Wind-borne dispersion of Echinococcus multilocularis eggs - a flight model.

The alveolar hydatid disease, also known as alveolar echinococcosis, of humans is certainly one of the most dangerous zoonoses worldwide. The disease is caused by Echinococcus multilocularis - the fox tapeworm. Red foxes (Vulpes vulpes) are currently counted as the most important carriers (reservoirs) of E. multilocularis in the Northern Hemisphere. The possible routes of infection of E. multilocularis to humans are complex and still require research. Until now, it has been unknown whether E. multilocularis eggs can be moved by wind at all. This analysis shows, based on calculations, that E. multilocularis eggs can be transported by wind. Using a mathematical model, flight distances depending on wind speed and take-off heights are calculated for dense and less dense (coniferous) forest areas. The results - differentiated for seasons and as overall average - are based on mean values of wind speeds which were measured over a ten-year period in an experimental forest stand in the Solling (Germany). Due to their rate of descent, wind-related spreading of E. multilocularis eggs is possible. The average flight distance covered by E. multilocularis eggs in forest areas, depending on their starting altitude and wind speed, is between approximately 1.3 m and approximately 17 m. From the mathematical point of view, the wind factor can definitely be seen as one of the multiple vectors associated with environmental contamination by E. multilocularis eggs. Consequently, the possible wind-borne spread of E. multilocularis eggs poses an infection risk to humans that should be considered and requires further research.

Metastatic mammary carcinoma despite histologically negative sentinel lymph nodes: are there any indicators for estimating recurrence and metastasis rates?.

OBJECTIVE: This study aimed to identify indicators for an increased frequency of recurrent or metastatic disease in women with mammary carcinoma staged negative for nodal involvement. MATERIALS AND METHODS: 202/270 patients (age: mean 57.5, range 24-83 years) with histologically confirmed early stage mammary carcinoma negative for metastasis to the sentinel lymph nodes (SLN) were observed with respect to their clinical course for a mean period of 3.6 years following SLN extirpation. RESULTS: Forty of 202 patients with negative SLN underwent chemotherapy (38/188 in the recurrence-free group vs. 2/14 in the group with progressive disease) and 79% of both subcollectives did not undergo chemotherapy. Seven of 188 of patients in the recurrence-free group received immunotherapy and none of the patients in the group with disease progression were treated with this modality. One hundred sixty-two of 202 patients with negative SLN underwent hormone therapy, 157/188 in the recurrence-free group and 5/14 in the group with disease progression. One hundred sixty-four of 202 patients with negative nodal status received adjuvant radiation therapy of the affected breast, 156/188 in the recurrence-free group and 8/14 in the group with disease progression. CONCLUSIONS: When assessing the risk profile for disease recurrence or the occurrence of metastatic disease, statistically significant differences with respect to disease progression were identified for the parameters chemo-, antibody, hormone, and radiation therapy. The preliminary observations of this study show that even those patients in an early disease stage and with negative SLNs profit from these adjuvant non-surgical therapy options.

Incidence and natural history of challenge-proven cow's milk allergy in European children--EuroPrevall birth cohort.

BACKGROUND: Cow's milk allergy (CMA) is one of the most commonly reported childhood food problems. Community-based incidence and prevalence estimates vary widely, due to possible misinterpretations of presumed reactions to milk and differences in study design, particularly diagnostic criteria. METHODS: Children from the EuroPrevall birth cohort in 9 European countries with symptoms possibly related to CMA were invited for clinical evaluation including cows' milk-specific IgE antibodies (IgE), skin prick test (SPT) reactivity and double-blind, placebo-controlled food challenge. RESULTS: Across Europe, 12 049 children were enrolled, and 9336 (77.5%) were followed up to 2 years of age. CMA was suspected in 358 children and confirmed in 55 resulting in an overall incidence of challenge-proven CMA of 0.54% (95% CI 0.41-0.70). National incidences ranged from 1% (in the Netherlands and UK) to <0.3% (in Lithuania, Germany and Greece). Of all children with CMA, 23.6% had no cow's milk-specific IgE in serum, especially those from UK, the Netherlands, Poland and Italy. Of children with CMA who were re-evaluated one year after diagnosis, 69% (22/32) tolerated cow's milk, including all children with non-IgE-associated CMA and 57% of those children with IgE-associated CMA. CONCLUSIONS: This unique pan-European birth cohort study using the gold standard diagnostic procedure for food allergies confirmed challenge-proven CMA in <1% of children up to age 2. Affected infants without detectable specific antibodies to cow's milk were very likely to tolerate cow's milk one year after diagnosis, whereas only half of those with specific antibodies in serum 'outgrew' their disease so soon.

