Characteristics of spinal cord stroke in clinical neurology.
Spinal cord stroke accounts for about 0.3% of all strokes in our department. Thirty-two patients (15 males, 17 females; mean age 63.3 years) treated in the period 1995-2010 were included. Patients underwent thorough investigation including the use of different stroke scales (National Institute of Health Stroke Scale, Barthel Index and modified Rankin Scale). Twenty-eight patients had infarctions, 3 had hemorrhages, and 1 had arterio-venous fistula. Twenty-eight spinal cord strokes were spontaneous, 2 were secondary to aorta aneurysms, and 2 post surgery. Biphasic ictus was seen in 17% of all spontaneous infarctions. Younger age, male gender, hypertension, diabetes mellitus, and higher blood glucose on admission regardless of diabetes mellitus, were risk factors associated with more severe spinal cord stroke. Treatment and prevention of these risk factors should be essential in spinal cord stroke. We recommend a clinical classification into upper (cervical) and lower (thoracic or medullary conus) spinal cord strokes. Patients with upper strokes in this study had more severe strokes initially, but they had a better prognosis. Therefore it is important to identify this patient group.Acute sensory spinal cord deficit symptoms, common initial symptoms in biphasic spinal cord strokes, should be considered as possible spinal cord stroke, especially when preceded by radiating pain between the shoulders.


Accelerated RNA turnover in toad urinary bladder epithelial cells during early aldosterone action.
Demonstration of increased nuclear RNA specific radioactivity in epithelial cells scraped from isolated toad urinary bladder after brief treatment with aldosterone is shown to depend on the quantity of exogenous uridine supplied. By comparing the rate of incorporation of the nucleoside [6-3H] uridine into nuclear RNA at two different exogenous uridine concentrations, an estimate of the relative contribution of exogenous and endogenous nucleoside to the intracellular precursor pool was obtained. Based upon such an experimental model, we found that aldosterone significantly increased the contribution from endogenous precursor and conclude that one effect of the steroid in this isolated tissue is to accelerate RNA turnover. Accelerated RNA turnover, resulting from hormone treatment, was further substantiated by demonstarting a significant decrease in [6-3H] uridine concentration of the precursor pool of prelabeled cells following unlabeled uridine chase. Although evaluated, no evidence for aldosterone increasing the uptake of [6-3H] uridine into the acid-soluble precursor pool was found. In addition, the uridine concentration was shown not to be a rate-limiting step for the bioelectric demonstration of aldosterone-stimulated active Na+ transport.


Vascular endothelial growth factor +405 G/C,-460 T/C and -2578 A/C polymorphisms are not associated with insulin resistance in polycystic ovary syndrome.
Insulin resistance (IR) and pancreatic beta-cell dysfunction are usual comorbidities in polycystic ovary syndrome (PCOS). Vascular endothelial growth factor (VEGF) is known to play an important role in the pathogenesis of PCOS. This study examined firstly the possible association of common +405 G/C,-460 T/C and -2578 A/C polymorphisms of VEGF gene with fasting glucose, fasting insulin and the indices of IR [glucose/insulin ratio (GIR), homoeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI)] in 137 patients with PCOS. None of the studied polymorphisms were found to affect IR indices significantly. However, there was a trend towards higher HOMA in +405 G and -460 T allele carriers in comparison with homozygotes +405 CC and -460 CC, respectively. With regard to -2578 A/C polymorphism, although not significant, in -2578 C carriers HOMA was lower, and GIR was higher in comparison with -2578 AA genotype. Alteration of QUICKI between genotypes was minimal and varied from 4% to 7%. Because of the relatively small sample size, more studies with greater number of cases are necessary to confirm our observations before any statement can be made about the relationship between VEGF gene polymorphism and IR parameters in PCOS.


Pain, disability, and diagnostic accuracy of clinical instability and endurance tests in subjects with lumbar spondylolisthesis.
The aims of this study were (1) to investigate the relationship between the main clinical tests to detect spinal instability, the perceived pain and disability, and symptomatic spondylolisthesis (SPL) characteristics, (2) to investigate the relationship between endurance and instability tests, and (3) to measure the diagnostic accuracy of these tests in unstable SPL diagnosed against dynamic radiographs. Four instability tests were evaluated on 119 subjects: aberrant movements, active straight leg raising (ASLR), prone instability test, and passive lumbar extension test (PLE); and 2 endurance tests, prone bridge test and supine bridge test (SBT). The results were compared with the numeric rating scale for pain and the Oswestry Disability Index for disability. These tests were used as index tests and compared with dynamic radiographs as reference standard on 64 subjects. A significant relationship between disability and all the clinical tests but ASLR was observed. The relation between tests and pain was weaker, not significant for prone instability test and aberrant movement and critical for ASLR (P = .05). There was a low relationship between endurance tests and instability tests. Only PLE showed a significant association with dynamic radiographs (P = .017). Endurance and instability tests appear to be weakly related to the amount of pain but significantly related to the disability in symptomatic SPL. Of the tests evaluated, PLE exhibited the best ability to predict positive dynamic radiographs.


[Newly developed stenocardia: various clinical characteristics of its stable and unstable course].
A total of 130 anginal patients were examined within 3 months after the onset of anginal attacks. Angina was stable (SA) in 100 patients and unstable (UA) in 30. There were no differences between SA and UA patients in terms of the degree and spread of coronary arterial stenoses. Signs of coronary arterial spasm were detected in 27 (20.8%) of 130 patients, being more frequent in UA (53%), as compared to SA (11%; p less than 0.001). Acute myocardial ischemia produced groups of ventricular extrasystoles more frequently than it did isolated extrasystoles in patients with recent angina (78.6% vs. 16.7%; p less than 0.001). Groups of ventricular extrasystoles were recorded more frequently in UA patients, as compared to SA ones (23.3% vs. 7%; p less than 0.05).


Use of a Binocular Optical Coherence Tomography System to Evaluate Strabismus in Primary Position.
Current clinical methods for assessing strabismus can be prone to error. Binocular optical coherence tomography (OCT) has the potential to assess and quantify strabismus objectively and in an automated manner. To evaluate the use of a binocular OCT prototype to assess the presence and size of strabismus. Fifteen participants with strabismus were recruited in 2016 as part of the EASE study from Moorfields Eye Hospital National Health Service Foundation Trust, London, England, and 15 healthy volunteers underwent automated anterior segment imaging using the binocular OCT prototype. All participants had an orthoptic assessment, including alternating prism cover test (APCT), before undergoing imaging. Simultaneously acquired pairs of OCT images, captured with 1 eye fixating, were analyzed using ImageJ (National Institutes of Health) to assess the presence and angle of strabismus. The direction and size of strabismus measured using binocular OCT was compared with that found using APCT. The median age for participants with strabismus was 55 years (interquartile range [IQR], 33-66.5 years) and for the healthy group, 50 years (IQR, 41-59 years); 15 participants (50%) were women, and 25 participants (83.3%) were white. The median magnitude of horizontal deviation was 20∆ (IQR, 13-35∆) and for vertical deviation, 3∆ (IQR, 0-5∆). Binocular OCT imaging correctly revealed the type and direction of the deviation in all 15 participants with strabismus, including horizontal and vertical deviations. The APCT and OCT measurements were strongly correlated for the horizontal (Pearson r = 0.85; 95% CI, 0.60-0.95; P < .001) and vertical (r = 0.89; 95% CI, 0.69-0.96; P < .001) deviations. In the healthy cohort, 9 of 15 participants (60%) had a latent horizontal deviation on APCT results (median magnitude 2∆, range 2-4∆). Six (40%) had orthophoria. Horizontal deviations were observed on OCT imaging results in 12 of the 15 participants (80%), and a vertical deviation was visible in 1 participant (6.7%). These findings suggest that binocular anterior segment OCT imaging can provide clinicians with a precise measurement of strabismus. The prototype can potentially incorporate several binocular vision tests that will provide quantitative data for the assessment, diagnosis, and monitoring of ocular misalignments.


Development and application of a high-content virion display human GPCR array.
Human G protein-coupled receptors (GPCRs) respond to various ligands and stimuli. However, GPCRs rely on membrane for proper folding, making their biochemical properties difficult to study. By displaying GPCRs in viral envelopes, we fabricated a Virion Display (VirD) array containing 315 non-olfactory human GPCRs for functional characterization. Using this array, we found that 10 of 20 anti-GPCR mAbs were ultra-specific. We further demonstrated that those failed in the mAb assays could recognize their canonical ligands, suggesting proper folding. Next, using two peptide ligands on the VirD-GPCR array, we identified expected interactions and novel interactions. Finally, we screened the array with group B Streptococcus, a major cause of neonatal meningitis, and demonstrated that inhibition of a newly identified target, CysLTR1, reduced bacterial penetration both in vitro and in vivo. We believe that the VirD-GPCR array holds great potential for high-throughput screening for small molecule drugs, affinity reagents, and ligand deorphanization.


