Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO).

BACKGROUND: Current evidence on myelopoietic growth factors is difficult to overview for the practicing haematologist/oncologist. International guidelines are sometimes conflicting, exclude certain patient groups, or cannot directly be applied to the German health system. This guideline by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Medical Oncology (DGHO) gives evidence-based recommendations for the use of G-CSF, pegylated G-CSF, and biosimilars to prevent infectious complications in cancer patients undergoing chemotherapy, including those with haematological malignancies. METHODS: We systematically searched and evaluated current evidence. An expert panel discussed the results and recommendations. We then compared our recommendations to current international guidelines. RESULTS: We summarised the data from eligible studies in evidence tables, developed recommendations for different entities and risk groups. CONCLUSION: Comprehensive literature search and expert panel consensus confirmed many key recommendations given by international guidelines. Evidence for growth factors during acute myeloid leukaemia induction chemotherapy and pegfilgrastim use in haematological malignancies was rated lower compared with other guidelines.

Diagnosis of invasive fungal infections in hematology and oncology--guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO).

Invasive fungal infections (IFIs) are a primary cause of morbidity and mortality in patients with hematological malignancies. Establishing a definite diagnosis of IFI in immunocompromised patients is particularly challenging and time consuming, but delayed initiation of antifungal treatment increases mortality. The limited overall outcome has led to the strategy of initiating either 'empirical' or 'preemptive' antifungal therapy before the final diagnosis. However, diagnostic procedures have been vastly improved in recent years. Particularly noteworthy is the introduction of newer imaging techniques and non-culture methods, including antigen-based assays, metabolite detection and molecular detection of fungal DNA from body fluid samples. Though varying widely in cancer patients, the risk of IFI is highest in those with allogeneic stem cell transplantation and those with acute leukemia. The AGIHO presents recommendations for the diagnosis of IFIs with risk-adapted screening concepts for febrile episodes in patients with haemato-oncological disorders.

The cellular basis of cell sorting kinetics.

Cell sorting is a dynamical cooperative phenomenon that is fundamental for tissue morphogenesis and tissue homeostasis. According to Steinberg's differential adhesion hypothesis, the structure of sorted cell aggregates is determined by physical characteristics of the respective tissues, the tissue surface tensions. Steinberg postulated that tissue surface tensions result from quantitative differences in intercellular adhesion. Several experiments in cell cultures as well as in developing organisms support this hypothesis. The question of how tissue surface tension might result from differential adhesion was addressed in some theoretical models. These models describe the cellular interdependence structure once the temporal evolution has stabilized. In general, these models are capable of reproducing sorted patterns. However, the model dynamics at the cellular scale are defined implicitly and are not well-justified. The precise mechanism describing how differential adhesion generates the observed sorting kinetics at the tissue level is still unclear. It is necessary to formulate the concepts of cell level kinetics explicitly. Only then it is possible to understand the temporal development at the cellular and tissue scales. Here we argue that individual cell mobility is reduced the more the cells stick to their neighbors. We translate this assumption into a precise mathematical model which belongs to the class of stochastic interacting particle systems. Analyzing this model, we are able to predict the emergent sorting behavior at the population level. We describe qualitatively the geometry of cell segregation depending on the intercellular adhesion parameters. Furthermore, we derive a functional relationship between intercellular adhesion and surface tension and highlight the role of cell mobility in the process of sorting. We show that the interaction between the cells and the boundary of a confining vessel has a major impact on the sorting geometry.

A prospective, randomised study on the use of well-fitting masks for prevention of invasive aspergillosis in high-risk patients.

The problem of inhalation of Aspergillus spores outside rooms with high-efficiency particulate air (HEPA) filtration has not been resolved as yet. Well-fitting masks are used in industrial and health care settings to protect from inhaling particles of 0.3-0.5 mum size. To investigate the efficacy and tolerability of well-fitting masks in high-risk patients, we conducted a prospective, randomised, multicentre study comparing standard hospital hygiene procedures with or without wearing masks in adults undergoing chemotherapy for acute leukaemia or allogeneic haematopoietic stem-cell transplantation (aHSCT). Forty-one patients were randomly assigned to wearing masks and 39 to the control group. In all, 76% of patients were treated in laminar airflow or HEPA-filtered rooms, 84% received oral polyenes, and three aHSCT recipients were given fluconazole. Duration of neutropenia was similar in both treatment groups. Invasive fungal infections were diagnosed in eight patients in either study arm. One patient in each arm died from proven invasive aspergillosis. There was no difference in the use of systemic antifungals. Of patients in the mask group, 65% described the comfort as acceptable, 26% as unpleasant, and 9% as intolerable. This first randomised study on the use of well-fitting masks failed to show a reduction of invasive fungal infections.

CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives.

Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH2(33)]CCK4 (2) (KI = 2.8 nM), Boc-[Phg31,1Nal-NH2(33)]CCK4 (15) (KI = 14 nM), and Boc-[Phg31,1Nal-N(CH3)2(33)]CCK4 (17) (KI = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain KI(CCK-B) = 51 nM as compared to the Merck antagonist L365,260,KI(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist state of brain CCK-B receptors.

Decrease in phosphocreatine level in skeletal muscle of SIV-infected rhesus macaques correlates with decrease in intracellular glutathione.

Loss of skeletal muscle tissue (cachexia) is one of the hallmarks of HIV infection. It has been found (1) that creatine kinase, i.e., an enzyme of pivotal importance in muscular mitochondrial energy metabolism, is inhibited by oxidative glutathiolation, and (2) that reduced glutathione (GSH) is decreased in skeletal muscle of SIV-infected rhesus monkeys. We, therefore, have studied the phosphocreatine (P-Cr) levels. Muscle tissue from SIV-infected macaques showed significantly decreased P-Cr but normal creatine (Cr), ATP, and ADP when compared with uninfected macaques. Individual P-Cr levels were significantly correlated with GSH. Our findings may explain the dysregulation of energy metabolism in cachexia.

Treatment of Adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL).

The German Multicenter Study Group for Adult Acute Lymphoblastic leukemia (GMALL) has conducted 5 consecutive trials with more than 3000 patients since 1981. This article provides an overview on aims, treatment concepts, and results of these studies. It includes brief summaries on the development of prognostic models within the GMALL group and on approaches for prophylaxis of CNS relapse, and it summarizes specific treatment concepts for mature B-lineage acute lymphocytic leukemia.

Prospective randomized study to compare imipenem 1.5 grams per day vs. 3.0 grams per day in infections of granulocytopenic patients.

The objective of this presented prospective randomized study was to compare the efficacy of empirical antimicrobial monotherapy with imipenem 3 x 0.5 g per day to 3 x 1.0 g per day for treatment of infections in neutropenic patients. A total of 192/220 febrile episodes were evaluable for clinical efficacy. The overall response rate was 53/93 (57%) vs. 57/99 (58%). Of the different infection types, fever of unknown origin (FUO) showed the best response, with defervescence in 29/41 (71%) and 36/42 (86%) cases, respectively (not significant). Unfavourable results were found in pneumonias [5/20 (25%) vs. 4/23 (17%)]. The median time until persistent defervescence was equal in both groups (2 days), likewise the median duration of imipenem therapy in responders (7 days). The most frequent micro-organisms were Gram-negative, documented in 22% of the febrile episodes in the lower dosage group vs. 17% of all episodes in the patients with imipenem 3.0 g per day (Gram-positives 17% vs. 14%, fungal 5% vs. 8%). In the lower dosage group, fever with abdominal symptoms occurred less frequently (8% vs. 15%), and significantly more patients tolerated imipenem without any side-effects (95.8% vs. 79.4%), especially regarding severe nausea/vomiting (2.1% vs. 11.8%). Of the initial non-responders, 35/40 (88%) vs. 41/42 (98%) were cured after therapy modification. There was no significant difference in the use of further antibiotics such as aminoglycosides, glycopeptides, ceftazidime or amphotericin B, except a marginally higher use of metronidazole in patients with imipenem 3.0 g per day (3% vs. 10%). Overall, we found no significant differences in efficacy between the two study groups, but more frequent side-effects with imipenem 3.0 g per day.

[Computed tomographic appearance of pulmonary mucormycosis]. / Computertomographisches Erscheinungsbild der pulmonalen Mukormykose.