Multimodality treatment for early-stage hepatocellular carcinoma: a bridging therapy for liver transplantation.

PURPOSE: To evaluate the efficiency of a multimodality approach consisting of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) as bridging therapy for patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) and to evaluate the histopathological response in explant specimens. MATERIALS AND METHODS: Between April 2001 and November 2011, 36 patients with 50 HCC nodules (1.4-5.0 cm, median 2.8 cm) on the waiting list for liver transplantation were treated by TACE and RFA. The drop-out rate during the follow-up period was recorded. The local efficacy was evaluated by histopathological examination of the explanted livers. RESULTS: During a median follow-up time of 29 (4.0-95.3) months the cumulative drop-out rate for the patients on the waiting list was 0, 2.8, 5.5, 11.0, 13.9 and 16.7% at 3, 6, 12, 24, 36 and 48 months, respectively. 16 patients (with 26 HCC lesions) out of 36 (44.4%) were transplanted by the end of study with a median waiting list time of 13.7 (2.5-37.8) months. The histopathological examination of the explanted specimens revealed a complete necrosis in 20 of 26 HCCs (76.9%), whereas 6 (23.1%) nodules showed viable residual tumor tissue. All transplanted patients are alive at a median time of 29.9 months. Imaging correlation showed 100% specificity and 66.7% sensitivity for the depiction of residual or recurrent tumor. CONCLUSION: We conclude that TACE combined with RFA could provide an effective treatment to decrease the drop-out rate from the OLT waiting list for HCC patients. Furthermore, this combination therapy results in high rates of complete tumor necrosis as evaluated in the histopathological analysis of the explanted livers. Further randomized trials are needed to demonstrate if there is a benefit in comparison with a single-treatment approach.

An amyloid beta vaccine that safely drives immunity to a key pathological species in Alzheimer's disease: pyroglutamate amyloid beta.

Pyroglutamate amyloid beta3-42 (pGlu-Abeta3-42), a highly amyloidogenic and neurotoxic form of Abeta, is N-terminally truncated to form a pyroglutamate and has recently been proposed as a key target for immunotherapy. Optimized ACI-24, a vaccine in development for the treatment and prevention of Alzheimer's disease, focuses the antibody response on the first 15 N-terminal amino acids of Abeta (Abeta1-15). Importantly, clinical data with an initial version of ACI-24 incorporating Abeta1-15, established the vaccine's safety and tolerability with evidence of immunogenicity. To explore optimized ACI-24's capacity to generate antibodies to pGlu-Abeta3-42, pre-clinical studies were carried out. Vaccinating mice and non-human primates demonstrated that optimized ACI-24 was well-tolerated and induced an antibody response against Abeta1-42 as expected, as well as high titres of IgG reactive with pyroGlu-Abeta. Epitope mapping of the polyclonal response confirmed these findings revealing broad coverage of epitopes particularly for Abeta peptides mimicking where cleavage occurs to form pGlu-Abeta3-42. These data are in striking contrast to results obtained with other clinically tested Abeta targeting vaccines which generated restricted and limited antibody diversity. Taken together, our findings demonstrate that optimized ACI-24 vaccination represents a breakthrough to provide a safe immune response with a broader Abeta sequence recognition compared to previously tested vaccines, creating binders to pathogenic forms of Abeta important in pathogenesis including pGlu-Abeta3-42.

Throwing light on dark states of α-oligothiophenes of chain lengths 2 to 6: radical anion photoelectron spectroscopy and excited-state theory.

In this work, we apply photodetachment photoelectron spectroscopy (PD-PES) on radical anions to access the lowest excited electronic states of neutral α-oligothiophenes nT (n = 2-6, where n denotes the number of thiophene rings) in the gas phase. Besides electron affinities, the spectra provide the energies of the T(1) and T(2) states which are otherwise difficult to investigate in neutral molecules due to spin selection rules. The assignment of the spectra is assisted by quantum chemical calculations using a combined density functional theory and multi-reference configuration interaction approach. For all α-oligothiophenes investigated in this work, the T(2) state is situated below S(1). In the gas phase, the S(1) state energies lie higher than in non-polar solution (0.2 to 0.4 eV). The geometry optimizations show that the S(0) state and especially the excited states gain planarity with increasing chain length. A non-planar structure or out-of-plane vibrational activity is needed to allow an efficient intersystem crossing (ISC) dynamics from S(1) to T(2), followed by internal conversion to T(1). Our theoretical calculations predict that in 6T a doubly excited state becomes nearly isoenergetic to S(1). This state is not observed by PD-PES, which is explained by the analysis of the calculated contributing electron configurations.

