bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Study on Viscosity and Phase Segregation of Al–Si Powders in Microsemisolid Powder Forming
Authors: Wu Yufeng , Kim Gap-Yong , Anderson Iver E. , Lograsso Thomas A.
Published: February 2010

Semisolid powder forming is a promising approach for near-net shape forming of features in macro-/microscale. In this paper, viscosity and phase segregation behavior of Al–Si powders in the semisolid state were studied with back extrusion experiments. The effects of process parameters including shear rate, extrusion ratio, heating time, and precompaction pressure were analyzed using the design of experiments method. The results showed that the effects of shear rate, extrusion, ratio and heating time were statistically significant factors influencing the viscosity. The semisolid state powders showed a shear thinning behavior. Moreover, microstructure analysis of extruded parts indicated severe phase segregation during the forming process. As the extrusion opening became small (∼400 μm), the phase segregation increased. This study expanded the semisolid processing technology by exploring the use of powdered materials instead of typical bulk materials for applications in micro-/mesomanufacturing. Replacing bulk materials with powdered materials may add a new dimension to the technique by allowing tailoring of material properties.
Polymer Film Production: Modeling and Control of the Forward Draw
Authors: MacLaine C. R. , Acarnley P. , Shanahan J. , Mousalli P. , Deighton M.
Published: February 2010

Many industrial processes involve the transportation of a continuous web of material over a series of rollers to obtain a finished product. The manufacture of polymer film is one such web transport process, which utilizes a series of rotating elements that act to manipulate the film. This paper develops a dynamic mathematical model of the “forward draw” in a polymer film production process. The model is capable of being implemented in real-time for control purposes, yet includes significant physical phenomena such as material damping. Experimental results from a pilot production plant are used to validate the model under steady-state and transient conditions. The model is then used as a basis for a feed-forward control scheme, which reduces speed variations in the forward draw by a factor of 8 and therefore improves considerably the film quality.
The Impact of Surface Forces on Particle Flow and Membrane Fouling in the Microfiltration of Metalworking Fluids
Authors: Ham Seounghyun , Kapoor Shiv G. , DeVor Richard E. , Wentz John
Published: February 2010

Microfiltration is an in-process recycling method that shows great potential to extend fluid life and reduce bacterial concentrations in synthetic and semisynthetic metalworking fluids. The primary problem facing the use of microfiltration is membrane fouling, which is the blocking of membrane pores causing reduced flux. In this paper a fluid dynamic model of partial and complete blocking in sintered alumina membranes is developed that includes hydrodynamic, electrostatic, and Brownian forces. Model simulations are employed to study the impact of electrostatic and Brownian motion forces on the progression of partial blocking. The simulations also examine the effects of fluid velocity, particle size, and particle surface potential. The inclusion of electrostatic and Brownian forces is shown to significantly impact the progression of the partial blocking mechanism. The addition of a strong interparticle electrostatic force is shown to eliminate the partial blocking build-up of small particles due to the presence of the repulsive forces between the particles. As a result, the time to complete blocking of the test pore was lengthened, suggesting that flux decline is reduced in the presence of electrostatic forces. The Brownian motion is shown to have a large impact at low fluid velocities. The most effective parameter set is a low fluid velocity, small particle sizes, high microemulsion surface potential, and high membrane surface potential.
Deformation Size Effects Due to Specimen and Grain Size in Microbending
Authors: Parasiz Sunal Ahmet , VanBenthysen Reid , Kinsey Brad L.
Published: February 2010

Sheet metal forming often consists of bending processes in which gradients of deformation exists through the thickness of the workpiece in a localized deformation area. In microscale bending, these deformation gradients become much steeper, as the changes in the deformation occur over short distances (in the order of micrometers). In addition, with miniaturization, the number of grains that are present through the thickness decreases significantly. In this research, the effect of grain size and specimen size on the deformation distribution through the thickness of microbent sheet specimens was investigated via microhardness evaluations. It was found that the deformation distribution, i.e., hardness profile, is not affected significantly by the grain size when the sheet thickness is large (for 1.625 mm specimens) or by miniaturization of the specimen size when the grain size is fine. However, the deformation distribution of the coarse grained specimens deviates from the fine grained ones and from the 1.625 mm thick sheet specimens when the specimen size is miniaturized.
Fixing the Legal Framework for Pharmaceutical Research
Authors: Knowles Sherry M.
Published: February 2010

The outdated Hatch-Waxman Act and judicial retroactivity challenge costly development of new pharmaceuticals.
Primary localised pleural neurofibroma: expanding the spectrum of spindle cell tumours of the pleura
Authors: Langman G , Rathinam S , Papadaki L
Published: February 2010

Aims

Primary localised pleural neoplasms are a rare group of thoracic tumours, with solitary fibrous tumour representing the most frequently encountered entity. Two cases of localised pleural neurofibromas involving the pleura are described.