Functional source separation and hand cortical representation for a brain-computer interface feature extraction.
A brain-computer interface (BCI) can be defined as any system that can track the person's intent which is embedded in his/her brain activity and, from it alone, translate the intention into commands of a computer. Among the brain signal monitoring systems best suited for this challenging task, electroencephalography (EEG) and magnetoencephalography (MEG) are the most realistic, since both are non-invasive, EEG is portable and MEG could provide more specific information that could be later exploited also through EEG signals. The first two BCI steps require set up of the appropriate experimental protocol while recording the brain signal and then to extract interesting features from the recorded cerebral activity. To provide information useful in these BCI stages, our aim is to provide an overview of a new procedure we recently developed, named functional source separation (FSS). As it comes from the blind source separation algorithms, it exploits the most valuable information provided by the electrophysiological techniques, i.e. the waveform signal properties, remaining blind to the biophysical nature of the signal sources. FSS returns the single trial source activity, estimates the time course of a neuronal pool along different experimental states on the basis of a specific functional requirement in a specific time period, and uses the simulated annealing as the optimization procedure allowing the exploit of functional constraints non-differentiable. Moreover, a minor section is included, devoted to information acquired by MEG in stroke patients, to guide BCI applications aiming at sustaining motor behaviour in these patients. Relevant BCI features - spatial and time-frequency properties - are in fact altered by a stroke in the regions devoted to hand control. Moreover, a method to investigate the relationship between sensory and motor hand cortical network activities is described, providing information useful to develop BCI feedback control systems. This review provides a description of the FSS technique, a promising tool for the BCI community for online electrophysiological feature extraction, and offers interesting information to develop BCI applications to sustain hand control in stroke patients.


Inhibitory effect of dioctyl sodium sulfosuccinate on pepsin activity.
The inhibitory effect of dioctyl sodium sulfosuccinate of hog pepsin activity was investigated over the pH 1.5-3.0 range. The inhibitory effect was studied using a natural substrate, hemoglobin, and a synthetic substrate, N-acetyl-L-phenylalanyl-L-diiodotyrosine. The mechanistic studies revealed that a substrate-inhibitor interaction was the major mechanism of inhibition with hemoglobin. However, some direct enzyme inhibition also was involved. With the synthetic substrate, the inhibition was due to a competition between the substrate and inhibitor molecules for the enzyme. The possible therapeutic significance of the inhibitory effect of the medicinal surfactant is discussed.


Nonfused Ring Electron Acceptors for Ternary Polymer Solar Cells with Low Energy Loss and Efficiency Over 18.
Ternary polymer solar cells(PSCs) have been identified as an effective approach to improving power conversion efficiency (PCE) of binary PSCs. However, most of the third component, especially Y-series non-fullerene acceptors, is a fused ring acceptor which often requires a rather tedious synthesis and the use of hazardous organostannane reagents. In this work, two nonfused ring acceptors IOEH-4F and IOEH-N2F are synthesized by a green synthetic route and incorporated into PM6:Y6 blend. Encouragingly, the IOEH-4F and IOEH-N2F-based ternary PSCs exhibited more efficient charge transfer, exciton separation, and lower energy loss than PM6:Y6-based PSCs. And the IOEH-4F and IOEH-N2F-based ternary PSCs achieved an impressive PCE of 17.80% and 18.13%, respectively, which are higher than that of PM6:Y6 based PSCs (16.18%). Notably, these PCE values are also the highest PCEs for ternary PSCs including non-fused ring acceptors. Importantly, even when the IOEH-N2F:Y6 ratios increased from 0.05:1.2 to 0.50:1.2, the PCE of IOEH-N2F-based ternary PSCs (16.70%) are still higher than that of PM6:Y6 based PSCs, indicating the great potential for cost saving. It is believed that the findings will help the design of better nonfused ring acceptors and the optimization of corresponding ternary PSCs with cost-saving advantage.


Effect of a multiphasic anodic spark deposition coating on the improvement of implant osseointegration in the osteopenic trabecular bone of sheep.
Anodic spark deposition techniques have been effectively applied to achieve a microporous morphology on metals. To investigate the effect of a new anodic spark deposition-based treatment in the enhancement of titanium implant osseointegration in trabecular bone of aged and ovariectomized sheep, a histomorphometric and microhardness study was carried out. Ten sheep were divided into 2 groups. Five were submitted to a bilateral ovariectomy to induce an estrogen-deficiency osteopenia (Ovariectomized), and 5 were left untreated (Aged). Twenty-four months later, they underwent a bilateral implantation of commercially pure titanium screw threads in the lateral surface of femoral condyles: electrochemically treated titanium (SP) and acid-etching treated titanium (BioRough). Twelve weeks after the second operation, the animals were sacrificed and femur segments and iliac crest biopsy specimens were examined for histomorphometric and microhardness evaluations. The histomorphometry of the trabecular bone of the iliac crest biopsy specimens and that around screws showed marked signs of bone rarefaction in the Ovariectomized group when compared to the Baseline and Aged groups. Significantly greater bone-implant contact was observed for SP implants in comparison with BioRough implants in both the Aged (P < .001) and Ovariectomized (P < .01) groups. No significant differences in terms of microhardness were found between SP and BioRough implants within the Aged group, while a significantly higher Bone Maturation Index was observed for SP in the Ovariectomized group (P < .05). The novel electrochemical treatment SP produced the most promising results and was able to introduce substantial improvements in achieving the fast and stable osseointegration of implants in osteopenic bone.


Identification of loci controlling non-host disease resistance in Arabidopsis against the leaf rust pathogen Puccinia triticina.
SUMMARY Plant immunity against the majority of microbial pathogens is conveyed by a phenomenon termed non-host resistance (NHR). This multifactorial trait provides durable protection against a given pathogen species. We investigated the molecular basis of NHR in Arabidopsis against the wheat leaf rust pathogen, Puccinia triticina (Ptr). Urediospores germinated with high efficiency and grew randomly over the Arabidopsis leaf surface. However, only 12% of urediospores produced a germ tube that successfully located a stoma and just 0.2% of urediospores went on to produce a haustorium within a penetrated mesophyll cell. Attempted Ptr infection induced the production of reactive oxygen intermediates (ROIs), nitric oxide (NO), salicylic acid (SA) and camalexin. The expression of SA, jasmonic acid (JA) and ROI-dependent genes was also detected. A series of well-characterized defence-related mutants were challenged with Ptr, but none of these lines exhibited significantly increased susceptibility to this fungus. Our findings also suggest that attempted Ptr infection triggers transient stomatal closure in Arabidopsis. We assessed the response of a collection of 79 geographically diverse Arabidopsis accessions to Ptr. Wa-1 plants supported a striking increase in Ptr substomatal vesicle frequency relative to all other tested accessions. Furthermore, SA and camalexin levels became elevated in Wa-1 plants relative to the Col reference line, in response to attempted Ptr infection. Additionally, the kinetics of SA-dependent gene expression was expedited in this accession relative to Col plants. To uncover the genetic architecture of NHR against Ptr, we assayed the response of the Arabidopsis Landsberg erecta (Ler) x Columbia (Col) recombinant inbred population to this fungus. Multiple small-to-medium effect quantitative trait loci were identified that govern the expression of NHR in Arabidopsis against Ptr.


Inonotus obliquus sclerotia epidermis were different from internal tissues in compound composition, antioxidant activity, and associated fungi.
Inonotus obliquus is a medicinal fungus with potential for use in various health applications. To better utilize this fungus, this study focused on epidermis and internal tissues of five sclerotia from different regions in Jilin, Inner Mongolia, and Heilongjiang, examining their polyphenols, polysaccharides, flavonoids, and total triterpenes contents. And evaluated the extracts from sclerotia for their total antioxidant capacity and scavenging ability of DPPH free radicals. The study also isolated the associated fungi from the epidermis and internal tissues of three sclerotia. Results revealed that the polyphenol content was higher in the epidermis than in internal tissue of every sclerotium. However, flavonoid and total triterpenoid content was lower in the epidermis of every sclerotium. The polysaccharide content was no significant in different parts of three sclerotia, but the epidermal polysaccharide content in two sclerotia was significantly higher than in internal tissues. The internal tissue extracts from tested sclerotia exhibited better scavenging ability of DPPH free radicals than those from the epidermis. There was no significant difference in total antioxidant capacity among different parts of three sclerotia, and the internal tissues' total antioxidant capacity in two sclerotia was higher than the epidermis. The number and species of associated fungi in the internal tissues were far less than that in the epidermis. The study suggests separating the epidermis and internal tissue for medicinal use. The research provides insights into the bioactive components and associated fungi of I. obliquus to inform its practical application in medicine.


"Raising Him … to Pull His Own Weight": Boys' Household Work in Single- Mother Households.
In this study, the authors examine boys' household work in low- and moderate-income single-mother families. Through describing the work that boys do, why they do this work, and the meaning that they and their mothers give to this work, they add to the understanding of housework as an arena for gender role reproduction or interruption. Their data reveal that adolescent boys did a significant amount of work and took pride in their competence. Mothers grounded their expectations of boys' household contributions in life experience. They both needed their sons' day-to-day contributions and wanted their sons to grow into men who were competent around the house and good partners. In demanding household work from their sons, these single mothers themselves work to undermine the traditional gendered division of such labor.