Dysplasia epiphysealis hemimelica of the distal ulna: a case report and review of the literature.

Dysplasia epiphysealis hemimelica (DEH) or Trevor's Disease is a very rare disease with an estimated incidence of one in 1.000.000. The majority of cases reported affect the lower limb and only 25 case reports of 33 cases with affection of the upper limb have been published. Here we present a case of DEH affecting the distal ulnar epiphysis and the lunate in an eleven-year-old girl, a DEH location described extremely rarely before. We firstly do not only present clinical and radiological findings (plane radiographs, CT, MRI), but also the surgical approach and the histopathological results of DEH in this uncommon location. Although extremely rare, DEH should be considered also in non-typical locations.

Adverse events associated with deep brain stimulation in patients with childhood-onset dystonia.

BACKGROUND: Data on pediatric DBS is still limited because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We evaluate short- and long-term adverse events (AEs) of patients undergoing deep brain stimulation (DBS) during childhood and adolescence. METHODS: Data collected by the German registry on pediatric DBS (GEPESTIM) were analyzed according to reversible and irreversible AEs and time of occurrence with relation to DBS-surgery: Intraoperative, perioperative (<4 weeks), postoperative (4 weeks < 6 months) and long term AEs (>6 months). RESULTS: 72 patients with childhood-onset dystonia from 10 DBS-centers, who received 173 DBS electrodes and 141 implantable pulse generators (IPG), were included in the registry. Mean time of postoperative follow-up was 4.6 ±â€¯4 years. In total, 184 AEs were documented in 53 patients (73.6%). 52 DBS-related AEs in 26 patients (36.1%) required 45 subsequent surgical interventions 4.7 ±â€¯4.1 years (range 3 months-15 years) after initial implantation. The total risk of an AE requiring surgical intervention was 7.9% per electrode-year. Hardware-related AEs were the most common reason for surgery. There was a tendency of a higher rate of AEs in patients aged 7-9 years beyond 6 months after implantation. DISCUSSION: The intraoperative risk of AEs in pediatric patients with dystonia undergoing DBS is very low, whereas the rate of postoperative hardware-related AEs is a prominent feature with a higher occurrence compared to adults, especially on long-term follow-up. CONCLUSION: Factors leading to such AEs must be identified and patient management has to be focused on risk minimization strategies in order to improve DBS therapy and maximize outcome in pediatric patients.

Serum metabolomic profiling highlights pathways associated with liver fat content in a general population sample.

BACKGROUND/OBJECTIVES: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD. SUBJECTS/METHODS: In a population-based sample (n=555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses. RESULTS: In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD (n=219; odds ratio: 1.36; 95% confidence interval: 1.27-1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD. CONCLUSIONS: A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.

TorsinB expression in the developing human brain.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein, which is restricted to neuronal cells and present in all brain regions by the age of 2 months has been described recently in human developing brain. TorsinB is a member of the same family of proteins and is highly homologous with its gene adjacent to that for torsinA on chromosome 9q34. TorsinA and torsinB share several remarkable features suggesting that they may interact in vivo. This study examined the expression of torsinB in the human brain of fetuses, infants and children up to 7 years of age. Our results indicate that torsinB protein expression is temporarily and spatially regulated in a similar fashion as torsinA. Expression of torsinB protein was detectable beginning at four to 8 weeks of age in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia and was predominantly restricted to neuronal cells. In contrast to torsinA, torsinB immunoreactivity was found more readily in the nuclear envelope. High levels of torsinB protein were maintained throughout infancy, childhood and adulthood suggesting that torsinB is also needed for developmental events occurring in the early postnatal phase and is necessary for functional activity throughout life.