Methods and results

The patients were both female: 78 and 29 years of age. In the former a pleural-based lesion was identified on a chest radiograph after she presented with shoulder pain. The second patient was known to have neurofibromatosis type I, and the pleural lesion was found incidentally during excision of a metastatic malignant peripheral nerve sheath tumour of the lung. Both tumours were localised and composed histologically of bland neoplastic spindle cells embedded in a loose collagenous matrix. There was variable immunoreactivity for S100 and CD34, while ultrastructure examination in the two cases showed a mixture of nerve sheath cell types.

Conclusion

To the best of the authors' knowledge, localised neurofibromas have not been previously reported within the pleura. The presence of a bland spindle cell pleural neoplasm immunoreactive for CD34 may potentially be mistaken for a solitary fibrous tumour. While distinction is usually achieved on close attention to the histological features, staining with S100 protein, especially in small biopsies, should be considered to exclude a neurofibroma.
TCR-Vβ flow cytometric analysis of peripheral blood for assessing clonality and disease burden in patients with T cell large granular lymphocyte leukaemia
Authors: Feng B , Jorgensen J L , Hu Y , Medeiros L J , Wang S A
Published: February 2010

Aims

T cell large granular lymphocytes (T-LGLs) are commonly increased in reactive conditions as well as T-LGL leukaemia. This differential diagnosis often requires a combined assessment of clonality and tumour burden. In this study we assessed the utility of flow cytometric (FC) analysis of T cell receptor β chain variable region (TCR-Vβ) expression by using 24 antibodies reactive to 70% of the TCR-Vβ repertoire.

Methods

Analyses were performed on peripheral blood samples obtained from 20 patients with a confirmed diagnosis of T-LGL leukaemia and 18 patients without known T cell lymphoproliferative diseases.

Results

The results were compared with TCR gene rearrangement status assessed by PCR. By FC analysis, 19/20 T-LGL leukaemia cases were CD3+CD8+ and one case was CD3+CD4+. All the cases demonstrated at least one immunophenotypic aberration, with altered CD5 expression being most frequent. Abnormal Vβ expression was detected by FC in 19 of 20 (95%) T-LGL leukaemia cases, but in none of the controls; this showed 100% concordance with TCR gene rearrangement studies. In addition to establishing clonality, FC Vβ analysis enables calculation of absolute numbers of clonal T cells; this is important in monitoring tumour burden after treatment.

Conclusions

It is concluded that FC Vβ analysis is a fast, reliable and quantitative method that can simultaneously assess T-LGL leukaemia clonality and tumour burden.
Cardiac findings in leptospirosis
Authors: Shah Kinjal , Amonkar Gayathri P , Kamat Rima N , Deshpande Jaya R
Published: February 2010

Background/aim

In leptospirosis, although cardiac involvement in the form of ECG changes and myocarditis is known, it is not considered to be significant. This study analysed cardiac changes in leptospirosis.

Methods

Twenty-four hearts from patients who had died from leptospirosis were studied. Detailed gross and light microscopic examination was carried out.

Results

Myocarditis was noted in 96% of cases. Endocardial inflammation was seen in 50% of cases. This endocardial inflammation correlates with vasculitis, which is the principal pathogenetic mechanism of the disease.

Conclusions

There is definite cardiac involvement in leptospirosis, which even though not symptomatically evident, may add to the morbidity or be contributory to the mortality associated with the disease. In addition, a possibility of dilated cardiomyopathy as a delayed consequence of severe myocarditis remains, and may need evaluation.
Histopathological reporting of pT4 tumour stage in colorectal carcinomas: dotting the ‘i’s and crossing the ‘t’s
Authors: Swamy R
Published: February 2010

A histological diagnosis of pT4 stage is used as the basis for offering adjuvant therapy to patients with colorectal cancer. Histological features diagnostic of pT4 stage in colorectal cancer include: (1) presence of tumour perforation, (2) invasion of an adjacent organ, (3) direct or discontinuous tumour extending to the non-peritonealised resection margin, and (4) tumour breaching the visceral peritoneum. Histological parameters to identify these features are not always entirely straightforward, making recognition of pT4 stage difficult at times. The presence of a cellular mesothelial reaction and/or inflammation extending to the serosal surface causes considerable confusion and may result in upstaging pT3 tumours. Conversely, involvement of the non-peritonealised margin in colonic tumours other than rectal cancers is at a risk of being understaged. Audits have shown that significant differences remain in the frequency with which serosal involvement is found between individual pathologists and multidisciplinary teams. The recognition of the criteria that define pT4a and pT4b subsets in pT4 stage to highlight different therapeutic connotations is not universally accepted, and this is likely to affect future reporting of the subsets. The review article highlights the contentious issues in histopathological recognition of pT4 tumour stage based on microscopic parameters in colorectal cancer.
Composite renal cell carcinoma with clear cell renal cell carcinomatous and carcinoid tumoral elements: a first case report
Authors: Bressenot A , Delaunay C , Gauchotte G , Oliver A , Boudrant G , Montagne K
Published: February 2010