AIM: Analysis of the morphological characteristics of pulmonary mucormycosis using computed tomography (CT). MATERIAL AND METHODS: Prospective analysis of CT studies in 9 patients out of 19 patients with proven pulmonary mucormycosis. RESULTS: Pulmonary mucormycosis was most frequently found in the upper lobe bilaterally (51% of all nodules). In 22% of the manifestations, the morphological criterion of a "bird's nest" could be verified in CT, in 37% central necrotic areas were detected. In 37% an open bronchus was diagnosed, in 6% we observed bronchiectases. 43% of all nodules presented with a halo sign. In three patients we found pleural effusions, enlarged mediastinal lymph nodes were diagnosed in one patient. CONCLUSION: Computed tomography allows an improved diagnosis and therapeutic follow-up in patients suffering from pulmonary mucormycosis.

Piperacillin/tazobactam versus cefepime as initial empirical antimicrobial therapy in febrile neutropenic patients: a prospective randomized pilot study.

The objective of the presented prospective, randomized study was to compare the efficacy of empirical antimicrobial monotherapy with piperacillin/tazobactam (PIP/TAZ) to cefepime (CEFP) for treatment of infections in neutropenic patients. From a total of 102 febrile episodes 100 were evaluable. The most frequent microorganisms were gram-negative, documented in 22% vs. 24% of the febrile episodes (gram-positives 18% vs. 16%, fungi 2% vs. 4%). The response rate was similar with 22/51 (43%) of episodes treated with PIP/TAZ vs. 19/49 (39%) with CEFP. Of the different infection types classified at the end of the febrile episodes, patients with fever of unknown origin (FUO) and primary bacteremias showed the best initial responses with 25/44 (57%) and 11/22 (50%). Lower initial response rates were found in pneumonias with totally 3/13 (23%) and other clinically documented infections with 2/21 (10%), without any difference between both groups. Gram positive infections showed a higher response with PIP/TAZ than with CEFP (4/9 vs. 0/8), gram negative responded less frequently (3/11 vs. 7/13). The median time until persistent defervescence was equal in both groups (2.5 vs. 2 days), likewise the response rates after the different steps of therapy modifications (change to imipenem or ceftazidim, or addition of gentamycin, vancomycin or amphotericin B). Totally, 96% of febrile episodes responded in both therapy arms. Overall, we found no significant differences in efficacy between the two therapeutic regimens. In conclusion, PIP/TAZ as well as CEFP might be a sufficient initial therapy for febrile neutropenia, but further randomized trials with larger patient numbers are necessary.

Shear bond strengths attained in vitro with light-cured glass ionomers vs composite adhesives in bonding ceramic brackets to metal or porcelain.

PURPOSE: The aim of this in vitro study was to evaluate whether light-cured resin-modified glass ionomers provide sufficient bond strength for bonding ceramic brackets to metal and porcelain. In addition, the effect of mechanically retentive vs. silanized bracket bases on shear bond strength was investigated. MATERIALS AND METHODS: Flat specimens made from amalgam, a precious metal alloy, or ceramic were air-abraded with Al2O3 for 3 s and subsequently bonded with either Transcend 6000 or Fascination ceramic brackets. Alternatively, 20 porcelain specimens were treated with 9.6% HF for 2 min. Fuji Ortho LC and Photac Bond (light-cured glass ionomer cements [GIC]) served as adhesives. Two composite adhesives (Concise orthodontic and Transbond) in combination with various conditioners formed the control groups. After water storage for 24 hours, the shear bond strengths of all specimens were determined. RESULTS: Taking 10 MPa as a clinically sufficient bond strength, both resin-modified GICs produced a reliable retention of Transcend 6000 brackets on ceramic and amalgam, while the silanized Fascination brackets yielded a lower shear bond strength. On the precious metal alloy, only Fuji Ortho LC showed adequate strength. Various composite-conditioner combinations produced higher maximum bond strengths than the GICs. The location of bond failure varied considerably, and with most adhesives, bracket fractures occurred occasionally under shear stress. CONCLUSION: The investigated light-cured GICs provide sufficient strength for bonding ceramic brackets, but in terms of bond failure site and bracket fracture, they provide no advantage over composite adhesives.

