molecules oriented perpendicular to the projectile beam. They are compared with the predictions of a CDW-EIS calculation.

We developed a clinical prediction rule for bone marrow involvement (BMI) in Hodgkin lymphoma based on 826 patients and validated it in 654 additional patients. Independent prognostic factors for BMI were x1, B symptoms; x2, stage III/IV prior to bone marrow biopsy; x3, anemia; x4, leukocytes fewer than 6 × 109/L; x5, age 35 years or older; and x6, iliac/inguinal involvement. Each factor was graded as xi= 1, if present, or xi= 0, if absent. A simplified score Zs= 8x1+ 6x2+ 5x3+ 5x4+ 3x5+ 3x6– 8 was assigned to each patient. The sensitivity, specificity, and positive and negative predictive value of this prediction rule was 97.8%, 51.5%, 10.6%, and 99.8%, respectively. In the validation group, they were 98.1%, 40.3%, 12.7%, and 99.6%. According to Zsvalue, 3 risk groups for BMI were defined: low risk (Zs< 0, 44% of patients, 0.3% risk), standard risk (Zs, 0-9; 37% of patients; 4.2% risk), and high risk (Zs≥ 10, 20% of patients, 25.5% risk). Patients with low risk (stage IA/IIA without anemia and leukopenia; stage IA/IIA, younger than 35 years, with either anemia or leukopenia but no inguinal/iliac involvement; and stage IIIA/IVA without any of these 4 risk factors) do not need bone marrow (BM) biopsy. Patients with standard risk should be staged with unilateral biopsy, but patients with high risk may benefit from bilateral biopsy.

Waldenström's macroglobulinemia (WM) is characterized by lymphoplasmacytic infiltration of bone marrow and/or other tissues and by the presence of serum monoclonal immunoglobulin M ([IgM], without cutoff limit). Differential diagnosis from other B-cell disorders (BCDs) is usually easy based on clinical, morphologic, histopathologic, immunophenotypic, and genetic features. However, all BCDs potentially produce monoclonal IgM. In this study we reviewed the medical files of 130 patients with IgM-secreting BCDs. Eighty-four patients were diagnosed with WM, 5 with IgM-monoclonal gammopathy of undetermined significance (MGUS), and 41 with other BCDs (9 with B-cell chronic lymphocytic leukemia, 5 with small lymphocytic lymphoma, 14 with marginal zone lymphoma, 5 with mantle-cell lymphoma, 2 with follicular lymphoma, 2 with diffuse large B-cell lymphoma, 2 with cryoglobulinemia, and 2 with low-grade lymphoma not otherwise specified). Median IgM levels were 3215 mg/dL in WM, 840 mg/dL in IgM-MGUS, and 285 mg/dL in other BCDs (5 had IgM levels 1500 mg/dL). In 10% of non-WM BCDs, monoclonal IgM was found only when more sensitive immunofixation methods were used. Forty-four percent of patients with BCDs (splenic marginal zone lymphoma or small lymphocytic lymphoma) had diagnoses that corresponded to that of WM. Careful diagnosis requires the concomitant evaluation of all parameters of BCDs together. Marginal zone lymphoma is the most frequently overlapping entity. Special attention should be given to mantle cell lymphoma in its atypical forms. Research in this field should continue to further clarify the disease entities that overlap with WM. New technology such as gene-expression profile techniques may contribute to this purpose.

Waldenstrom's macroglobulinemia (WM) is a rare lymphoproliferative disorder (LPD) characterized by lymphoplasmacytic infiltration of the bone marrow (BM) and/or occasionally other tissues and by the presence of a serum monoclonal IgM. The disease belongs to the lymphoplasmacytic lymphoma (LPL) subtype. Whether WM is indeed a separate entity or is merely an IgM-secreting subtype of low-grade B-cell lymphoma is still controversial. In our series of 67 patients, WM has a long median overall survival of 110 months, and the male/female ratio is 1.2/1. Clinical features include a wide spectrum of manifestations, many of which may be common to other LPDs. Differential diagnosis is based on: (1) clinical and laboratory features (anemia, organomegaly, lymphadenopathy, IgM paraproteinemia), (2) cell morphology (lymphocytes, lymphoplasmacytes, few plasma cells), (3) histopathology of bone marrow or lymph node, (4) immunophenotype (CD5 expression and the intensity of CD5, CD20, and CD79b antigens may help in discrimination from other LPDs and atypical CLL), and (5) characteristic genetic features (present in other LPDs). Based on the former, diagnosis is usually easy. It may be harder in LPL cases not secreting IgM. We consider that WM should be, for the time being, handled as a separate entity. Further studies are necessary. Semin Oncol 30:201-205. © 2003 Elsevier Inc. All rights reserved.

To analyze the time course of serum protein S-100b in patients with traumatic brain injury deteriorating to brain death and to investigate the predictive value of initial S-100b levels in relation to clinical and radiologic measures of injury severity with regard to brain death.