Renal endocrine tumours are extremely rare, and carcinoid tumoral elements in renal cell carcinoma have never been reported. This is the first report of a composite renal cell carcinoma containing a clear cell renal cell carcinoma associated with carcinoid tumoral elements, in a patient with synchronous metastatic disease. In the absence of specific radiological and clinical manifestations, typical morphological features as well as an immunostaining profile of neuroendocrine differentiation were identified by microscopy. Secondary nodal and liver localisations were characterised by carcinoid elements only. Despite antiangiogenic therapy, liver metastasis progressed, suggesting that adjuvant therapy cannot be based on the presence of the clear cell renal cell carcinoma component. In this context, extensive tissue sampling is recommended to reveal the endocrine component that is the most aggressive element of such a composite carcinoma.
Leiomyoma of the gallbladder: a case report with review of the literature and discussion of the differential diagnosis: Figure 1
Authors: Wachter D L , Büttner M J , Grimm K , Hartmann A , Agaimy A
Published: February 2010

Mesenchymal neoplasms of the gallbladder are rare, and most represent sarcomas of various histological types. To our knowledge, only a few patients with multiple Epstein–Barr virus (EBV)-associated smooth muscle tumours of the gallbladder in the setting of immunodeficiency have been reported in the English literature, but no single case of conventional leiomyoma has been well documented to date. A case of gallbladder leiomyoma in a healthy 34-year-old woman is described here. The tumour was found incidentally on a routine ultrasound examination and was removed by simple cholecystectomy. The patient is alive and well at last follow-up, 6 months after surgery. Histology and immunohistochemistry were consistent with a benign smooth muscle neoplasm that is very similar to conventional uterine leiomyoma. The tumour was negative for both EBV-encoded nuclear RNAs and EBV latent membrane antigen. The patient had no history of uterine leiomyoma or other neoplasms or clinical evidence of an immune defect. Leiomyoma should be included in the differential diagnosis of spindle cell tumours of the gallbladder and must be distinguished from leiomyosarcoma and the rare gastrointestinal stromal tumour-like neoplasms reported recently at this unusual anatomical site.
Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome
Authors: Herwadkar A , Gennery A R , Moran A S , Haeney M R , Arkwright P D
Published: February 2010

Aims

Although poor thymic function leading to viral and fungal infections can be a feature of chromosome 22q11.2 deletion syndrome, most patients have relatively normal immunity. The aim of this study was to investigate which clinical and laboratory parameters best predict the likelihood of serious or recurrent infections in patients with this syndrome.

Methods

Clinical and laboratory parameters from 64 patients with 22q11.2 deletion syndrome referred to two immunology centres in the north of England were studied retrospectively.

Results

31 (48%) patients had no problems with infection, 21 (33%) had bacterial infections, and 12 (19%) had recurrent or persistent thrush and/or viral enteritis and bronchiolitis, the latter suggestive of a significant T cell immunodeficiency. Patients with a history of thrush/viral infections, but not those with bacterial infections, had significantly lower CD4+ and CD8+ T lymphocyte numbers (relative risk (95% CI) 0.3 (0.1 to 0.8)) and phytohaemagglutinin mitogen responses (0.4 (0.2 to 0.8)) adjusted for age at testing. Hypoparathyroidism was associated with low T lymphocyte numbers and function (p<0.05) as well as an increased risk of thrush/viral infections (p<0.0001) after adjusting for age at testing.

Conclusions

22q11.2 syndrome patients with hypoparathyroidism are more likely to have a clinically significant T cell immunodeficiency and lower laboratory parameters of T cell function, with a higher risk of thrush and viral bronchiolitis and enteritis. Measurement of absolute CD3 count is a simple and accurate predictor of fungal/viral infection risk, with phytohaemagglutinin mitogen responses providing little or no further value in most patients.
Angiomatoid fibrous histiocytoma including cases with pleomorphic features analysed by fluorescence in situ hybridisation
Authors: Matsumura T , Yamaguchi T , Tochigi N , Wada T , Yamashita T , Hasegawa T
Published: February 2010

Background

Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue tumour of uncertain differentiation and low metastatic potential. Cytogenetics and/or molecular genetics have revealed that most have a rearrangement of theEWSR1gene, whereas aFUSgene rearrangement is present in a minority of cases. Although some cases of AFH display striking pleomorphism and mitotic activity, there are no known clinical, morphological or genetic factors that predict metastasis. The authors present clinicopathological features of AFH, including cases showing a pleomorphic histological appearance, and results of fluorescence in situ hybridisation analysis ofEWSR1andFUSrearrangements.

Methods

Tumour samples from 10 patients were subjected to clinicopathological and immunohistochemical analysis and dual-colour fluorescence in situ hybridisation forEWSR1andFUSwith split-signal probes.