The homeopathic preparation Neurexan vs. valerian for the treatment of insomnia: an observational study.
Insomnia is prevalent and complementary therapies are common, but data are lacking on the effectiveness and tolerability of preparations beyond valerian. Here we report on an open-label, prospective cohort study in 89 German centers offering both conventional and complementary therapies. Subjects received the homeopathic preparation Neurexan or valerian for 28 days. Doses were at physicians' judgments. Sleep duration and latency were evaluated based on patients' sleep diaries over 14 days; sleep quality was evaluated at 28 +/- 1 days. A total of 409 subjects were enrolled. The groups were balanced at baseline for age, sex, weight, and sleep disturbances. At day 14, both groups reported improved sleep latency and duration; latency was reduced from baseline by 37.3 +/- 36.3 min with Neurexan and by 38.2 +/- 38.5 min with valerian. The duration of sleep increased by 2.2 (+/-1.6) h in the Neurexan group and by 2.0 (+/-1.5) h in the valerian group. Differences between the groups in improvement on sleep duration were significantly in favor of Neurexan therapy at days 8, 12, and 14. At day 28, quality of sleep was improved in both groups with no significant differences between the treatments. Significantly more patients reported lack of daytime fatigue with Neurexan than with valerian therapies (49% vs. 32%; p < 0.05 for the comparison). For patients favorable towards a CAM-based therapy, Neurexan might be an effective and well-tolerated alternative to conventional valerian-based therapies for the treatment of mild to moderate insomnia.


SAR92 clade bacteria are potentially important DMSP degraders and sources of climate-active gases in marine environments.
Dimethylsulfoniopropionate (DMSP) is one of Earth's most abundant organosulfur molecules, which can be catabolized by marine bacteria to release climate-active gases through the cleavage and/or demethylation pathways. The marine SAR92 clade is an abundant oligotrophic group of Gammaproteobacteria in coastal seawater, but their ability to catabolize DMSP is untested. Three SAR92 clade strains isolated from coastal seawater in this study and the SAR92 representative strain HTCC2207 were all shown to catabolize DMSP as a carbon source. All the SAR92 clade strains exhibited DMSP lyase activity producing dimethylsulfide (DMS) and their genomes encoded a ratified DddD DMSP lyase. In contrast, only HTCC2207 and two isolated strains contained the DMSP demethylase dmdA gene and potentially simultaneously demethylated and cleaved DMSP to produce methanethiol (MeSH) and DMS. In SAR92 clade strains with dddD and dmdA, transcription of these genes was inducible by DMSP substrate. Bioinformatic analysis indicated that SAR92 clade bacteria containing and transcribing DddD and DmdA were widely distributed in global oceans, especially in polar regions. This study highlights the SAR92 clade of oligotrophic bacteria as potentially important catabolizers of DMSP and sources of the climate-active gases MeSH and DMS in marine environments, particularly in polar regions.IMPORTANCECatabolism of dimethylsulfoniopropionate (DMSP) by marine bacteria has important impacts on the global sulfur cycle and climate. However, whether and how members of most oligotrophic bacterial groups participate in DMSP metabolism in marine environments remains largely unknown. In this study, by characterizing culturable strains, we have revealed that bacteria of the SAR92 clade, an abundant oligotrophic group of Gammaproteobacteria in coastal seawater, can catabolize DMSP through the DMSP lyase DddD-mediated cleavage pathway and/or the DMSP demethylase DmdA-mediated demethylation pathway to produce climate-active gases dimethylsulfide and methanethiol. Additionally, we found that SAR92 clade bacteria capable of catabolizing DMSP are widely distributed in global oceans. These results indicate that SAR92 clade bacteria are potentially important DMSP degraders and sources of climate-active gases in marine environments that have been overlooked, contributing to a better understanding of the roles and mechanisms of the oligotrophic bacteria in oceanic DMSP degradation.


Staphylococcal protein A primed leukocytes enhance the autologous mixed lymphocyte reaction.
Human peripheral blood mononuclear cells (PBMC) were preincubated for 3 days in medium alone or with various mitogens then washed and irradiated. The preincubated cells then were cultured with autologous T-cells in an autologous mixed lymphocyte reaction (AMLR). Staphylococcal protein A (SPA) pretreatment of PBMC enhanced autologous T-lymphocyte proliferation from 1375 +/- 321 cpm (mean +/- SEM untreated PBMC) to 42,467 +/- 7,985 cpm (SPA primed PBMC) (p less than 0.01). The ability of SPA treated PBMC to enhance the AMLR was not simply a reflection of their proliferation in preculture, as PBMC precultured with phytohemagglutinin and concanavalin A showed greater proliferation than SPA-treated PBMC yet only minimally enhanced the AMLR. Kinetic studies and pre-exposure of PBMC to graded doses of gamma radiation showed that SPA augmentation of the AMLR was mediated by 2 components which differed in kinetics and radiosensitivity. Although incubation of PBMC with SPA did not increase the percentage of cells with detectable surface Ia antigen, SPA did increase the density of Ia in the preincubated cells. Cell separation studies revealed that SPA enhancement of the AMLR was not mediated by T-cells, but was mediated by a non-adherent non-E-rosetting fraction of cells. SPA enhancement of the AMLR was associated with an increased Ia density in the stimulator population but not with an increase in Ia positive cells and was mediated by proliferation-dependent and proliferation-independent mechanisms.


Automatic Spinal Cord Gray Matter Quantification: A Novel Approach.
Currently, accurate and reproducible spinal cord GM segmentation remains challenging and a noninvasive broadly accepted reference standard for spinal cord GM measurements is still a matter of ongoing discussion. Our aim was to assess the reproducibility and accuracy of cervical spinal cord GM and WM cross-sectional area measurements using averaged magnetization inversion recovery acquisitions images and a fully-automatic postprocessing segmentation algorithm. The cervical spinal cord of 24 healthy subjects (14 women; mean age, 40 ± 11 years) was scanned in a test-retest fashion on a 3T MR imaging system. Twelve axial averaged magnetization inversion recovery acquisitions slices were acquired over a 48-mm cord segment. GM and WM were both manually segmented by 2 experienced readers and compared with an automatic variational segmentation algorithm with a shape prior modified for 3D data with a slice similarity prior. Precision and accuracy of the automatic method were evaluated using coefficients of variation and Dice similarity coefficients. The mean GM area was 17.20 ± 2.28 mm2 and the mean WM area was 72.71 ± 7.55 mm2 using the automatic method. Reproducibility was high for both methods, while being better for the automatic approach (all mean automatic coefficients of variation, ≤4.77%; all differences, P < .001). The accuracy of the automatic method compared with the manual reference standard was excellent (mean Dice similarity coefficients: 0.86 ± 0.04 for GM and 0.90 ± 0.03 for WM). The automatic approach demonstrated similar coefficients of variation between intra- and intersession reproducibility as well as among all acquired spinal cord slices. Our novel approach including the averaged magnetization inversion recovery acquisitions sequence and a fully-automated postprocessing segmentation algorithm demonstrated an accurate and reproducible spinal cord GM and WM segmentation. This pipeline is promising for both the exploration of longitudinal structural GM changes and application in clinical settings in disorders affecting the spinal cord.


[The use of fludarabine phosphate (Fludara) to treat chronic B-cell lymphocytic leukemia and non-Hodgkin's lymphoma resistant to standard chemotherapy].
Following monochemotherapy with fludarabin phosphate (fludara), complete (18%), and partial remission (27%) with stabilization (45%) was recorded in patients with B-cell chronic lymphocytic leukemia, most of whom were resistant to alkylating cytostatic drugs and their combinations containing anthracyclines. Long-term remission was registered in patients with low and moderate grade non-Hodgkin's lymphoma, resistant to standard cytostatic treatment, due to the therapeutic synergism of fludara and cytosinarabinoside (FAVAMP).


How to recruit caring and compassionate HCAs.
Heathcare organisations are faced with the challenge of recruiting staff who have caring and compassionate values so need to ensure these can be identified at interview. We piloted multiple mini-interviews as a possible solution to recruiting healthcare assistants. This article outlines how these were implemented and highlights some of the pitfalls of using this approach. Although the work has not been evaluated formally we decided to share our early experiences of using this approach so others can learn from our practice.


Total Energy Expenditure of Infants with Congenital Heart Disease Who Have Undergone Surgical Intervention.
Growth failure is often observed in infants with congenital heart disease (CHD); it is unclear, however, whether growth failure is due to increased total energy expenditure (TEE). An observational study of infants with CHD and surgical intervention within the first 30 days of life and healthy infants of similar age was undertaken. TEE was measured using the doubly labeled water method in 3-month-old infants (n = 15 CHD, 12 healthy) and 12-month-old infants (n = 11 CHD, 12 healthy). Multiple linear regression models were fit to examine the association between health status (CHD vs. healthy) and TEE. The accuracy of equations for calculating TEE was also determined. TEE for CHD infants was not significantly different from healthy infants at 3 and 12 months; TEE in CHD infants was 36.4 kcal/day higher (95 % CI -46.3, 119.2; p = 0.37) and 31.7 kcal/day higher, (95 % CI -71.5, 134.8; p = 0.53) at 3 and 12 months, respectively, compared to healthy infants. The 2002 Dietary Reference Intake (DRI) equation and the 1989 Recommended Dietary Allowance equation over-estimated measured TEE to a lesser extent than CHD specific equations; the 2002 DRI yielded the smallest mean difference between calculated versus measured TEE (difference 79 kcal/day). During the first year of life, TEE of infants with CHD and interventional surgery within the first month of life was not different than age-matched healthy infants. When calculating TEE of ≤12-month-old infants with CHD who have undergone surgical intervention, the 2002 DRI equation may be used as a starting point for estimating initial clinical energy intake goals.


Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci.
Complex traits arise from the interplay between genetic and environmental factors. The actions of these factors usually appear to be additive, and few compelling examples of gene-environment synergy have been documented. Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2 p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD). Synergy between adiposity and genotype promoted the full spectrum of NAFLD, from steatosis to hepatic inflammation to cirrhosis. We found no evidence of strong interaction between adiposity and sequence variants influencing other adiposity-associated traits. These results indicate that adiposity augments genetic risk of NAFLD at multiple loci that confer susceptibility to hepatic steatosis through diverse metabolic mechanisms.


Impact of messages about scientific uncertainty on risk perceptions and intentions to use electronic vaping products.
The science surrounding e-cigarettes and other electronic vaping products (EVPs) is rapidly evolving, and the health effects of vaping are unclear. Little research has explored how individuals respond to information acknowledging scientific uncertainty. The aim of the present study was to understand the impact of messages about scientific uncertainty regarding the health effects of vaping on risk perceptions and behavioral intentions. Adults in an online experiment (n = 2508) were randomly exposed to view either a control message (a short factual statement about EVPs) or an uncertainty message (the control message plus additional information describing why EVP-related research is limited or inconclusive). Participants rated the risks of vaping and their intentions to try or stop vaping. Individuals who viewed the uncertainty message rated vaping as less risky than those who viewed the control message. Message exposure did not impact intentions to try vaping soon or intentions to stop vaping in the next 6 months. Acknowledging scientific uncertainty made EVP use seem less risky. Future research should explore possible drivers of this response, such as deeper message processing or emotional reactions. Researchers and practitioners designing public health campaigns about vaping might consider a cautious approach to presenting information about scientific uncertainty.


Metal Coordination Is Crucial for Geranylgeranyl Diphosphate Synthase-Bisphosphonate Interactions: A Crystallographic and Computational Analysis.
Geranylgeranyl diphosphate synthase (GGPPS) is a central metalloenzyme in the mevalonate pathway, crucial for the prenylation of small GTPases. As small GTPases are pivotal for cellular survival, GGPPS was highlighted as a potential target for treating human diseases, including solid and hematologic malignancies and parasitic infections. Most available GGPPS inhibitors are bisphosphonates, but the clinically available compounds demonstrate poor pharmacokinetic properties. Although the design of novel bisphosphonates with improved physicochemical properties is highly desirable, the structure of wild-type human GGPPS (hGGPPS) bound to a bisphosphonate has not been resolved. Moreover, various metal-bisphosphonate-binding stoichiometries were previously reported in structures of yeast GGPPS (yGGPPS), hampering computational drug design with metal-binding pharmacophores (MBP). In this study, we report the 2.2 Å crystal structure of hGGPPS in complex with ibandronate, clearly depicting the involvement of three Mg2+ ions in bisphosphonate-protein interactions. Using drug-binding assays and computational docking, we show that the assignment of three Mg2+ ions to the binding site of both hGGPPS and yGGPPS greatly improves the correlation between calculated binding energies and experimentally measured affinities. This work provides a structural basis for future rational design of additional MBP-harboring drugs targeting hGGPPS. SIGNIFICANCE STATEMENT: Bisphosphonates are inhibitors of geranylgeranyl diphosphate synthase (GGPPS), a metalloenzyme crucial for cell survival. Bisphosphonate binding depends on coordination by Mg2+ ions, but various Mg2+-bisphosphonate-binding stoichiometries were previously reported. In this study, we show that three Mg2+ ions are vital for drug binding and provide a structural basis for future computational design of GGPPS inhibitors.


[Morphological inversions during the ontogenesis of the ixodid ticks (Acari: Ixodidae) from the viewpoint of the hypermorphosis conception and their significance for systematics].
Morphological inversions during the ontogenesis of the ixodid ticks consist in the deranges of species-specific tendencies in the development of some external structures by the female line. The inversions, which included a wide range of organs and their fine structures, have been described for the first time in 14 species of 4 from 7 Palearctic ixodid genera. Emphasis is placed on the study of the structures, which serve as differential characters for closely related species. It is shown, that the using of the structures subjected to inversions is unavoidable in systematics because of the great similarity of closely related species, especially in immature stages. It is established by the data on the variability of all active stages in the species distribution ranges, that the degree of the inversions manifestation may somewhat fluctuate in different subspecies or geographic morphotypes of the same species, but the peculiarity of the inversions always remains a species-specific character. The cause of inversions origin is the evolution of the Ixodidae by the way of morpho-ecological specialization, namely hypertrophic, giantism, the growth of teguments in the period of nutrition act by pasture ambushing, which led to the derange of the development coordination of the organs during ontogenesis. Biological implication of the inversions is a guarantee of the adaptive potential of species during the process of microevolution. Even though the inversions make identification of closely related species difficult, their substantial importance is that they form integral species-specific character for the whole active part of the species ontogenesis.


Ribotype diversity of porcine Pasteurella multocida from Australia.
To use the technique of ribotyping to investigate the genetic diversity of Australian isolates of Pasteurella multocida associated with outbreaks of clinical disease in Australian pigs. One hundred and seven porcine P multocida isolates were analysed by ribotyping using the restriction enzymes HpaII and HindIII. The genetic population structure of the Australian porcine P multocida isolates was determined through statistical analysis of the joint ribotype patterns, and this was then compared with biochemical and epidemiological data available for the population. A total of 25 combined ribotypes were recognised, which were grouped into five ribotype clusters. Despite the deliberate selection of diverse isolates, the study revealed only a limited degree of genetic diversity. Fourteen of the ribotypes contained multiple isolates, and 12 of these ribotypes were present on more than one farm. Three of the seven biovars analysed in the study showed very limited diversity. All fifteen biovar 2 isolates (subsp multocida) were found in a single cluster (III), while all four biovar 8 isolates, which correspond to P multocida subsp gallicida, were allocated by themselves to a single cluster (IV). All nine of the biovar 12 isolates (lactose-positive subsp multocida) were assigned to a single cluster (I), together with the single biovar 14 isolate, which was the only other lactose-positive isolate in the population (ODC-negative). A limited number of ribotypes of P multocida are associated with Australian pigs. The majority of these ribotypes are widely distributed across multiple farms, and across multiple states. Individual farms can possess multiple ribotypes of P multocida. Some of the unusual biochemical variants of P multocida present in Australian pigs have a very limited genetic diversity. The nature of pig production in Australia, primarily involving continuous flow systems with few closed herds, has possibly contributed to the widespread distribution of a limited number ribotypes.


Relationship of mixed lymphocyte culture response to HL-A histocompatibility antigens. Effect of allele plus one antigen match.
The influence of varying degrees of incompatibility for HL-A antigens on one-way mixed lymphocyte cultures (MLC) has been investigated. Reactions have been compared to a simple expression of HL-A antigens, allele compatibility, and a proposal considering the potential influence of antigen matching in relationship to allele compatibility. As expected, HL-A compatibility was associated with nonstimulated cultures, but significant correlation was not observed when incompatibility was expressed in terms of HL-A antigen or allele mismatching. When the relationship of both was considered, however, a second distinctive group was demonstrated that shared one allele plus one antigen of the second allele. Within this group no stimulation, even with augmented culture conditions, was observed in some families. Employing these same criteria, there was no significant difference in the MLC response in those groups that were incompatible for both alleles regardless of the number of matched antigens or the group that shared an allele but differed by both antigens of the second allele. These results support the concept of an intimate relationship between the loci coding for HL-A antigens and mixed culture reactions. They suggest that HL-A haplotype incompatibility acting as a unit is the primary stimulus of the MLC response, and that the immunogenicity of the haplotype also relates to whether or not one antigen is common to the stimulating and responding cell.


The Quality of Life Impact of Refractive Correction (QIRC) Questionnaire: development and validation.
The purpose of the study was to develop a questionnaire that could quantify the quality of life (QOL) of people with refractive correction by spectacles, contact lenses, and refractive surgery in the prepresbyopic age group. The questionnaire was developed and validated using traditional methods and Rasch analysis. A 90-item pilot questionnaire was developed through extensive literature search and use of professional and lay focus groups. Pilot study data were obtained from 306 subjects for item reduction to produce the 20-item Quality of Life Impact of Refractive Correction (QIRC) questionnaire. Validity and reliability studies (test-retest reliability with intraclass correlation coefficient and Bland-Altman limits of agreement, and internal consistency with Rasch fit statistics, factor analysis, and Cronbach's alpha) were performed from data of an additional 312 subjects. Rasch analysis demonstrated QIRC has good precision, reliability, and internal consistency (person separation, 2.03; reliability, 0.80; root-mean-square measurement error, 3.25; mean square +/- SD infit, 0.99 +/- 0.38; outfit, 1.00 +/- 0.39; item infit range, 0.70 to 1.24; and item outfit range, 0.78 to 1.32). The items (mean score, 50.3 +/- 7.3) were well targeted to the subjects (mean score, 47.8 +/- 5.5) with a mean difference of 2.45 (scale range, 0 to 100) units. Test-retest reliability (intraclass correlation coefficient, 0.88; coefficient of repeatability, +/-6.85 units), factor loading range (0.40 to 0.76), and Cronbach's alpha (0.78) also indicated the reliability and validity of QIRC. The 20-item QIRC questionnaire, which quantifies the QOL of people with refractive correction by spectacles, contact lenses, and refractive surgery in the prepresbyopic age group, was developed using Rasch analysis and shown to be valid and reliable. The use of Rasch scaling allows scores to be treated as a valid continuous variable. QIRC has broad applicability for cross-sectional and outcomes research.