The epidemiological consequences of leprosy-tuberculosis co-infection.

While in antiquity both leprosy and tuberculosis were prevalent in Europe, leprosy declined thereafter and, simultaneously, tuberculosis prevalence increased. Since both diseases are caused by mycobacterial infections, it has been suggested that there might be a causal relationship between both epidemics. Chaussinand observed the inverse prevalence of leprosy and tuberculosis and suggested that individuals with a latent tuberculosis infection are protected from acquiring leprosy. His cross-immunity hypothesis has been countered more recently by a co-infection hypothesis. The latter suggestion, proposed by Donoghue, states that people being infected with multi-bacillary leprosy are more susceptible to tuberculosis, which leads to increased mortality from the disease. This study utilizes mathematical modeling to explore the epidemiological consequences of the co-infection hypothesis for realistically confined parameter values. While the co-infection hypothesis appears plausible at first glance, a second thought reveals that it comprises also substantial consequences for tuberculosis epidemics: if co-infection raises the mortality rate above that of purely tuberculosis infected persons, then tuberculosis might as well be eradicated by leprosy. It is the specific interplay of both increased susceptibility towards tuberculosis and increased death rate when co-infected that determines the epidemiological fate. As a result of this analysis, it is shown that there is a large parameter region where the eventual disappearance of leprosy could indeed be explained by co-infection. This parameter region is considerably larger than that predicted by the cross-immunity hypothesis. This shows that the co-infection hypothesis should be considered a significant alternative to the cross-immunity hypothesis. The time scales at which the effects of co-infection are observed depend critically on the spatial distribution of the individuals but reach epidemiologically realistic values for rather immobile individuals with local interaction.

Diagnosis of invasive aspergillosis and mucormycosis in immunocompromised patients by seminested PCR assay of tissue samples.

Aspergillosis and mucormycosis are the most common mold infections in patients with hematological malignancies. Infections caused by species of the genus Aspergillus and the order Mucorales require different antifungal treatments depending on the in vitro susceptibility of the causative strain. Cultures from biopsy specimens frequently do not grow fungal pathogens, even from histopathologically proven cases of invasive fungal infection. Two seminested PCR assays were evaluated by amplifying DNA of zygomycetes and Aspergillus spp. from organ biopsies of 21 immunocompromised patients. The PCR assays correctly identified five cases of invasive aspergillosis and six cases of mucormycosis. They showed evidence of double mold infection in two cases. Both assays were negative in five negative controls and in two patients with yeast infections. Sequencing of the PCR products was in accordance with culture results in all culture-positive cases. In six patients without positive cultures but with positive histopathology, sequencing suggested a causative organism. Detection of fungal DNA from biopsy specimens allows rapid identification of the causative organism of invasive aspergillosis and mucormycosis. The use of these PCR assays may allow guided antifungal treatment in patients with invasive mold infections.

[Pneumonia after cytostatic drug therapy]. / Pneumonien nach Zytostatikatherapie.

On account of its high mortality, pneumonia is a particularly feared infectious complication in granulocytopenic patients. One of the main reasons for the fatal outcome is the increasing rate of pulmonary mycoses. Fungal infections offer considerable problems concerning diagnostics and therapy. To improve the prognosis of pulmonary mycoses undelayed diagnostics--even by more invasive methods like bronchoalveolar lavage--and immediate start of antifungal treatment (Amphotericin B/5-Flucytosine are still considered as standard therapy) is necessary. A further problem are gram positive organisms, insufficiently prevented by the standard prophylactic regimens. Particularly pneumonia by Staphylococcus aureus and Viridans-Streptococci may show lethal outcome. The initial treatment with glycopeptides is discussed. Treatment of infections by gram negative organisms however, is less controversial. Finally pneumonias in granulocytopenic patients present serious problems in diagnostics and therapy requiring interdisciplinary co-operation of hematology, radiology, pneumology and microbiology.

Systemic fungal infections in patients with hematologic malignancies: indications and limitations of the antifungal armamentarium.