Results

All cases showed clinical features (sites: extremities followed by trunk; age: adolescent to young adult), morphology (multinodular proliferation of spindle cells, lymphoid cuffs and pseudovascular spaces) and immunohistochemical results (more than half were positive for CD68, CD99, desmin and epithelial membrane antigen) typical of AFH. There were two local recurrences in each of two patients. Two patients developed distant metastases and died from the disease; tumours of these two patients showed focal proliferation of large pleomorphic cells with hyperchromatic nuclei and high proliferative activity (>10/10 high-power field and Ki-67 labelling index >10%). There were no clinical, histological or immunohistochemical differences between the nine cases withEWSR1rearrangement and one case withFUSrearrangement.

Conclusions

Wide surgical excision and careful follow-up are necessary for patients with AFH in view of its risk of local recurrence and metastasis leading to a fatal outcome.
AXIAL ANOMALY
Authors: JACKIW ROMAN W.
Published: February 2010

The axial anomaly is a quantum term that violates the classical conservation of the the axial current.
Analysis of the liver mitochondrial proteome in response to ethanol andS-adenosylmethionine treatments: novel molecular targets of disease and hepatoprotection
Authors: Andringa Kelly K. , King Adrienne L. , Eccleston Heather B. , Mantena Sudheer K. , Landar Aimee , Jhala Nirag C. , Dickinson Dale A. , Squadrito Giuseppe L. , Bailey Shannon M.
Published: February 2010

S-adenosylmethionine (SAM) minimizes alcohol hepatotoxicity; however, the molecular mechanisms responsible for SAM hepatoprotection remain unknown. Herein, we use proteomics to determine whether the hepatoprotective action of SAM against early-stage alcoholic liver disease is linked to alterations in the mitochondrial proteome. For this, male rats were fed control or ethanol-containing liquid diets ± SAM and liver mitochondria were prepared for proteomic analysis. Two-dimensional isoelectric focusing (2D IEF/SDS-PAGE) and blue native gel electrophoresis (BN-PAGE) were used to determine changes in matrix and oxidative phosphorylation (OxPhos) proteins, respectively. SAM coadministration minimized alcohol-dependent inflammation and preserved mitochondrial respiration. SAM supplementation preserved liver SAM levels in ethanol-fed rats; however, mitochondrial SAM levels were increased by ethanol and SAM treatments. With use of 2D IEF/SDS-PAGE, 30 proteins showed significant changes in abundance in response to ethanol, SAM, or both. Classes of proteins affected by ethanol and SAM treatments were chaperones, beta oxidation proteins, sulfur metabolism proteins, and dehydrogenase enzymes involved in methionine, glycine, and choline metabolism. BN-PAGE revealed novel changes in the levels of 19 OxPhos proteins in response to ethanol, SAM, or both. Ethanol- and SAM-dependent alterations in the proteome were not linked to corresponding changes in gene expression. In conclusion, ethanol and SAM treatment led to multiple changes in the liver mitochondrial proteome. The protective effects of SAM against alcohol toxicity are mediated, in part, through maintenance of proteins involved in key mitochondrial energy conserving and biosynthetic pathways. This study demonstrates that SAM may be a promising candidate for treatment of alcoholic liver disease.
Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction
Authors: Tan Sih Min , Zhang Yuan , Connelly Kim A. , Gilbert Richard E. , Kelly Darren J.
Published: February 2010

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.
RT variability unrelated to heart period and respiration progressively increases during graded head-up tilt
Authors: Porta Alberto , Tobaldini Eleonora , Gnecchi-Ruscone Tomaso , Montano Nicola
Published: February 2010

Open-loop linear parametric models were exploited to describe ventricular repolarization duration (VRD) variability during graded head-up tilt. Surface ECG and thoracic movements were recorded in 15 healthy humans (age: 24–54 yr, median: 28 yr; 6 women and 9 men). Tilt table inclinations ranged from 15 to 90° and were varied in steps of 15°. All subjects underwent recordings at every step in random order. Heart period was assessed as the time difference between two consecutive R-wave peaks (RR) and the respiratory signal (R) as the sampling of the thoracic movement signal at the R-wave peaks. VRD was measured automatically as the temporal difference between the R-wave peak and T-wave apex (RTa) or T-wave end (RTe). The best model decomposed RT variability as due to RR changes (RR-related RT variability) to direct respiratory-related inputs (R-related RT variability) and to unknown rhythmical sources unrelated to RR changes and R (RR-R-unrelated RT variability). Using this model, RTe variability was found to be less predictable than RTa variability and composed of a smaller fraction of RR-related RT variability and a larger fraction of RR-R-unrelated RT variability. Predictability progressively decreased with tilt table angles, suggesting increased complexity of RT regulation. RT variance progressively increased with tilt table inclination. This increase was characterized by a gradual rise of the amount of RR-R-unrelated RT variability, whereas the amount of RR-related RT variability remained unchanged. These results suggest that the amount of RT variability, complexity of RT dynamics, and amount of RR-R-unrelated RT variability increase with the magnitude of the sympathetic drive directly related to tilt table inclination. We propose the utilization of the amount of RR-R-unrelated RT variability instead of overall RT variability as an indirect measure of autonomic regulation directed to ventricles.
Speeding of V̇o2 kinetics with endurance training in old and young men is associated with improved matching of local O2 delivery to muscle O2 utilization
Authors: Murias Juan M. , Kowalchuk John M. , Paterson Donald H.
Published: February 2010