Rh isoimmunization related to amniocentesis.
We report on the incidence of Rh isoimmunization after genetic amniocentesis at our institution. In 115 Rh negative women who underwent amniocentesis and subsequently delivered Rh positive infants, there were 4 (3.4%) sensitizations before birth. This was significantly greater than the 1.5% rate of gestational sensitization found in pooled populations of women who did not undergo amniocentesis. We also noted a significant increase in the number of sensitizations that occurred before 28 weeks. The results were consistent with those of previous studies of this issue, and are discussed in relation to current policies for managing Rh negative women who have second trimester amniocentesis.


Increased Alpha-Rhythm Dynamic Range Promotes Recovery from Visuospatial Neglect: A Neurofeedback Study.
Despite recent attempts to use electroencephalogram (EEG) neurofeedback (NFB) as a tool for rehabilitation of motor stroke, its potential for improving neurological impairments of attention-such as visuospatial neglect-remains underexplored. It is also unclear to what extent changes in cortical oscillations contribute to the pathophysiology of neglect, or its recovery. Utilizing EEG-NFB, we sought to causally manipulate alpha oscillations in 5 right-hemisphere stroke patients in order to explore their role in visuospatial neglect. Patients trained to reduce alpha oscillations from their right posterior parietal cortex (rPPC) for 20 minutes daily, over 6 days. Patients demonstrated successful NFB learning between training sessions, denoted by improved regulation of alpha oscillations from rPPC. We observed a significant negative correlation between visuospatial search deficits (i.e., cancellation test) and reestablishment of spontaneous alpha-rhythm dynamic range (i.e., its amplitude variability). Our findings support the use of NFB as a tool for investigating neuroplastic recovery after stroke and suggest reinstatement of intact parietal alpha oscillations as a promising target for reversing attentional deficits. Specifically, we demonstrate for the first time the feasibility of EEG-NFB in neglect patients and provide evidence that targeting alpha amplitude variability might constitute a valuable marker for clinical symptoms and self-regulation.


Evaluation of Trends in the Use of InterStim for Fecal Incontinence.
Fecal incontinence (FI) represents a large source of morbidity and is a challenging clinical problem to manage. InterStim was approved to treat FI in 2011. Little is known about its adoption. We sought to characterize patterns of use of Interstim since Food and Drug Administration approval for FI. The New York State SPARCS database was used to evaluate InterStim use for FI from 2011 to 2014. The primary endpoint was the number of successful implantations of InterStim. Secondary endpoints included device removal, median time to removal of device, 90-day infection rates, and percentage of procedures performed by surgeon specialty and geographic location. A total of 369 patients with FI underwent "Stage 1" of InterStim from 2011 to 2014. A total of 302 patients underwent "Stage 2," yielding a trial period failure rate of 18.2%. The majority of patients who underwent successful implantation were female (87.7%) and White (78.8%). Twenty-nine patients underwent device removal after a median duration of 147 days. Estimated risk of removal at median follow-up of 2 years was 11.8%. Colorectal surgeons comprised 51.1% of all providers followed by gynecologic (24.4%) and urologic surgeons (17.8%). A total of 71.7% of providers performed <5 procedures, while 3 of the highest volume providers performed 50.7% of all procedures. InterStim for FI has been used by a wide variety of providers in New York State although only a few high-volume providers have performed the majority of procedures. White, female patients with Medicare are the most common recipients of InterStim. Further work must be done to develop strategies for improving access to this technology and to determine whether volume relates to outcomes.


[Pyogenic liver abscess. Review of 33 cases].
Thirty three cases of pyogenic liver abscess, (24 single and 9 multiple), diagnosed in our department during the past 6 years, were reviewed. Mean patient age was 54 years with a male predominance over females (1.5:1). The most frequently encountered underlying pathology was bile duct disease (33%), followed by previous liver disease (21%). Causal pathology could not be found in 4 cases (12%). The most frequent sign was fever (76%). Diagnosis was made by clinical picture and complementary exam (echography, CT scan and hepatic gammagraphy) in 29 cases (88%). Blood and pus cultures were positive in 47 and 67% of cases respectively. Thirty nine per cent of microbial abscesses were polymicrobial. E. coli and S. milleri were the most frequently isolated. No micro-organism were identified in 5 cases (15%). Antibiotic treatment was given to 33 patients. Surgical drainage was performed in 24 cases and percutaneous drainage in 7 patients. Two patients received antibiotics exclusively. Five patients died (15%), three of whom had a multiple abscess (33%) and the other two had a single abscess (8%). The efficacy of percutaneous drainage for diagnosis and treatment is analyzed reviewing recent literature.


Dual-responsive degradable core-shell nanogels with tuneable aggregation behaviour.
We report the synthesis of core-shell nanogels by sequential addition of thermoresponsive monomers; N-isopropylacrylamide (NIPAM) and N-isopropylmethacrylamide (NIPMAM). The aggregation behaviour of aqueous dispersions of these particles in the presence of salt can be tuned by varying the monomer ratio. The inclusion of degradable cross-linker bis(acryloyl)cystamine (BAC) allows the nanogels to degrade in the presence of reducing agent, with nanogels composed of a copolymer of the two monomers not showing the same high levels of degradation as the comparable core-shell particles. These levels of degradation were also seen with physiologically relevant reducing agent concentration at pH 7. Therefore, it is hoped that the aggregation of these nanogels will have applications in nanomedicine and beyond.


Medical evaluation of overweight children and adolescents: reports from pediatricians, pediatric nurse practitioners, and registered dietitians.
The primary aim of this study was to determine how pediatric health care providers identify overweight in children and adolescents and how they evaluate obesity-related medical complications. This information can guide development of programs to help providers improve their evaluation practices. A secondary objective was to examine the association of certain provider characteristics with recommended evaluation practices. A random sample of pediatricians, pediatric nurse practitioners (PNPs), and registered dietitians received a questionnaire about their evaluation of overweight children and adolescents. Results were compared with published recommendations. Associations between respondent characteristics and adherence to published recommendations were examined. A total 940 providers responded (response rate: 19%-33%). Among all 3 groups a majority frequently used clinical impression, weight-for-age percentile, weight-for-height percent, and weight-for-height percentile to assess degree of overweight. Nearly all pediatricians and PNPs routinely evaluated blood pressure, but a minority routinely looked for orthopedic problems, insulin resistance, and sleep disorders. Less than 10% followed all recommendations for history and physical examination. Two thirds of pediatricians and PNPs routinely tested for lipid abnormalities. Most providers asked about family history of overweight, hypertension, cardiovascular disease, and diabetes, but only one third asked about gallbladder disease. In general, the provider's specialty, years in practice, gender, and body mass index were not associated with adherence to recommended practices. Medical evaluation of overweight children and adolescents fell short of recommended practices. These results point to the need for educational efforts to increase awareness of medical risks and for tools to facilitate more complete evaluation during office visits.


Rhythmic myoclonias including spinal myoclonus.
In rare cases, rhythmic limb movements may appear in association with palatal myoclonus. There is a similar slow rate, below 4/sec. A review by Rondot and Ben Hamida (33) showed that the limb movements had much in common with postural tremors. Lhermitte and Sigwald (23) observed a peculiar pattern of upper limb oscillations in a patient with palatal myoclonus. It resembles a rare type of slow postural tremor, often called rubral tremor, described by Holmes (19). We found that a large group of alcoholics, showing signs of cerebellar degeneration, exhibit a stereotyped pattern of slow, coarse leg oscillations. There is a stable rhythm, in the 3/sec range, in alternating as well as in nonalternating muscle contractions. Both are in several maintained postures bicrurally synchronous, which is a feature of experimental and clinical myoclonus never observed in classic tremors. A few of these patients have upper limb oscillations, and these are of the kind described by Holmes (19) and Lhermitte and Sigwald (23). The cerebellar degeneration is of the anteromedial type; it is often associated with olivary changes (cerebelloolivary atrophy). Swanson et al. (40) and others included in the spinal category patients with myoclonus restricted to muscles innervated from one or more spinal cord segments and no recognizable neurological abnormality at higher levels. The most convincing cases of purely spinal origin are those in which segmental jerks are caused by a spinal tumor. These repetitive jerks may sometimes show a slow rhythm.


2.5-Gb/s hybridly-integrated tunable external cavity laser using a superluminescent diode and a polymer Bragg reflector.
We presented a hybridly-integrated tunable external cavity laser with 0.8 nm mode spacing 16 channels operating in the direct modulation of 2.5-Gbps for a low-cost source of a WDM-PON system. The tunable laser was fabricated by using a superluminescent diode (SLD) and a polymer Bragg reflector. The maximum output power and the power slope efficiency of the tunable laser were 10.3 mW and 0.132 mW/mA, respectively, at the SLD current of 100 mA and the temperature of 25 degrees C. The directly-modulated tunable laser successfully provided 2.5-Gbps transmissions through 20-km standard single mode fiber. The power penalty of the tunable laser was less than 0.8 dB for 16 channels after a 20-km transmission. The power penalty variation was less than 1.4 dB during the blue-shifted wavelength tuning.


