Applicability of the EORTC/MSG criteria for IFD in clinical practice.

Invasive fungal disease (IFD) is a feared complication in patients with hematological malignancies. In 2008, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG) published updated criteria for the diagnostic workup within clinical studies for immunosuppressed patients with suspected fungal infection. We applied these criteria in a routine clinical setting with regard to their feasibility for bedside practice at our institution in a 1-year period. One hundred seventy consecutive patients with a recent history of chemotherapy-induced neutropenia (n = 100) or allogeneic stem cell recipients (n = 70) who had received a CT scan of the chest in search of pulmonary IFD were examined. We analyzed all available radiological and microbiological data according to the EORTC/MSG criteria. The quality of images was good in 94.7%, microbiological diagnostics performed in 94.1% patients. Five patients had histopathologic-proven IFD, 18 patients were classified as "probable," 55 patients as "possible" IFD, and 92 patients did not fulfill any criteria ("no IFD"). Microbiology revealed suggestive findings in 29 patients. These were either galactomannan antigen (Gm-AG) in serum (n = 18) and/or broncho-alveolar lavage (BAL) (n = 5). CT scan showed pulmonary infiltrates in 106 patients; 78 were classified as typical for IPA, further discriminated by morphology and number of nodules, as well as additional signs (halo, air crescent, cavity). We observed a better overall survival in patients without infiltrates compared to those with any type of infiltrate (p = 0.042) and a trend toward favorable survival in patients who had micronodular lesions (p = 0.058). We also found a higher probability of Gm-AG positivity in the group of allogeneic stem cell transplantation (allo-SCT) patients (p = 0.001) and a trend toward an association of Gm-AG positivity and positive findings on CT (p = 0.054). The applicability of criteria was good, both with regard to radiological and mycological evidence and sufficient for the categorization of IFD according to EORTC/MSG in the clinical setting. However, our findings suggest that feasibility improves with stringency of mycological workup, which is reflected in the two subgroups. Radiology harvests by far more suggestive findings which can only partly be correlated with mycological evidence. Although feasible, whether the EORTC/MSG criteria are the appropriate tool for early identification of IFD remains open for discussion.

Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene and is characterized by global developmental delays and autism spectrum disorder (ASD). Based on several converging lines of preclinical and clinical evidence supporting the use of insulin-like growth factor-1 (IGF-1) in PMS, this study aims to follow-up a previous pilot study with IGF-1 to further evaluate this novel therapeutic for core symptoms of ASD in children with PMS. METHODS: Ten children aged 5-9 with PMS were enrolled. Participants were randomized to receive IGF-1 or placebo (saline) using a 12-week, double-blind, crossover design. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as secondary outcome measures reflecting core symptoms of ASD. To increase power and sample size, we jointly analyzed the effect of IGF-1 reported here together with results from our previous controlled trail of IGF-1 in children with PMS (combined N = 19). RESULTS: Results on the ABC-SW did not reach statistical significance, however significant improvements in sensory reactivity symptoms were observed. In our pooled analyses, IGF-1 treatment also led to significant improvements in repetitive behaviors and hyperactivity. There were no other statistically significant effects seen across other clinical outcome measures. IGF-1 was well tolerated and there were no serious adverse events. LIMITATIONS: The small sample size and expectancy bias due to relying on parent reported outcome measures may contribute to limitations in interpreting results. CONCLUSION: IGF-1 is efficacious in improving sensory reactivity symptoms, repetitive behaviors, and hyperactivity  in children with PMS. Trial registration NCT01525901.

[Knee dislocation--a simple diagnosis? Compartment syndrome with occlusion of the popliteal artery and lesion of the peroneal nerve after inadequate trauma]. / Die Kniegelenkluxation--eine einfache Diagnose? Kompartmentsyndrom mit Verschluss der A. poplitea und Läsion des N. fibularis communis nach inadäquatem Trauma.

Knee dislocations are rare and often associated with damage to the surrounding structures. We present a case where a soldier sustained a complex knee dislocation during routine training. This trauma was associated with a compartment syndrome, occlusion of the popliteal artery, lesion of the peroneal nerve and multiple lesions of ligaments and tendons of the knee.