TorsinA expression is detectable in human infants as young as 4 weeks old.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein and its message has been described previously in several regions of normal adult human and rodent brain. This study examines the expression of torsinA in the developing human brain of fetuses, infants and children up to 7 years of age in four selected brain regions. Expression of torsinA protein was detectable beginning at 4 to 8 weeks of age postnatally in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia. Prominent torsinA immunoreactivity was not seen before 6 weeks of age postnatally, a period associated with synaptic remodeling, process elimination and the beginning of myelination. Our results indicate that torsinA protein expression is temporally and spatially regulated and is present in all brain regions studied by the age of 2 months on into adulthood.

Modeling of nonlinear Lévy processes by data analysis.

The paper presents a method to analyze time series of nonlinear Lévy processes. The Lévy stability index as well as the nonlinear deterministic and stochastic parts of the dynamics together with their uncertainties can be calculated numerically. As last step of the analysis the membership of the investigated system to the regarded class of dynamical systems is validated. For demonstration the algorithm is applied to artificially created time series with different Lévy indices.

Results of a prospective study comparing the clinical efficacy of cryoablation of renal cell cancer followed by immediate partial nephrectomy.

PURPOSE: Evaluation if cryoablation of small renal tumours (RT) would facilitate the technique of laparoscopic partial nephrectomy (LPN) in a prospective study. PATIENTS AND METHODS: In a prospective non-randomised study between April 2007 and October 2009, 16 patients with a mean age of 68 years (48-80 years) and a peripherally located RT were candidates for nephron-sparing surgery (5 open partial nephrectomy (OPN), 11 LPN). Cryoablation of RT was followed in the same session by open (K-OPN) and laparoscopic (K-LPN) partial nephrectomy. Perioperative and follow-up parameters were estimated. A matched-pair cohort of 41 patients (20 OPN, 21 LPN) who underwent standard operations due to the same indication has been selected for retrospective comparison (controls). RESULTS: Mean age for K-OPN was 74 years (69-83) with mean blood loss 140 ml (50-200); for K-LPN: 66.6 years (48-80) with 100 ml (50-700). All procedures were completed successfully without conversions (K-LPN), transfusions or intra-operative complications. Compared to OPN/LPN, K-OPN and K-LPN were associated with a longer operative time (P < 0.05) and a comparable postoperative hospital stay. There were no early postoperative complications. Cryoablation has not affected the histopathological evaluation of tumours or resection margins. Histopathology showed cytologic changes suggesting fresh coagulative necrosis, glomerular vascular congestion and interstitial haemorrhages following cryotherapy. One patient (K-LPN) developed a pararenal abscess necessitating puncture after 7 weeks. The follow-up (9-42 months) was uneventful. CONCLUSIONS: The current study shows that K-LPN is feasible without increasing procedure morbidity or compromising surgical and oncological outcomes. It adds no advantage to tumour excision. Pathological findings document early cryoablation effects but viable tissue.

[Metastases in patients with breast cancer despite of negative sentinel lymph node. Has the concept to be changed?]. / Metastasierung beim Mammakarzinom trotz histologisch negativem Wächterlymphknoten. Muss das Konzept geändert werden?

UNLABELLED: The sentinel lymph node (SLN) is of considerable prognostic relevance, because extended lymph node dissection may not be performed in patients presenting with histologically negative SLN. The aim of this study was to prove the prognostic value of the SLN-concept in these patients in long term follow-up. PATIENTS, METHODS: The clinical follow-up of 202 women with histologically proven breast cancer and metastatically uninvolved (negative) SLN, as determined using Tc-99m-nanocolloid, was observed for a mean period of 43.4 months. Histological examination included standard methods (HE-Test) and special histochemical techniques (antibodies against cytokeratin). All patients underwent clinical examinations and mamography according a standardised schema; other procedures like ultrasound examination, routine blood tests, and chest X-ray scans were performed in patients considered doubtful after clinical examination or mamography. RESULTS: Despite of negative SLN-findings in 14/202 patients (6.9%) metastases were found after a mean time period of 35.9 months. 4 patients showed local re-lapses, 3 patients presented with regional lymph node recurrences in the previously mapped (negative) SLN-basin, and 7 Patients developed distant metastases outside the primary lymphatic basin. CONCLUSION: In patients negative on SLN-biopsy the axillary lymph-node-recurrence-rate was low; in 3/202 patients (1.5%) a progression in the SLN-basin could be assessed, being real concept failures. Our results underline that there is no evidence to question this concept in patients presented with clinically metastatically uninvolved early stage of breast cancer.

[Oncological and functional results of open intrafascial radical prostatectomy]. / Onkologische und funktionelle Ergebnisse der offenen intrafaszialen radikalen Prostatektomie.