B‐CLL is the most common adult leukemia in the Western world. It is a neoplasia of mature looking B‐monoclonal lymphocytes co‐expressing the CD5 antigen (involving the blood, the bone marrow, the lymph nodes and related organs). Much new information about the nature of the neoplastic cells, including chromosomal and molecular changes as well as mechanisms participating in the survival of the leukemic clone have been published recently, in an attempt to elucidate the biology of the disease and identify prognostic subgroups. For the time being, clinical stage based on Rai and Binet staging systems remains the strongest predictor of prognosis and patients' survival, and therefore it affects treatment decisions. In the early stages treatment may be delayed until progression. When treatment is necessary according to well‐established criteria, there are nowadays many different options. Chlorambucil has been the standard regimen for many years. During the last decade novel modalities have been tried with the emphasis on fludarabine and 2‐chlorodeoxyadenosine and their combinations with other drugs. Such an approach offers greater probability of a durable complete remission but no effect on overall survival has been clearly proven so far. Other modalities, included in the therapeutic armamentarium, are monoclonal antibodies, stem cell transplantation (autologous or allogeneic) and new experimental drugs. Supportive care is an important part of patient management and it involves restoring hypogammaglobulinemia and disease‐related anemia by polyvalent immunoglobulin administration and erythropoietin respectively. Copyright © 2002 John Wiley & Sons, Ltd.

Adverse effects of paclitaxel and carboplatin have been well described; however, pulmonary toxicity after patients receive this regimen has not been investigated extensively. To clarify this issue, 33 consecutive patients who were treated with paclitaxel and carboplatin underwent prospective evaluation of respiratory function, which included pulmonary symptoms, pulmonary function tests (PFTs), arterial blood gas levels, and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with substantial declines in PFTs, defined as a decline ≥ 20 percent in forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were reassessed 5 months later. After chemotherapy, there were no significant changes in forced vital capacity (FVC; 111% ± 21% of the predicted value before chemotherapy vs. 111 ± 20% of the predicted value after chemotherapy), FEV1 (108% ± 24% of the predicted value before chemotherapy vs. 107% ± 22% of the predicted value after chemotherapy), FEV1/FVC ratio (79% ± 8% before chemotherapy vs. 78% ± 6% after chemotherapy), alveolar volume (VA; 95% ± 14% of the predicted value before chemotherapy vs. 96% ± 14% of the predicted value after chemotherapy), or TLC (96% ± 14% of the predicted value before chemotherapy vs. 97% ± 13% of the predicted value after chemotherapy). In contrast, there was a significant decline in DLCO (101% ± 20% of the predicted value before chemotherapy vs. 96 ± 21% of the predicted value after chemotherapy; P &lt; 0.05). Arterial blood gas levels did not change after treatment. No patient had decreased FEV1 or TLC levels by ≥ 20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (≥ 20%) in DLCO that persisted 5 months after treatment (DLCO at baseline, immediately after chemotherapy, and 5 months after the completion of chemotherapy, respectively: 99% ± 36% of the predicted value vs. 75% ± 28% of the predicted value vs. 74% ± 31% of the predicted value; P &lt; 0.05). None of the 33 patients developed respiratory symptoms or had radiologic signs suggestive of lung toxicity. Among the various risk factors examined, baseline DLCO and FEV1 levels were associated with changes in DLCO post-treatment. This prospective analysis showed that the combination of paclitaxel with carboplatin induced an isolated decrease in DLCO level in the absence of clinical or radiologic evidence of toxicity. Further studies are needed to clarify whether this reduction in DLCO is predictive of subsequent pulmonary impairment. Cancer 2002;94:452–8. © 2002 American Cancer Society.

To investigate thyroid function in chronic obstructive pulmonary disease (COPD), 46 consecutive patients (35 men) with stable, mild-to-severe disease, having a mean (SD) age of 67 [plusmn] 7 years were studied. All subjects underwent pulmonary function tests (PFTs), arterial blood gas determination, and measurement of serum total thyroxine (TT4), total triiodothyronine (TT3), resin T3 uptake (RT3U), reverse triiodothyronine (rT3), and thyroid-stimulating hormone (TSH) levels. The free thyroxine and free triiodothyronine indexes (FT4I = RT3U/30TT4 and FT3I = RT3U/30TT3, respectively) along with the TT3/TT4 ratio were calculated; the latter was used as a marker of peripheral conversion of thyroxine into triiodothyronine. Interleukin (IL)-6 was also measured to evaluate its potential associations with thyroidal hormone levels. On the basis of forced expiratory volume in 1 second (FEV1), patients were divided in 2 groups: group 1, (FEV1[ge ] 50% of predicted, n = 26), with mild-to-moderate COPD and group 2 (FEV1[lt ] 50% of predicted, n = 20) having severe disease. All subjects had normal serum thyroid hormone levels; for the entire COPD population, mean values were 7.80 [plusmn] 1.60 [mu ]g/dL for TT4, 1.12 [plusmn] 0.20 ng/mL for TT3, 29.0 [plusmn] 1.88 for RT3U, 7.54 [plusmn] 1.34 for FT4I, 1.07 [plusmn] 0.16 for FT3I, 18.71 [plusmn] 5.89 ng/dL for rT3, and 1.15 [plusmn] 0.6 [mu ]U/mL for TSH. Mean TT3/TT4 ratio was 0.14 [plusmn] 0.03. In group 1, TT3, TT4, and TT3/TT4 ratio did not correlate with age, FEV1, PaO2, or inhaled corticosteroids. Similarly, in group 2, TT3 and TT4 were unrelated to the above-mentioned variables; however, there was a strong positive correlation between TT3/TT4 ratio and PaO2(r= .61, P= .004). IL-6 was within normal limits in all subjects, and it did not correlate with any thyroid hormone either in group 1 or in group 2. It is concluded that in stable COPD, severity of disease through hypoxemia is important in determining the peripheral metabolism of thyroid hormones. Whether this constitutes an adaptation is not known.