Physical determinants of vascular network remodeling during tumor growth.

The process in which a growing tumor transforms a hierarchically organized arterio-venous blood vessel network into a tumor specific vasculature is analyzed with a theoretical model. The physical determinants of this remodeling involve the morphological and hydrodynamic properties of the initial network, generation of new vessels (sprouting angiogenesis), vessel dilation (circumferential growth), vessel regression, tumor cell proliferation and death, and the interdependence of these processes via spatio-temporal changes of blood flow parameters, oxygen/nutrient supply and growth factor concentration fields. The emerging tumor vasculature is non-hierarchical, compartmentalized into well-characterized zones, displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size, and transports drug injections efficiently. Implications for current theoretical views on tumor-induced angiogenesis are discussed.

Lameness in fattening pigs - Mycoplasma hyosynoviae, osteochondropathy and reduced dietary phosphorus level as three influencing factors: a case report.

BACKGROUND: Multiple diagnostic procedures, their results and interpretation in a case with severe lameness in fattening pigs are described. It is shown that selected diagnostic steps lead to identification of various risk factors for disease development in the affected herd. One focus of this case report is the prioritization of diagnostic steps to verify the impact of the different conditions, which finally led to the clinical disorder. Assessing a sufficient dietary phosphorus (P) supply and its impact on disease development proved most difficult. The diagnostic approach based on estimated calculation of phosphorus intake is presented in detail. CASE PRESENTATION: On a farrow-to-finishing farm, lameness occurred in pigs with 30-70 kg body weight. Necropsy of three diseased pigs revealed claw lesions and alterations at the knee and elbow joints. Histologic findings were characteristic of osteochondrosis. All pigs were positively tested for Mycoplasma hyosynoviae in affected joints. P values in blood did not indicate a P deficiency, while bone ashing in one of three animals resulted in a level indicating an insufficient mineral supply. Analysis of diet composition revealed a low phosphorus content in two diets, which might have led to a marginal P supply in individuals with high average daily gains with respect to development of bone mass and connective tissue prior to presentation of affected animals. Finally, the impact of dietary factors for disease development could not be evidenced in all submitted animals in this case. CONCLUSIONS: Mycoplasma (M.) hyosynoviae was identified to be an important etiologic factor for disease. Other, non-infectious factors, such as osteochondrosis and claw lesions might have favored development of lameness. In addition, a relevant marginal P supply for pigs was found in a limited time period in a phase of intense growing, but the potential interaction with infection by M. hyosynoviae is unknown. The presented case of severe lameness in fattening pigs revealed that three different influences presumably act in pathogenesis. Focusing only on one factor and ignoring others might be misleading regarding subsequent decision-making for prevention and therapy. Finally, clinical symptoms disappeared after some changes in diet composition and anti-inflammatory treatment of individual animals.

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth.

We formulate a theoretical model to analyze the vascular remodelling process of an arterio-venous vessel network during solid tumour growth. The model incorporates a hierarchically organized initial vasculature comprising arteries, veins and capillaries, and involves sprouting angiogenesis, vessel cooption, dilation and regression as well as tumour cell proliferation and death. The emerging tumour vasculature is non-hierarchical, compartmentalized into well-characterized zones and transports efficiently an injected drug-bolus. It displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size. The corresponding cluster size distribution is algebraic, reminiscent of a self-organized critical state. The intra-tumour vascular-density fluctuations correlate with pressure drops in the initial vasculature suggesting a physical mechanism underlying hot spot formation.

Infectious complications after allogeneic stem cell transplantation: incidence in matched-related and matched-unrelated transplant settings.