Aldosterone-producing adrenal cortical cancer: a case report and analysis of steroidogenic enzymes in the tumor.
A case of hyperaldosteronism caused by adrenal cortical cancer observed in a 32-year-old man was reported. The patient showed marked hypertension and hypokalemia, but neither obesity nor hyperglycemia was observed. Endocrine studies revealed hyperaldosteronism and concurrent excessive secretion of cortisol, but diurnal rhythms of plasma ACTH and cortisol were normal. Imaging studies revealed a large left adrenal mass, and the positive accumulation of radiolabelled material by adrenal scintigraphy was observed both in the tumor and the contralateral adrenal gland. The removed tumor was predominantly composed of dark compact cells with marked nuclear pleomorphism, and mitotic figures and sinusoidal invasion were also observed. The analysis of steroidogenic enzyme activities revealed that the activity of aldosterone-synthesizing enzyme (P-450aldo) which was usually undetectable in normal adrenal tissues and adenomas other than aldosterone-producing adenoma (APA) was detectable as one-third of that of APA. Although activities of other enzymes were reduced, the expression of P-450aldo activity was considered to be the specific character of this cancer.


Iruplinalkib: First Approval.
Iruplinalkib (Trade name: ®; Code name: WX-0593), a highly selective oral anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), is being developed by Qilu Pharmaceutical Co., Ltd. for the treatment of ALK-positive (ALK+) or ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC). In June 2023, iruplinalkib was approved in China for the treatment of patients with locally advanced or metastatic ALK+ NSCLC who have progressed after prior crizotinib therapy or are intolerant to crizotinib. This article summarizes the milestones in the development of iruplinalkib leading to this first approval for the treatment of patients with locally advanced or metastatic ALK+ NSCLC.


[Interaction of muscle glycogen phosphorylase b with nicotinic acid, nicotinamide, N-nicotinyl-gamma-aminobutyric acid and nicotinamide coenzymes].
The inhibitory action of nicotinic acid, nicotinamide, N-nicotinoyl-gamma-aminobutyric acid, NAD, NADH, NADP, and NADPH on the rabbit skeletal muscle glycogen phosphorylase b has been studied. The inhibition is reversible and positively cooperative (the value of Hill coefficients were determined for the following compounds: nicotinic acid (28 mM; 1.4), nicotinamide (4.4 mM; 1.2), N-nicotinoyl-gamma-aminobutyric acid (9.5 mM; 1.4), NAD (4.4 mM; 1.2), NADH (0.93 mM; 1.2). NADH-binding site of glycogen phosphorylase b subunit was characterized by the sedimentation velocity method. Microscopic dissociation constant was found to be 86 +/- 9 microM (pH 6.8; 20 degrees C). AMP-induced association of glycogen phosphorylase b is hindered by NADH.


Leading North American programs in clinical assessment research: an assessment of productivity and impact.
To identify doctoral programs with strong concentrations in clinical assessment, I measured productivity and impact of faculty at North American institutions with American Psychological Association accredited clinical programs. Publications, citations, and h-indexes derived from 4 top assessment journals were calculated over a 10-year period (1999-2009). I identified a total of 42 leading programs that collectively accounted for more than half of the publications and citations in these journals. I found a moderate relationship between assessment productivity and both US News & World Report program rankings as well as general productivity rankings of clinical programs reported in an earlier study.


Is the prophylaxis of patent ductus arteriosus useful in extremely premature infants?
This study was aimed to verify the efficacy and safety of ibuprofen prophylaxis of patent ductus arteriosus in very preterm infants, in order to select infants receiving higher benefits from this intervention. Two hundred neonates with gestational age (GA) < or = 28 weeks receiving ibuprofen within the first two hours of life were included. Ductus closure rate was 68%, and results were significantly dependent on GA (48.8% among neonates with GA < 26 weeks vs 73.2% among those with GA > or = 26 weeks, p < 0.01). Neonates with GA < 26 weeks showed a lower ductus closure after the primary course of therapy (20% vs 57.5%, p < 0.01), as well as higher reopening rate (16.2% vs 3.8%, p < 0.05) and need for surgical ligation (38.8% vs 5.8%, p < 0.01). During the prophylaxis period, 11 neonates (5.5%) showed pulmonary hypertension. Considering risks/benefits, we recommend prophylaxis only in infants with GA < 26 weeks.


Molecular aetiology and pathogenesis of basal cell carcinoma.
Recent insights into the cell biology of the epidermis and its appendages are transforming our understanding of the pathogenesis of basal cell carcinoma (BCC). The significant progress that has been made warrants a comprehensive review of the molecular and cellular pathology of BCC. The items addressed include environmental and genetic risk factors, the biology of the putative precursor cell(s), and the contribution of aberrations in processes such as apoptosis, cell proliferation, differentiation and signalling to carcinogenesis. Furthermore, established and novel treatment modalities are discussed with particular attention to future biological approaches.


Synchronization of isolated downstates (K-complexes) may be caused by cortically-induced disruption of thalamic spindling.
Sleep spindles and K-complexes (KCs) define stage 2 NREM sleep (N2) in humans. We recently showed that KCs are isolated downstates characterized by widespread cortical silence. We demonstrate here that KCs can be quasi-synchronous across scalp EEG and across much of the cortex using electrocorticography (ECOG) and localized transcortical recordings (bipolar SEEG). We examine the mechanism of synchronous KC production by creating the first conductance based thalamocortical network model of N2 sleep to generate both spontaneous spindles and KCs. Spontaneous KCs are only observed when the model includes diffuse projections from restricted prefrontal areas to the thalamic reticular nucleus (RE), consistent with recent anatomical findings in rhesus monkeys. Modeled KCs begin with a spontaneous focal depolarization of the prefrontal neurons, followed by depolarization of the RE. Surprisingly, the RE depolarization leads to decreased firing due to disrupted spindling, which in turn is due to depolarization-induced inactivation of the low-threshold Ca2+ current (IT). Further, although the RE inhibits thalamocortical (TC) neurons, decreased RE firing causes decreased TC cell firing, again because of disrupted spindling. The resulting abrupt removal of excitatory input to cortical pyramidal neurons then leads to the downstate. Empirically, KCs may also be evoked by sensory stimuli while maintaining sleep. We reproduce this phenomenon in the model by depolarization of either the RE or the widely-projecting prefrontal neurons. Again, disruption of thalamic spindling plays a key role. Higher levels of RE stimulation also cause downstates, but by directly inhibiting the TC neurons. SEEG recordings from the thalamus and cortex in a single patient demonstrated the model prediction that thalamic spindling significantly decreases before KC onset. In conclusion, we show empirically that KCs can be widespread quasi-synchronous cortical downstates, and demonstrate with the first model of stage 2 NREM sleep a possible mechanism whereby this widespread synchrony may arise.


Delayed glial clearance of degenerating axons in aged Drosophila is due to reduced PI3K/Draper activity.
Advanced age is the greatest risk factor for neurodegenerative disorders, but the mechanisms that render the senescent brain vulnerable to disease are unclear. Glial immune responses provide neuroprotection in a variety of contexts. Thus, we explored how glial responses to neurodegeneration are altered with age. Here we show that glia-axon phagocytic interactions change dramatically in the aged Drosophila brain. Aged glia clear degenerating axons slowly due to low phosphoinositide-3-kinase (PI3K) signalling and, subsequently, reduced expression of the conserved phagocytic receptor Draper/MEGF10. Importantly, boosting PI3K/Draper activity in aged glia significantly reverses slow phagocytic responses. Moreover, several hours post axotomy, early hallmarks of Wallerian degeneration (WD) are delayed in aged flies. We propose that slow clearance of degenerating axons is mechanistically twofold, resulting from deferred initiation of axonal WD and reduced PI3K/Draper-dependent glial phagocytic function. Interventions that boost glial engulfment activity, however, can substantially reverse delayed clearance of damaged neuronal debris.


Therapeutic touch as energy exchange: testing the theory.
Previous investigators have suggested that the effects of therapeutic touch are the result of an energy exchange between the client and the nurse. In this investigation, the theory of energy exchange is viewed as part of the broader conceptual system proposed by Rogers. The theorem that the effects of therapeutic touch do not depend on actual physical contact is derived, tested, and supported via an experimental pretest-posttest design. Subjects treated with noncontract therapeutic touch demonstrated a significantly greater decrease in state anxiety than subjects treated with a mimic control intervention. Implications for further theory development are presented.