The time course and mechanisms of adjustment of pulmonary oxygen uptake (V̇o2) kinetics (time constant τV̇o2p) were examined during step transitions from 20 W to moderate-intensity cycling in eight older men (O; 68 ± 7 yr) and eight young men (Y; 23 ± 5 yr) before training and at 3, 6, 9, and 12 wk of endurance training. V̇o2p was measured breath by breath with a volume turbine and a mass spectrometer. Changes in deoxygenated hemoglobin concentration (Δ[HHb]) were measured by near-infrared spectroscopy. V̇o2p and Δ[HHb] were modeled with a monoexponential model. Training was performed on a cycle ergometer three times per week for 45 min at ∼70% of peak V̇o2. Pretraining τV̇o2p was greater ( P < 0.05) in O (43 ± 10 s) than Y (34 ± 8 s). τV̇o2p decreased ( P < 0.05) by 3 wk of training in both O (35 ± 9 s) and Y (22 ± 8 s), with no further changes thereafter. The pretraining overall adjustment of Δ[HHb] was faster than τV̇o2p in both O and Y, resulting in Δ[HHb]/V̇o2p displaying an “overshoot” during the transient relative to the subsequent steady-state level. After 3 wk of training the Δ[HHb]/V̇o2p overshoot was attenuated in both O and Y. With further training, this overshoot persisted in O but was eliminated after 6 wk in Y. The training-induced speeding of V̇o2p kinetics in O and Y at 3 wk of training was associated with an improved matching of local O2 delivery to muscle V̇o2 (as represented by a lower Δ[HHb]/V̇o2p). The continued overshoot in Δ[HHb]/V̇o2p in O may reflect a reduced vasodilatory responsiveness that may limit muscle blood flow distribution during the on-transient of exercise.
Cell Type Differentiation Dynamics in the Developing Porcine Retina
Authors: Ghosh Fredrik , Arnér Karin
Published: February 2010

The dynamics of retinal embryogenesis have been well characterized previously in terms of cell proliferation, genesis and migration, whereas overall cell type differentiation within the retinal layers has been less thoroughly explored. In the present study, phenotypical differentiation of all 7 major retinal cell types was examined in the developing porcine retina using one cell-specific immunohistochemical marker per cell type. At the end of the first trimester at E39 (39 days after gestation), neurofilament labeled ganglion cells, recoverin labeled photoreceptors, vimentin labeled Müller cells and synaptophysin labeled presynaptic vesicles were found. Rhodopsin labeled rod photoreceptors were present at E60, whereas cone transducin labeled cone photoreceptors were not seen until E99. Differentiation of inner nuclear cells coincided with the appearance of the retinal layers at E70–E99 with the presence of parvalbumin labeled amacrine cells, calbindin labeled horizontal cells and PKC labeled rod bipolar cells. At postnatal day 4, all retinal subtypes except for cone photoreceptors displayed a labeling pattern corresponding to the one found in the adult porcine retina. The immunohistochemical labeling pattern suggests that phenotypic differentiation of the 7 principal retinal cell types in the porcine retina follows a central-to-peripheral spatio-temporal gradient similar to the one reported for cell proliferation and genesis. Differentiation of the non-laminated retinal cell mass appears to be initiated at its outer and inner margins and progresses inwards, a process which ends in the formation of the characteristic plexiform and nuclear layers. The dynamics of retinal cell type differentiation are of interest from a biological standpoint and are also important for therapeutical strategies in retinal degenerative disease.
Periventricular Heterotopia in Common Microdeletion Syndromes
Authors: van Kogelenberg M. , Ghedia S. , McGillivray G. , Bruno D. , Leventer R. , MacDermot K. , Nelson J. , Nagarajan L. , Veltman J.A. , de Brouwer A.P. , McKinlay Gardner R.J. , van Bokhoven H. , Kirk E.P. , Robertson S.P.
Published: February 2010

Periventricular heterotopia (PH) is a brain malformation characterised by heterotopic nodules of neurons lining the walls of the cerebral ventricles. Mutations in FLNA account for 20–24% of instances but a majority have no identifiable genetic aetiology. Often the co-occurrence of PH with a chromosomal anomaly is used to infer a new locus for a Mendelian form of PH. This study reports four PH patients with three different microdeletion syndromes, each characterised by high-resolution genomic microarray. In three patients the deletions at 1p36 and 22q11 are conventional in size, whilst a fourth child had a deletion at 7q11.23 that was larger in extent than is typically seen in Williams syndrome. Although some instances of PH associated with chromosomal deletions could be attributed to the unmasking of a recessive allele or be indicative of more prevalent subclinical migrational anomalies, the rarity of PH in these three microdeletion syndromes and the description of other non-recurrent chromosomal defects do suggest that PH may be a manifestation of multiple different forms of chromosomal imbalance. In many, but possibly not all, instances the co-occurrence of PH with a chromosomal deletion is not necessarily indicative of uncharacterised underlying monogenic loci for this particular neuronal migrational anomaly.
Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis
Authors: Tartaglia M. , Zampino G. , Gelb B.D.
Published: February 2010

Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.
Incidence of Retinopathy of Prematurity over the Last Decade in the Central Netherlands
Authors: Hoogerwerf A. , Schalij-Delfos N.E. , van Schooneveld M.J. , Termote J.U.M.
Published: February 2010

Background and Objectives: To retrospectively analyze changes in incidence and risk factors of retinopathy of prematurity (ROP) over two periods, 10 years apart, in the central Netherlands. Methods: Data of 570 infants admitted between 2001 and 2005, screened for ROP according to the Dutch National guideline, were compared to those of 538 infants admitted between 1991 and 1995. Results: Incidence of ROP decreased significantly over the last decade (40.9% in 1991–1995 vs. 23.3% in 2001–2005, p < 0.001), together with incidence of severe ROP (stage ≧3) (3.3 vs. 1.2%, p < 0.05). In infants with a birth weight (BW) <1,000 g incidence of ROP dropped significantly (67.0 vs. 41.8%, p < 0.001), as well as incidence of severe ROP (8.1 vs. 3.0%, p < 0.05). For infants with a BW ≧1,000 g incidence of ROP also declined significantly (27.1 vs. 13.0%, p < 0.001), that of severe ROP remained unchanged (0.8 vs. 0.3%). In both periods gestational age, duration of artificial ventilation, small for gestational age (SGA) and postnatal steroids were independent risk factors for ROP. Conclusions: In the central Netherlands, incidence of ROP and severe ROP has significantly decreased, also in infants with BW <1,000 g. Risk factors remained unchanged.
Work-Related Allergy and Asthma in Spice Mill Workers – The Impact of Processing Dried Spices on IgE Reactivity Patterns
Authors: van der Walt Anita , Lopata Andreas L. , Nieuwenhuizen Natalie E. , Jeebhay Mohamed F.
Published: February 2010

Background: Three spice mill workers developed work-related allergy and asthma after prolonged exposure to high levels (>10 mg/m3) of inhalable spice dust. Patterns of sensitization to a variety of spices and putative allergens were identified. Methods: Work-related allergy and asthma were assessed on history, clinical evaluation, pulmonary function and fractional exhaled nitric oxide. Specific IgE reactivity to a range of common inhalant, food and spice allergens was evaluated using ImmunoCAP and allergen microarray. The presence of non-IgE-mediated reactions was determined by basophil stimulation (CAST-ELISA). Specific allergens were identified by immunoblotting to extracts of raw and dried processed garlic, onion and chili pepper. Results: Asthma was confirmed in all 3 subjects, with work-related patterns prominent in worker 1 and 3. Sensitization to multiple spices and pollen was observed in both atopic workers 1 and 2, whereas garlic and chili pepper sensitization featured in all 3 workers. Microarray analysis demonstrated prominent profilin reactivity in atopic worker 2. Immunoblotting demonstrated a 50-kDa cross-reactive allergen in garlic and onion, and allergens of approximately 40 and 52 kDa in chili pepper. Dry powdered garlic and onion demonstrated greater IgE binding. Conclusions: This study demonstrated IgE reactivity to multiple spice allergens in workers exposed to high levels of inhalable spice dust. Processed garlic and onion powder demonstrated stronger IgE reactivity than the raw plant. Atopy and polysensitization to various plant profilins, suggesting pollen-food syndrome, represent additional risk factors for sensitizer-induced work-related asthma in spice mill workers.
Indoor Determinants of Endotoxin and Dust Mite Exposures in Hong Kong Homes with Asthmatic Children
Authors: Leung Ting Fan , Wong Yun Sze , Chan Iris H.S. , Yung Edmund , Wong Chun Kwok , Lam Christopher W.K. , Wong Gary W.K.
Published: February 2010

Background: Domestic endotoxin enhances airway inflammation and increases asthma severity in Caucasian children, but little data are published on indoor endotoxin exposure in Asian countries. This study investigated house dust endotoxin and Der p 1 levels in Hong Kong families with asthmatic children, and their effects on asthma severity. Methods: 115 asthmatics from a pediatric clinic underwent fractional exhaled nitric oxide (FeNO) and spirometric measurements. Home visits were then made within 2 weeks, during which parents completed the International Study of Asthma and Allergies in Childhood questionnaire. Settled dust was collected from patients’ mattresses, bedroom floors and living room floors. Endotoxin and Der p 1 were measured by limulus amebocyte lysate and immunoassay, respectively. Results: Endotoxin was detectable in all locations from all families, whereas Der p 1 was detectable in 58–70% of indoor sites. Floors of both bedroom and living rooms had higher endotoxin but lower Der p 1 levels than mattresses (p < 0.001 for both). Mattress endotoxin level correlated inversely with Der p 1 level (r = –0.308, p = 0.001). Household smoker, feather bedding and vacuum cleaning were independent determinants of indoor endotoxin. Timing of last bedding change was associated with Der p 1 levels at all sites. Mattress endotoxin level was associated with frequency of wheezing episodes (p = 0.044), but neither endotoxin nor Der p 1 was associated with FeNO and spirometric parameters. Conclusions: Domestic endotoxin levels are associated with frequency of wheezing episodes in asthmatic children but not their FeNO or spirometric measurements.
The Effect of Generalist and Specialist Care on Quality of Life in Asthma Patients with and without Allergic Rhinitis
Authors: Harmsen Lotte , Nolte Hendrik , Backer Vibeke
Published: February 2010