BACKGROUND: Bacterial, viral, and fungal pathogens frequently cause severe, life-threatening infections in immunocompromised patients after allogeneic hematopoietic stem cell transplantation (SCT). OBJECTIVE: To compare the frequency of infections in patients with matched-related (Group A) or with human leukocyte antigen (HLA)-matched-unrelated donors (Group B). PATIENTS AND METHODS: Patients treated at our transplantation unit between April 2004 and April 2005 were enrolled into this analysis. Documentation comprised demographic data, conditioning treatment, stem cell source, clinical course, as well as microbiological and clinical data and mortality. RESULTS: We analyzed 59 patients, 22 in Group A and 37 in Group B. Both groups were well balanced regarding demographic data. Diagnoses were acute myeloid leukemia (30 of 59 patients, 50.8%), multiple myeloma (15.2%), acute lymphoblastic leukemia (11.9%), and chronic myeloid leukemia (10.2%). Patients in Group A developed infections in 95.5% of the cases compared with 97.3% in patients in Group B. Most frequently detected pathogens were Staphylococcus species, human herpesvirus-6, and Epstein-Barr virus. Three proven fungal infections were detected in Group A compared with 9 proven fungal infections in Group B. Lung infiltrations were observed in equivalent incidence in both groups. Two years after transplantation, 55.9% of patients were alive (Group A: 68.2%; Group B: 48.6%, not significant). CONCLUSION: Allogeneic SCT from HLA-matched-unrelated donors does not have a higher infection risk than patients transplanted from matched-related donors.

Emergent vascular network inhomogeneities and resulting blood flow patterns in a growing tumor.

Tumors acquire sufficient oxygen and nutrient supply by coopting host vessels and neovasculature created via angiogenesis, thereby transforming a highly ordered network into chaotic heterogeneous tumor specific vasculature. Vessel regression inside the tumor leads to large regions of necrotic tissue interspersed with isolated surviving vessels. We extend our recently introduced model to incorporate Fahraeus-Lindqvist- and phase separation effects, refined tissue oxygen level computation and drug flow computations. We find, unexpectedly, that collapse and regression accelerates rather than diminishes the perfusion and that a tracer substance flowing through the remodeled network reaches all parts of the tumor vasculature very well. The reason for decreased drug delivery well known in tumors should therefore be different from collapse and vessel regression. Implications for drug delivery in real tumors are discussed.

Automated UHPLC separation of 10 pharmaceutical compounds using software-modeling.

Human mistakes are still one of the main reasons of underlying regulatory affairs that in a compliance with FDA's Data Integrity and Analytical Quality by Design (AQbD) must be eliminated. To develop smooth, fast and robust methods that are free of human failures, a state-of-the-art automation was presented. For the scope of this study, a commercial software (DryLab) and a model mixture of 10 drugs were subjected to testing. Following AQbD-principles, the best available working point was selected and conformational experimental runs, i.e. the six worst cases of the conducted robustness calculation, were performed. Simulated results were found to be in excellent agreement with the experimental ones, proving the usefulness and effectiveness of an automated, software-assisted analytical method development.

Phase II study of regional chemotherapy using the hypoxic abdominal perfusion technique in advanced abdominal carcinoma. 5-FU pharmacokinetics, complications and outcome.

UNLABELLED: The aim of this study was to verify the rationale of a hypoxic abdominal perfusion (HAP) technique for the perfusion of 5-FU, mitomycin C and cisplatin in patients with inoperable, recurrent abdominal cancer. PATIENTS AND METHODS: In a phase II study, 59 patients with various non-resectable abdominal tumours were treated with 102 perfusions by the HAP-technique. The HAP-technique was performed by using double-balloon arterial-venous catheters that selectively isolated the abdominal vascular section and perfusion was provided by an extracorporal pump for 20 min. Thirty-four patients with unresectable colorectal cancer, 11 with unresectable gastric cancer, eight with unresectable pancreatic cancer and six with cancer of the gall bladder were included. They were treated with a combination of 5-fluorouracil (5-FU 1 g/m(2)), mitomycin C (MMC, 10 mg/m(2)) plus cisplatin (50 mg/m(2)) infused into the isolated abdominal compartment. The cytostatic concentration of 5-FU was determined intrainterventionally within the systemic and regional compartment. Toxicity- and procedure-related complications were documented. Tumour responses were assessed by computer tomography. RESULTS: 5-FU concentration was 16.3-fold higher within the regional compared to the systemic compartment at its maximum, and the area under the curve (AUC) was 7.9 times larger. During the procedure two major complications were experienced (1x perforation of the A. iliaca, lx deep vein thrombosis), no deaths occurred during surgery or in the postoperative period. Minimal systemic and local toxicities were observed (WHO grade III-IV 1%, grade I-II 33%). No complete response but 22 partial responses were observed. Median survival was 15.5 months for colorectal cancer, 12. 5 months for gastric cancer, 12.7 months for pancreatic cancer and 7.8 months for gall bladder cancer. CONCLUSION: The hypoxic abdominal perfusion is a safe and effective palliative treatment for patients with unresectable advanced colorectal, gastric and pancreatic carcinoma. The HAP has not shown promising results for advanced gall bladder cancer. These encouraging clinical results require further evaluation.