The rates of fungal infections have increased substantially in Europe as well as in North America. Most frequently Aspergillus spp. and Candida spp. are isolated. Despite the recent introduction of new azoles and lipid-based formulations of amphotericin B, there are relatively few randomized, controlled studies on the use of antifungal drugs in patients with hematological malignancies and invasive fungal infections. Conventional amphotericin B is considered the gold standard for the treatment of invasive fungal infections; however, adverse events limit conventional amphotericin B treatment. The newer azoles, fluconazole and itraconazole, are well tolerated; however, fluconazole has no activity against Aspergillus spp. An additional serious problem is the emerging resistance of nonalbicans Candida spp. to fluconazole. In this situation, lipid formulations of amphotericin B seem to be attractive, since the use of these drugs has been shown to be safe and effective. Considerably higher medical costs limit broader application of lipid formulations of amphotericin B. Because of the rapidly increasing incidence of serious fungal infections, we have reviewed current strategies and the role of newer antifungal drugs for the treatment of deep-organ infections.

Liposomal amphotericin B as early empiric antimycotic therapy of pneumonia in granulocytopenic patients.

Twenty-three neutropenic patients with haematological malignancies and febrile pulmonary infiltrates were empirically treated with liposomal amphotericin B (AmBisome) in addition to broad-spectrum antibiotics. AmBisome was given on alternate days in two different dosages: 3 mg kg-1 in patients with pneumonia but without radiological signs or other evidence of Aspergillus infection and 5 mg kg-1 in pneumonia patients with suspected Aspergillus infection. The main objectives of this study were to compare the response and lethality of pneumonias treated early with empirically AmBisome with a historical group (treatment with conventional amphotericin B only in case of proven/highly probable aspergillosis) and to investigate the tolerability and efficacy of AmBisome 5 mg kg-1 in cases of proven/probable aspergilloses. Six out of seven (86%) patients without initially suspected aspergilloses receiving AmBisome 3 mg kg-1 responded completely. Twelve out of 16 patients with initial radiological signs of aspergillosis receiving AmBisome 5 mg kg-1 were evaluable. Body temperature normalized in 10/12 (83%) patients; eight experienced complete and two partial regression of their infiltrations and 9/10 patients with proven/probable aspergillosis responded. Acute AmBisome-related reactions were seen in three patients from each group; loss of potassium was noted in five subjects in each group and slightly increased plasma creatinine was found in two patients in the 5 mg kg-1 group. Altogether, the response of all pneumonia patients treated with early empirical AmBisome compared with the historical group was 17/19 vs. 49/72 (89% vs. 68%, NS); among those with proven/probable aspergilloses 11/12 vs. 7/17 (92% vs. 41%, P = 0.008) patients responded. Pneumonia lethality was 1/19 in the AmBisome-treated patients compared with 23/72 in the historical group (5% vs. 32%, P = 0.01); and among those with proven/probable aspergilloses it was 1/12 vs. 10/17 (8% vs. 59%, P = 0.008). In conclusion, early empiric treatment with AmBisome 3 mg kg-1 and 5 mg kg-1 on alternate days was well tolerated and greatly reduced the lethality of proven/probable Aspergillus pneumonias.

[Therapy of invasive organ mycoses in patients with systemic hematologic diseases]. / Therapie invasiver Organmykosen bei Patienten mit hämatologischen Systemerkrankungen.

Fungal infections have increased substantially in patients with acute leukemia as well as in patients receiving allogeneic stem cell transplantations. Most frequently Aspergillus ssp. and Candida ssp. are observed. Despite the recent introduction of new azoles and lipid-based formulations of amphotericin B, there are few randomized, controlled studies on the use of antifungal drugs in patients with proven invasive fungal infections. Conventional Amphotericin B is considered gold standard for the treatment of invasive fungal infections, however is limited by nephrotoxicity and infusion related adverse events. Treatment with azoles, e.g. fluconazole, itraconazole or voriconazole is generally well-tolerated. Fluconazole, however, has no activity against Aspergillus ssp. An additional serious problem is an emerging resistance of non-albicans species to fluconazole. Lipid-formulations of amphotericin B seem to be attractive alternative, but considerably higher medical costs limit broader application of lipid formulations of amphotericin B. The current strategies for the treatment of documented fungal infections as well as the role of new antifungal agents are discussed in this review.