Background: Treatment of asthma and rhinitis patients is often provided by both generalists (GPs) and specialists (SPs). Studies have shown differences in clinical outcomes of treatment between these settings. The aim of this study was to evaluate the effect of GP and SP care on health-related quality of life (HRQoL). Materials and Methods: Three hundred and eight asthma and allergic rhinitis patients randomized to 3 years’ treatment by an SP or GP were examined at baseline and at study completion. At both examinations, the HRQoL was measured with the Standardized Asthma Quality of Life Questionnaire (AQLQ) and the Rhinitis Quality of Life Questionnaire (RQLQ). Results: In the SP care, a significant improvement from baseline was found in HRQoL for both AQLQ total scores (6.19 ± 0.1 vs. 6.44 ± 0.1, respectively; p < 0.001) and RQLQ total scores (0.80 ± 0.1 vs. 0.58 ± 0.1, respectively; p <0.01). Patients in the GP care setting experienced no change in HRQoL total scores during the study. However, improvements were found predominantly in patients with concomitant rhinitis. Although no change in AQLQ was found in the GP setting in this group with double disease, an association between change in RQLQ and AQLQ was found (r = –0.245, p < 0.05, and r = –0.324, p < 0.001, respectively). Conclusion: The results provide evidence that compared with GP care, SP care leads to an improvement in both asthma and rhinitis quality of life. This is especially pronounced in patients with concomitant asthma and rhinitis and supports the guidelines recommending that SPs should monitor patients with complicated disease.
The Cannabinoid Receptor Agonist WIN 55,212-2 Inhibits Antigen-Induced Plasma Extravasation in Guinea Pig Airways
Authors: Fukuda Hironobu , Abe Toshio , Yoshihara Shigemi
Published: February 2010

Background: Although neurogenic inflammation of the airways via activation of C-fibers is thought to be important in the pathogenesis of asthma, the mechanisms regulating C-fiber activity remain uncertain. Objective: The influence of a cannabinoid receptor agonist, WIN 55,212-2, on C-fiber activation in guinea pig airways was investigated, as was the mechanism by which cannabinoids regulate antigen-induced airway inflammation. Methods: The inhibitory effect of WIN 55,212-2 on antigen-induced plasma extravasation was assessed in guinea pig tracheal tissues by photometric measurement of extravasated Evans blue dye after extraction with formamide. Results: Pretreatment with WIN 55,212-2 (0.001, 0.01 or 0.1 mg/kg) significantly and dose-dependently reduced tracheal plasma extravasation induced by inhaling a 5% ovalbumin solution for 2 min after pretreatment with a neutral endopeptidedase inhibitor (phosphoramidon at 2.5 mg/kg i.v.). A cannabinoid CB2 receptor antagonist (SR144528) blunted the inhibitory effect of WIN 55,212-2, while a cannabinoid CB1 antagonist (SR141716A) did not. Pretreatment with a neurokinin-1 receptor antagonist (FK888) significantly reduced ovalbumin-induced extravasation of Evans blue dye. Pretreatment with the combination of WIN 55,212-2 and FK888 reduced antigen-induced plasma extravasation more markedly than FK888 alone. Conclusions: These findings suggest that WIN 55,212-2 inhibits C-fiber activation via the cannabinoid CB2 receptor and thus suppresses antigen-induced inflammation in guinea pig airways.
Successful Treatment of Severe Hypertriglyceridemia with a Formula Diet Rich in Omega–3 Fatty Acids and Medium-Chain Triglycerides
Authors: Hauenschild Annette , Bretzel Reinhard G. , Schnell-Kretschmer Henning , Kloer Hans-Ulrich , Hardt Philip D. , Ewald Nils
Published: February 2010