Content in the Greek civic education curriculum presents significant discrepancies and discontinuities with the practices, concepts, and attitudes which frame the everyday lives of most students. The issues of democracy, immigration, political freedom, political participation, and integration of the European Union carry multiple and engaged meanings for Greek adolescents. Research in progress, as well as the results of the Youth and History survey, verify the complexity of their thinking on such issues. Civic education textbooks, however, formulate such issues in a descriptive manner that emphasizes formal institutional functioning over actual events and political processes. No explicit connection is made between the lived experience of the students and the formal approach of the textbooks. The civic education curriculum and student attitudes and practices appear to be on two independent and unconnected trajectories, thus depriving pupils of the opportunity for reflective consideration of the interplay of textbook content and everyday experience.

This paper seeks to determine the relative strength of the sales force as a corporate identity cue for pharmaceutical companies, as perceived by one of their most important and influential stakeholders, doctors. The research indicates that the sales force is deemed to be the third most important identity cue and that there is a high degree of correlation between the corporate image and the way the sales force is considered. The paper then determines which attributes of the sales force are the most significant according to doctors, and ranks knowledge/expertise, credibility and the ability to provide reliable and accurate information as the top three key attributes. Major pharmaceutical companies are ranked according to corporate image, sales force performance and their individual perceived capabilities against each of the main sales force attributes. The implication for management is that greater attention to particular sales force attributes may result in a stronger corporate image.

The distribution of large conjugative Haemophilus influenzae plasmids in the nasopharyngeal haemophili of a group of people and in a large collection of 541 H. influenzae type b (Hib) isolates was studied. A newly developed PCR-based assay was used to detect the plasmids. The target sequences were chosen from sequence analysis of part of p1056, a large multiresistance plasmid isolated from a clinical Hib isolate, 1056. Fifty-nine per cent of people were found to carry beta-lactamase-positive (beta-lac(+)), ampicillin-resistant (ampR) haemophili with detectable plasmid sequences. Of these, 83% were in Haemophilus parainfluenzae and 17% were in H. influenzae. In the collection of 541 Hib, antibiotic resistance [beta-lac(+)ampR, beta-lac(+)ampR plus tetracycline resistance (tetR) or tetR] was highly correlated with large plasmids. It was found that 2.3% of the isolates contained large cryptic plasmids (i.e. these isolates were susceptible to antibiotics). The distribution of plasmids between invasive and carried Hib did not differ significantly (25 of 245 and 23 of 276, respectively). Isolates with large plasmids occur at high frequency in the nasopharynx of the normal human population and consist of two populations in Hib, one associated with specific antibiotic resistance traits and the other cryptic. These plasmids do not appear to influence the invasiveness of Hib.

In this study, glycogen distribution during the development of larval salivary glands in two Drosophila species (D. melanogaster and D. auraria) was examined using the osmium tetroxide–potassium ferrocyanide technique at the ultrastructural level. Glycogen particles are found in big clumps in the salivary gland cells of D. melanogaster during the early third instar, mainly at the basal part of the cells; they are also found as scattered particles in the cytoplasm and very close to the apical plasma membrane during the secretory activity at this developmental stage. During the middle third instar, where the production of ‘glue’ secretory granules begins, glycogen particles are mainly scattered and they are seen near the Golgi complexes and secretory granules. No glycogen particles are seen during the late third instar and secretion of ‘glue’ secretory granules. Re-formation of glycogen begins after spiracle eversion. In the larval salivary gland cells of D. auraria, glycogen particles (scattered and in clumps) are seen in every developmental stage. In the larval fat body cells of both species, many huge clumps of glycogen particles are seen, independent of the developmental stage. These results indicate that glycogen provides an important source of energy during development of Drosophila salivary glands, but different species use glycogen at different metabolic pathways, according to their needs.