Role of Conserved Proline Residues in Human Apolipoprotein A-IV Structure and Function.
Apolipoprotein (apo)A-IV is a lipid emulsifying protein linked to a range of protective roles in obesity, diabetes, and cardiovascular disease. It exists in several states in plasma including lipid-bound in HDL and chylomicrons and as monomeric and dimeric lipid-free/poor forms. Our recent x-ray crystal structure of the central domain of apoA-IV shows that it adopts an elongated helical structure that dimerizes via two long reciprocating helices. A striking feature is the alignment of conserved proline residues across the dimer interface. We speculated that this plays important roles in the structure of the lipid-free protein and its ability to bind lipid. Here we show that the systematic conversion of these prolines to alanine increased the thermodynamic stability of apoA-IV and its propensity to oligomerize. Despite the structural stabilization, we noted an increase in the ability to bind and reorganize lipids and to promote cholesterol efflux from cells. The novel properties of these mutants allowed us to isolate the first trimeric form of an exchangeable apolipoprotein and characterize it by small-angle x-ray scattering and chemical cross-linking. The results suggest that the reciprocating helix interaction is a common feature of all apoA-IV oligomers. We propose a model of how self-association of apoA-IV can result in spherical lipoprotein particles, a model that may have broader applications to other exchangeable apolipoprotein family members.


On the titanium oxide neutral cluster distribution in the gas phase: Detection through 118 nm single-photon and 193 nm multiphoton ionization.
Titanium oxide clusters are generated in a supersonic expansion by laser ablation of the metal and reaction with oxygen (0.1-6%) in He expansion gas. Mass spectra of the titanium oxide clusters are observed by photoionization with lasers of three different wavelengths: 118, 193, and 355 nm. Only the 118 nm (10.5 eV) light can ionize Ti(m)O(n) neutral clusters without fragmentation. Both the 193 nm (6.4 eV) and 355 nm (3.5 eV) multiphoton ionization cause fragmentation of the neutral clusters during the ionization process and, thus, can complicate the determination of the stable neutral Ti(m)O(n) gas-phase species. Employing 118 nm single-photon ionization and line-width data, the Ti(m)O(2m) and Ti(m)O(2m+1) series are found to be the most stable neutral cluster species for high oxygen content in the expansion gas. Fragmentation during the multiphoton ionization process for 193 nm light yields the cluster ions Ti(m)O(2m-1,-2)+. These ions are formed by the loss of one or two oxygen atoms from Ti(m)O(2m,2m+1) neutral species. The dominant cluster growth process is suggested to be through the addition of TiO2 species. For low oxygen content (<2%) in the expansion gas, oxygen-deficient clusters of the form Ti(m)O(2m-1,-2) are also observed. These latter series are not fragmented by the 193 nm ionization process.


Prognostic Value of Cervical Nodal Necrosis Observed in Preoperative CT and MRI of Patients With Tongue Squamous Cell Carcinoma and Cervical Node Metastases: A Retrospective Study.
OBJECTIVE. The prognosis of tongue squamous cell carcinoma (SCC) with cervical lymph node metastases is poor, and a subset of patients with aggressive disease experiences treatment failure. The current study evaluated the prognostic value of cervical nodal necrosis (CNN) observed on preoperative imaging studies of patients with tongue SCC and cervical node metastases. MATERIALS AND METHODS. We identified patients with tongue SCC who had undergone preoperative neck CT or MRI (or both) and retrospectively reviewed their demographic and clinical data. Patients with metastatic cervical lymph nodes were divided into two groups according to the presence (CNN group) or absence (non-CNN group) of necrosis, and radiologic extranodal extension (ENE) was assessed for all patients. Follow-up biopsy, imaging, and clinical examinations were used to determine survival and treatment failure. Cox proportional hazard regression analyses were performed to determine clinical, demographic, and pathologic factors for survival. RESULTS. Seventy-two patients with a mean follow-up period of 28.4 months were included. The incidence of CNN was 55.6% (40/72). In univariate analysis, patient age, evidence of CNN on preoperative imaging, radiologic ENE, clinical N classification, and overall stage were significantly associated with survival. The multivariate Cox proportional hazard model showed that patient age and CNN on preoperative imaging were independent negative prognostic factors. CONCLUSION. CNN observed on preoperative imaging studies is an independent predictor of a poor prognosis for patients with tongue SCC, and it may serve as a useful imaging biomarker for tailoring individual treatment regimens.


Taking Action Towards Equity, Diversity, and Inclusion in the Pharmacy Curriculum and Continuing Professional Development.
Increased awareness of social injustices and inequities highlight the relevance and importance of diversity, equity, inclusion, and accessibility (DEIA) in health care. Former and recent graduates of pharmacy schools remain deficient in their knowledge of DEIA topics such as unconscious bias, which can directly influence health outcomes in an undesirable manner. Particular DEIA areas that are pertinent to pharmacy practice include: race, gender, sexual orientation, gender identity, ability status, religion, socioeconomic status, and political beliefs. The American Association of Colleges of Pharmacy (AACP) affirmed its commitment to DEIA as a priority. However, existing gaps in knowledge of pharmacy graduates in this area have the potential to contribute to health disparities and inequities, which are significant public health issues. We call on academic pharmacy institutions and professional pharmacy organizations to elevate DEIA topics and to designate them as essential to both addressing health equity and improving care for underserved populations. We also implore licensing boards to require continuing education related to DEIA as a foundational step to closing the knowledge gap for pharmacists in this area.


Two types of transient outward currents in adult human atrial cells.
It has been suggested in a previous article [Escande et al., Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H843-H850, 1985] that transient outward currents may participate in the initial repolarization of human atrial fibers. The present study substantiates the existence of such currents in human myocardium. Membrane currents were recorded in enzymatically dissociated cells using the whole cell patch-clamp technique. Two kinds of transient outward currents were observed: 1) a long-lasting outward current, (ilo), which was suppressed by 4-aminopyridine. The time to peak of ilo was 18.0 +/- 0.7 ms, and its inactivation time constant was 35.7 +/- 2.1 ms at room temperature (test pulses, +20 mV; holding potential, -40 mV); 2) a brief outward current (ibo), which persisted with 3 mM 4-aminopyridine and exhibited a shorter time to peak (5.5 +/- 0.2 ms) and a faster decay (time constant, 9.1 +/- 1.8 ms). ilo was inhibited by Ba but was insensitive to the calcium blocker Co. Co blocked both the slow inward current (isi) and ibo. It is concluded that two different transient outward currents control the repolarization in human atrial cells.


The risk of Colles' fracture is associated with the collagen I alpha1 Sp1 polymorphism and ultrasound transmission velocity in the calcaneus only in heavier postmenopausal women.
To compare the ability of the bone mineral density (BMD) at the distal forearm, collagen I alpha 1 (COLIA1) polymorphism, and ultrasound stiffness to identify individuals with increased risk of wrist fracture, we studied 183 postmenopausal Czech women with a wrist fracture and 178 postmenopausal controls, ages 45-70 years. The genotypes "Ss" and "ss" were significantly overrepresented among fracture cases. The BMD measurements at the femoral neck, total femur, and distal forearm as well as ultrasound stiffness of the heel, broadband ultrasound attenuation (BUA), and speed of sound (SOS) were significantly lower in the fracture cohort. BMD of the distal forearm was the main determinant of susceptibility to the wrist fracture. Weight, the COLIA1 genotype, and ultrasound SOS further strengthened the predictive value of BMD. However, we found interaction between weight and both the COLIA1 Sp1 polymorphism and ultrasound parameters. Presence of the "s" allele as well as low SOS acted as significant predictors of wrist fracture only in heavier women, (> or =62 kg) but not in women with a body weight of less than 62 kg. In heavier women, both the COLIA1 Sp1 polymorphism and ultrasound parameters acted as independent markers that contributed to BMD to enhance fracture prediction. However, the COLIA1 enabled a higher specificity (specificity 72.4%, sensitivity 44.2%), whereas SOS enabled a higher sensitivity (sensitivity 73.9%, specificity, 45.7%). We conclude that BMD at total forearm, the COLIA1 polymorphism, and ultrasound SOS are independent predictors of wrist fracture in postmenopausal women. The effect of the COLIA1 Sp1 polymorphism and SOS on wrist fracture risk is more pronounced in patients with a higher body weight.


Patterns and significance of CD44 expression in lung allografts.
Lung allograft rejection involves the interplay of multiple cellular populations, soluble mediators, and extracellular matrix proteins. The CD44 family of cell surface glycoproteins mediates a variety of cell-cell and cell-matrix interactions including lymphocyte homing to sites of antigenic challenge and fibroblast migration and invasion into extracellular matrix, processes integral to lung allograft rejection. We performed immunohistochemical staining for CD44 on biopsies from allograft recipients with differing rejection experiences: Group 1 (n = 5 patients/10 biopsies) never exceeded Grade A1 or B2 acute rejection (AR); Group 2 (n = 7 patients/26 biopsies) had 2 or more episodes of Grade A2 or higher AR and no obliterative bronchiolitis (OB); Group 3 (n = 6 patients/17 biopsies) had clinical and pathologic OB. Nine infected allograft biopsies, 8 near-normal lung sections (non-transplant controls), and 13 non-transplant biopsies showing bronchiolitis obliterans organizing pneumonia (BOOP), organizing diffuse alveolar damage (DAD), or usual interstitial pneumonia (UIP) were also studied. Allograft biopsies demonstrated significantly more CD44 staining among lymphocytes, macrophages, Type II pneumocytes, and respiratory epithelial cells than non-transplant controls, while staining of lymphocytes, macrophages, and Type II pneumocytes did not differ significantly between allograft groups. Fibroblast CD44 staining in Group 3 biopsies significantly exceeded that of controls and Groups 1 and 2, and biopsies with AR and/or OB showed more fibroblast staining than biopsies with BOOP, organizing DAD, or UIP. Alveolar CD44-positive fibroblasts did not predict development of OB, while bronchial CD44-positive fibroblasts were followed in one case by OB. These findings suggest that CD44 expression is characteristic of graft-infiltrating inflammatory cells and resident parenchymal cells, and may be related to the initiation and evolution of AR and OB.