Background: Patients with highly increased plasma triglyceride levels are at risk of developing serious complications such as pancreatitis, coronary heart disease and stroke. Therefore it is important to rapidly decrease plasma triglyceride levels. A sufficient control of triglyceride levels with drugs like fibrates, statins or nicotinic acid can usually only be attained after a couple of weeks. Plasma exchange appears to be a fast but expensive method to reduce triglyceride levels. In this study we describe the use of a new ω–3 fatty acid and medium-chain triglyceride-rich formula diet as a therapeutic concept to reduce plasma triglyceride levels fast and effectively. Methods: Thirty-two patients with severe hypertriglyceridemia were treated with the especially composed formula diet for a period of 7 days. Results: Within this period of time, plasma triglycerides decreased from 1,601 (402–4,555) to 554 (142–2,382) mg/dl (p < 0.05). Total cholesterol levels were reduced from 417 (211–841) to 287 (165–457) mg/dl (p < 0.001). Fasting glucose and uric acid levels also slightly decreased (–8%; –12%). The formula diet as a 1-week treatment was well tolerated and accepted by the patients. Conclusion: This diet was successfully used as an acute treatment in severe hypertriglyceridemia and showed effectiveness in rapidly and safely lowering plasma triglyceride levels.
Associations of Lipoprotein Lipase Gene Polymorphisms With Longitudinal Plasma Lipid Trends in Young Adults
Authors: Tang Weihong , Apostol George , Schreiner Pamela J. , Jacobs David R. , Boerwinkle Eric , Fornage Myriam
Published: February 2010

Background—

Genome-wide association studies in European Americans have reported several single-nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene associated with plasma levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides. However, the influences of the lipoprotein lipase SNPs on longitudinal changes of these lipids have not been systematically examined.

Methods and Results—

On the basis of data from 2045 African Americans and 2116 European Americans in the Coronary Artery Risk Development in Young Adults study, we investigated cross-sectional and longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including the 2 that have been reported in genome-wide association studies. Plasma levels of HDL-C and triglycerides were measured at 7 examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326, and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (
P
<0.005) and with their longitudinal changes over time (
P
<0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides, but only rs326 and rs13702 were associated with HDL-C (
P
<0.008). Rs328 showed a stronger association in European Americans than in African Americans, and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans.

Conclusions—

Our data suggest that aging interacts with
LPL
gene variants to influence the longitudinal lipid variations, and there is population-related heterogeneity in the longitudinal associations.
Moxibustion for Stroke Rehabilitation
Authors: Lee Myeong Soo , Shin Byung-Cheul , Kim Jong-In , Han Chang-ho , Ernst Edzard
Published: February 2010

Background and Purpose—

Positive effects of moxibustion for stroke rehabilitation may be seen in real clinical practice. Currently, no systematic reviews are available. The aim of this systematic review was to analyze the trial data on the effectiveness of moxibustion for stroke rehabilitation.

Methods—

Fourteen databases were searched without language restriction. Randomized clinical trials were included if moxibustion was tested as the sole treatment or as an adjunct to other treatments for stroke rehabilitation.

Results—

Nine randomized clinical trials met our inclusion criteria. Three randomized clinical trials reported favorable effects of moxibustion plus standard care on motor function versus standard care alone (N=142; standardized mean difference=0.72; 95% confidence interval, 0.37 to 1.08;
P
<0.0001). Three randomized clinical trials compared the effects of moxibustion on activities of daily living alone but failed to show favorable effects of moxibustion.

Conclusion—

This systematic review found limited effectiveness of moxibustion as an adjunct to standard care in stroke rehabilitation.
Drip, Ship, and Retrieve
Authors: Pfefferkorn Thomas , Holtmannspötter Markus , Schmidt Caroline , Bender Andreas , Pfister Hans-Walter , Straube Andreas , Mayer Thomas E. , Brückmann Hartmut , Dichgans Martin , Fesl Gunther
Published: February 2010

Background and Purpose—

In acute basilar artery occlusion, intra-arterial thrombolysis or endovascular mechanical recanalization may result in higher recanalization rates than intravenous thrombolysis. However, many patients are admitted to community hospitals, where endovascular therapy is usually not readily available. We initiated a “drip, ship, and retrieve” cooperative treatment protocol in 2006, in which thrombolysis was initiated in the community hospital with simultaneous referral to our stroke center and the use of endovascular mechanical recanalization as required.

Methods—

The outcome of all consecutive patients treated by this protocol between 2006 and June 2009 was compared with that of a similar population of referred patients who had received primary intra-arterial therapy with or without tirofiban bridging at our center between 2003 and 2005.

Results—

In both groups, 26 patients were identified. The rate of symptomatic intracranial hemorrhage was 12% in previous patients and 8% in those treated under the new protocol. Recanalization rates were similar: 92% in previous patients and 85% with the new protocol; 38% of these had recanalization after intravenous thrombolysis alone. Functional outcome was better among those treated with the new protocol, with more patients achieving a modified Rankin scale score ≤2 (38% versus 12%;
P
=0.03) and ≤3 (50% versus 23%;
P
=0.04).

Conclusions—

“Drip, ship, and retrieve” seems to be feasible and safe in acute basilar artery occlusion. Patients appear to benefit from initiation of intravenous thrombolysis in the community hospital before transfer. Randomized controlled trials will have to confirm the expected benefit of subsequent on-demand mechanical recanalization on clinical outcome.