Hepatic arterial infusion (HAI). Comparison of 5-fluorouracil, folinic acid, interferon alpha-2b and degradable starch microspheres versus 5-fluorouracil and folinic acid in patients with non-resectable colorectal liver metastases.

BACKGROUND: The prognosis of patients with advanced colorectal tumor is poor. Therefore, other therapy regimes for non-resectable hepatic metastases are necessary. In this prospective study, two regional chemotherapy protocols were compared. PATIENTS AND METHODS: An arterial port system was implanted in 64 patients. Sixty patients were assigned to the two therapy protocols for hepatic arterial infusion (HAI): protocol A (n=24): 5-FU/FA (300 mg/m2 folinic acid and 600 mg/m2 5-fluorouracil daily for 5 days with a 14-day interval); protocol B (n=36): 5-FU/FA/IFN/DSM (450 mg starch microspheres (DSM) with 5 million IU recombinant interferon (IFN), alpha 2b 500 mg/m2 FA and 600 mg/m2 5-FU). RESULTS: The response rate was 50% in protocol A patients and 69.4% in protocol B. The median times for disease progression were 11 months for protocol A and 20 months for protocol B (p = 0.038), while median survival times of 14 months and 26 months, respectively, were obtained (p = 0.015). There were no significant differences in terms of toxic side-effects. Major toxicity problems were observed in 12% of the protocol A-treated patients and in 11% of the protocol B-treated patients. CONCLUSION: Combination therapy with HAI-5-FU/FA/IFN/DSM was superior to HAI-5FU/FA, with a high response rate (69% vs. 55%) and few toxic side-effects. These findings suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases of colorectal cancer.

Improvement in 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) concentration by 5-fluorouracil-polyethylene-glycol-liposomes in abdominal stop-flow: treatment of VX2 liver-tumor-bearing rabbits.

The application of liposome-encapsulated cytostatics results in higher concentrations in tumor tissue. This effect can be further increased by blood flow retardation with longer retention time in the tumor and by arterial administration. In abdominal stop-flow therapy, a separate partial circulation with a defined flow is realized via a roller pump under hypoxic conditions. Forty chinchilla rabbits with VX-2 liver tumors were treated either intra-aortally (stop-flow therapy) or systemically with 50 mg 5-FU or 5-FU-PEG liposomes. During therapy, pH and pO2 were measured at regular intervals. After 20 minutes, concentrations of 5-FU and its metabolite FdUrd were determined by HPLC in different organs and the liver tumor. Compared to the i.v. application of monosubstances, the combination of i.a. 5-FU-PEG liposomes and flow retardation increased the concentration in tumor tissue by a factor of 44 and even 100-fold in the para-aortal lymph nodes (LN). The concentration of 5-FU and FdUrd was increased by flow reduction, intraaortal application and liposomal encapsulation of 5-FU.

Effects of chlorpromazine and some of its metabolites on the EEG and on dopamine metabolism of the isolated perfused rat brain.

The study concerned the effects of chlorpromazine (CPZ), monodesmethyl-chlorpromazine (NOR1-CPZ), didesmethyl-chlorpromazine (NOR2-CPZ), and chlorpromazine-N-oxide (CPZ-NO) on the EEG and on dopamine metabolism of the isolated perfused rat brain. Isolated brains were perfused with 100 ml of a perfusion medium containing 30% bovine red cells (v/v), 2 g bovine serum albumin, 14 mM glucose as well as one of the agents in a concentration of 10 micrometers. The main dopamine metabolite homovanillic acid (HVA) was measured fluorimetrically in the striatum of the isolated brain. The EEG was recorded by two symmetrical bipolar leads from the parietal regions at various times during the 30 min perfusion period and was stored on magnetic tape. The recordings were evaluated visually and quantitatively by automatic analysis. CPZ-NO was found to be the most active agent both in changing the EEG and in elevating the HVA level in the striatum. The mean EEG amplitude and the slow wave activity increased significantly. The increase of the HVA level in the striatum was correlated with the increase of delta waves as well as excess of kurtosis and skewness calculated from the amplitude histography data. The desmethylated metabolites caused only moderate central effects.