BACKGROUND: According to the recently published German-language S3 guidelines, various treatment options such as surgical management or radiation therapy are available to patients with locally advanced prostate cancer. METHODS: Particularly the establishment of minimally invasive endoscopic surgical techniques, which provide better optical images, has made it possible to visualize tissue layers that are usually difficult to identify with the open surgical technique. This contribution describes a pilot study on the establishment of open intrafascial radical prostatectomy. AIM: The goal of the study is to critically analyze both the functional and especially the oncological results, which should not be compromised by the nerve-sparing approach.

[Epidermoid cyst of the kidney : a rare cause of recurrent renal colic]. / Epidermoidzyste der Niere : Eine seltene Ursache für rezidivierende Nierenkoliken.

In contrast to epidermoid cysts of the dermis, epidermoid cysts of the kidneys are rare. We report on a female patient with recurrent renal colic caused by an epidermoid cyst of her right kidney. A malignant tumor was suspected by computed tomography but was ruled out through ureterorenoscopic biopsy. The epidermoid cyst was removed by a partial nephrectomy.

Cerebral angiitis in four patients with chronic GVHD.

There is growing evidence that GVHD affects the central nervous system (CNS). In this study, we describe the long-term follow-up of four allogeneic BM recipients who developed cerebral angiitis-like disease probably due to GVHD. The patients developed focal neurological signs, cognitive deficits and/or coma in association with GVHD, 2-18 years after transplantation, following reduction of immunosuppressive therapy. Magnetic resonance imaging was variable, showing generalized brain atrophy, ischemic lesions or leukoencephalopathy. Diagnosis of cerebral angiitis was confirmed by histopathological analysis of bioptic brain tissue and response to immunosuppressive therapy. By means of immunohistochemistry and immunofluorescence, perivascular lymphomononuclear cerebral infiltrates were shown to express the adhesion receptor, CD11a, and the chemokine receptor, CCR5. Our findings imply that GVHD should be considered in the differential diagnosis of noninfectious angiitis-like disease of the CNS in long-term survivors after allogeneic BMT. Infiltrating cells, in analogy to typical target organs of GVHD such as skin or liver, expressed CD11a and CCR5. These findings could be of etiopathological, diagnostic and therapeutic relevance.

Response to methotrexate in early rheumatoid arthritis is associated with a decrease of T cell derived tumour necrosis factor alpha, increase of interleukin 10, and predicted by the initial concentration of interleukin 4.

OBJECTIVE: This study was performed to assess whether there is any change in the T cell cytokine pattern in early rheumatoid arthritis (RA) patients treated with methotrexate (MTX) and whether the lymphocytic cytokine pattern correlates with disease activity. METHODS: Eight patients with RA (disease duration < six months) were studied serially before, after three, and after six to nine months of treatment with MTX for the cytokines tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin 4 (IL4) and interleukin 10 (IL10) by intracellular staining of T cells derived from peripheral blood. Response to treatment was assessed by the modified disease activitiy score. RESULTS: The clincial response was accompanied by a significant decrease of TNFalpha positive CD4(+) T cells from a median of 8.53% (interquartile range 5.83-10.91%) before treatment to 6.17% (2.15-6.81%) after six to nine months of treatment (p=0.021). Inversely, IL10 positive T cells increased from a median of 0.65% (interquartile range 0.6-0.93%) to a median of 1. 3% (1.22%-1.58%) after six to nine months of treatment (p=0.009). No significant change in the percentage of INFgamma positive T cells and a small decrease of IL4 positive T cells during treatment were observed. The percentage of IL4 positive CD4(+) T cells before treatment correlated with disease activity after six to nine months (r= -0.7066; p=0.05). CONCLUSIONS: During treatment of RA with MTX the percentage of TNFalpha producing T cells decreases whereas that of IL10 producing T cells increases. This may affect macrophage activation and, therefore, may represent a regulatory mechanism relevant to disease remission. Furthermore, the percentage of IL4 positive CD4(+) T cells at disease onset may be a useful prognostic marker.

Analysis of time series from stochastic processes

Analysis of time series from stochastic processes governed by a Langevin equation is discussed. Several applications for the analysis are proposed based on estimates of drift and diffusion coefficients of the Fokker-Planck equation. The coefficients are estimated directly from a time series. The applications are illustrated by examples employing various synthetic time series and experimental time series from metal cutting.