Anterior interosseous nerve compression after supracondylar fracture of the humerus: a metaanalysis.

OBJECT: The authors conducted a metaanalysis of reports of anterior interosseous nerve syndrome, a rare nerve compression neuropathy that affects only the motor branch of the median nerve. This syndrome is characterized by paralysis of the flexor pollicis longus, the flexor digitorum profundus to the index finger, and the pronator quadratus, with weakness on flexion of the interphalangeal joint of the thumb and the distal interphalangeal joint of the index finger without sensory loss. METHODS: The authors reviewed reports of 34 cases of anterior interosseous nerve syndrome combined with supracondylar fractures of the humerus in children. They have added a new case identified in a 7-year-old boy in whom a diagnosis was made from the clinical findings and whose treatment and outcome are analyzed. The ages of patients reported in the literature ranged from 4 to 10 years. Ten patients (29%) were treated with closed reduction and application of a cast, whereas 25 patients (71%) were treated with open reduction and fixation of the fracture. CONCLUSIONS: All patients regained full flexion and strength after 4 to 17 weeks. The fractures that were surgically treated showed no entrapment of the anterior interosseous nerve.

Advanced high-performance liquid chromatography method development. Discovering unexpected choices in chromatography.

The influence of some important experimental parameters on the resolution of compounds as well as the validity of widely used rules of thumb and of common expectations about how to improve resolution is discussed. It will be shown, on the basis of selected examples, that the general expectations about how the experimental parameters have to be adjusted for better resolution does not cover all chances for resolution improvement. The tool for understanding the method and to discover all chances for increasing selectivity is the resolution map of a method.

Aging and memory effects in a clathrate.

The out-of-equilibrium low-frequency complex susceptibility of the orientational glass methanol(73%)-beta-hydroquinone-clathrate is studied using temperature-stop protocols in aging experiments. Although the material does not have a sharp glass transition aging effects including rejuvenation and memory similar to the effects in spin glasses are found at low temperatures.

Random-bond Potts model in the large-q limit.

We study the critical behavior of the q-state Potts model with random ferromagnetic couplings. Working with the cluster representation the partition sum of the model in the large-q limit is dominated by a single graph, the fractal properties of which are related to the critical singularities of the random-Potts model. The optimization problem of finding the dominant graph, is studied on the square lattice by simulated annealing and by a combinatorial algorithm. Critical exponents of the magnetization and the correlation length are estimated and conformal predictions are compared with numerical results.

Critical behavior of the frustrated antiferromagnetic six-state clock model on a triangular lattice.

We study the antiferromagnetic six-state clock model with nearest neighbor interactions on a triangular lattice with extensive Monte Carlo simulations. We find clear indications of two phase transitions at two different temperatures: Below T(I) a chirality order sets in and by a thorough finite-size-scaling analysis of the specific heat and the chirality correlation length we show that this transition is in the Ising universality class (with a nonvanishing chirality order parameter below T(I)). At T(KT) (

The role of hemorheology in the pathophysiology and treatment of arterial occlusive disease.

Hemorheological types of treatment are more and more used in the field of clinical angiology. On the other hand a good portion of criticism is necessary not to go the wrong way. In spite of really attractive pathophysiological ideas the bed side situation is quite a different affair. Up to now it is not clear under which conditions and to what extent pathological hemorheological values are causative or at least aggravating factors of arterial occlusive diseases and the resultant functional impairment. So the essential points of what is called "clinical hemorheology" are not yet solved. Direct observation and documentation of hemorheological induced clinically interesting effects in humans as well as the serious trial to give definitions of clinical conditions in which the effects obtained are of clinical relevance are extremely necessary to enlighten an attractive and exciting component of clinical angiology.