The earliest transcribed zygotic genes are short, newly evolved, and different across species.
The transition from maternal to zygotic control is fundamental to the life cycle of all multicellular organisms. It is widely believed that genomes are transcriptionally inactive from fertilization until zygotic genome activation (ZGA). Thus, the earliest genes expressed probably support the rapid cell divisions that precede morphogenesis and, if so, might be evolutionarily conserved. Here, we identify the earliest zygotic transcripts in the zebrafish, Danio rerio, through metabolic labeling and purification of RNA from staged embryos. Surprisingly, the mitochondrial genome was highly active from the one-cell stage onwards, showing that significant transcriptional activity exists at fertilization. We show that 592 nuclear genes become active when cell cycles are still only 15 min long, confining expression to relatively short genes. Furthermore, these zygotic genes are evolutionarily younger than those expressed at other developmental stages. Comparison of fish, fly, and mouse data revealed different sets of genes expressed at ZGA. This species specificity uncovers an evolutionary plasticity in early embryogenesis that probably confers substantial adaptive potential.


Expression and characterization of antimicrobial peptides Retrocyclin-101 and Protegrin-1 in chloroplasts to control viral and bacterial infections.
Retrocyclin-101 (RC101) and Protegrin-1 (PG1) are two important antimicrobial peptides that can be used as therapeutic agents against bacterial and/or viral infections, especially those caused by the HIV-1 or sexually transmitted bacteria. Because of their antimicrobial activity and complex secondary structures, they have not yet been produced in microbial systems and their chemical synthesis is prohibitively expensive. Therefore, we created chloroplast transformation vectors with the RC101 or PG1 coding sequence, fused with GFP to confer stability, furin or Factor Xa cleavage site to liberate the mature peptide from their fusion proteins and a His-tag to aid in their purification. Stable integration of RC101 into the tobacco chloroplast genome and homoplasmy were confirmed by Southern blots. RC101 and PG1 accumulated up to 32%-38% and 17%∼26% of the total soluble protein. Both RC101 and PG1 were cleaved from GFP by corresponding proteases in vitro, and Factor Xa-like protease activity was observed within chloroplasts. Confocal microscopy studies showed location of GFP fluorescence within chloroplasts. Organic extraction resulted in 10.6-fold higher yield of RC101 than purification by affinity chromatography using His-tag. In planta bioassays with Erwinia carotovora confirmed the antibacterial activity of RC101 and PG1 expressed in chloroplasts. RC101 transplastomic plants were resistant to tobacco mosaic virus infections, confirming antiviral activity. Because RC101 and PG1 have not yet been produced in other cell culture or microbial systems, chloroplasts can be used as bioreactors for producing these proteins. Adequate yield of purified antimicrobial peptides from transplastomic plants should facilitate further preclinical studies.


The current place of high-dose immunoglobulins in the treatment of neuromuscular disorders.
High-dose immunoglobulins for intravenous administration (IVIg) have originally been developed for substitution therapy in hypogammaglobulinemia. Over the last decade they are increasingly used in the treatment of immune-mediated diseases. In this review the results in immune-mediated neuromuscular diseases are summarized. Positive effects are demonstrated in open studies in dermato- and polymyositis, myasthenia gravis, and inflammatory neuropathies. Properly conducted randomized clinical trials demonstrating the effect of IVIg are available in dermatomyositis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy, and smaller ones in multifocal motor neuropathy. In myasthenia gravis a trial is at present underway and only interim results are available. The results of a trial in the Lambert-Eaton myasthenic syndrome are in the process of publication. The therapeutic approach in individual patients is discussed, but often appears to be difficult. Considering chronic treatment with IVIg, proper long-term studies including cost-benefit studies are needed. Future developments aim for combination therapies, since IVIg and immune suppressants like prednisone are suggested to have a synergistic effect.


Hypomagnesemia and mortality in patients admitted to intensive care unit: a systematic review and meta-analysis.
Reports of mortality due to magnesium dysregulation in the critical care setting are controversial. We performed a systematic review and meta-analysis to evaluate the association between hypomagnesemia and mortality in patients admitted to the intensive care unit. Eligible studies assessing the association between hypomagnesemia or hypermagnesemia and mortality in the critical care setting were comprehensively searched in MEDLINE and EMBASE from their inception to September 2015. Inclusion criteria were published observational studies in adults who were admitted to the intensive or critical care setting with initial serum magnesium measurement. We used the definition of abnormal magnesium level defined by each study. Primary outcome was all-cause mortality. We performed meta-analysis using random-effects model and calculated pooled effect estimate of outcome comparing between hypomagnesemia and normal magnesium category. From 30 full-text articles, 6 studies involving 1550 participants were included in the meta-analysis. There was a statistically significant higher risk of mortality in critically ill patients who had hypomagnesemia with RR of 1.90 (95% CI: 1.48-2.44, P < 0.001, I(2 )=( )63.5%). Risk for needing mechanical ventilation was also higher in the hypomagnesemia group with RR of 1.65 (95% CI: 1.12-2.43, P = 0.01, I(2 )=( )84%). Length of ICU stay was also higher in the hypomagnesemia group with mean difference of 4.1 days (95% CI: 1.16-7.04, P = 0.01). The findings of this meta-analysis indicate hypomagnesemia is associated with higher mortality, the need of mechanical ventilation and also the length of ICU stay in patients admitted to ICU.


Primary postpartum hemorrhage.
Postpartum hemorrhage is the outstanding cause of maternal mortality, and a redoubtable contributor to puerperal death from other causes, notably infection and renal failure. The clinical situations in which hemorrhage is liable to occur must be better known, so that anticipatory and preventive measures can be taken. Recent knowledge about defibrinated blood in women with degenerative changes at the placental site must be incorporated in the thinking and practice of physicians dealing with obstetrical cases. The indications, limitations, and hazards of the various anesthetic methods available for parturient women should be carefully considered in the circumstances of each case.


Effects of carbon fibre spring orthoses on gait in ambulatory children with motor disorders and plantarflexor weakness.
A consecutive series of 17 children (six males, 11 females; mean age 11y 11mo [SD 4y 5mo]; range 3y 11mo-17y 4mo) with plantarflexor weakness was assessed to compare gait differences between a carbon fibre spring orthosis (CFSO) and participants' regular orthoses. Twelve children had myelomeningocele, four children had arthrogryposis, and one child had neuropathy with peripheral muscle pareses. All participants underwent clinical examination and 3D gait analysis. Parents answered a questionnaire to assess subjective perceptions of the orthoses. Results from 3D gait analysis provided evidence that CFSOs enhance gait function in most participants by improving ankle plantarflexion moment (p<0.001), ankle positive work (p<0.001), and stride length (p<0.001). The CFSO did not suit all participants, which emphasizes the importance of analyzing each patient's needs.


Salinibacter ruber gen. nov., sp. nov., a novel, extremely halophilic member of the Bacteria from saltern crystallizer ponds.
Five brightly red-pigmented, motile, rod-shaped, extremely halophilic bacteria were isolated from saltern crystallizer ponds in Alicante (two strains) and Mallorca (three strains), Spain. They grew optimally at salt concentrations between 20 and 30% and did not grow below 15% salts. Thus, these isolates are among the most halophilic organisms known within the domain Bacteria. The temperature optimum was 37-47 degrees C. A single, yet to be identified pigment was present, with an absorption maximum at 482 nm and a shoulder at 506-510 nm. The G+C content of the DNA was 66.3-67.7 mol% and, together, they formed a homogeneous genomic group with DNA-DNA similarities above 70%. The 16S rRNA gene sequences were almost identical to sequences recovered earlier from the saltern biomass by amplification of bacterial small-subunit rRNA genes from DNA extracted from the environment. This phylotype, earlier described as 'Candidatus Salinibacter', was shown by fluorescence in situ hybridization to contribute between 5 and 25% of the prokaryote community of the saltern crystallizers. We have therefore succeeded in isolating a bacterium from the natural environment that, although being a major component of the community, was previously known by its phylotype only. Isolation of the organism now allows formal description of a novel genus and species, for which we propose the name Salinibacter ruber gen. nov., sp. nov. The type strain is strain M31T (= DSM 13855T = CECT 5946T).


Electrophysiological mapping and radiofrequency catheter ablation for ventricular tachycardia in a patient with peripartum cardiomyopathy.
A 38-year-old female with prior failed endocardial ablation for ventricular tachycardia (VT) was referred for further treatment. She had been diagnosed with peripartum cardiomyopathy 7 years before and had persistent left ventricular dysfunction with an ejection fraction of 20%. Epicardial voltage mapping showed extensive epicardial scar despite absence of endocardial scar. Five distinct VT morphologies were induced. Ablation was aided by electrogram characteristics, pace mapping, entrainment mapping, and establishing electrical inexcitability along areas of epicardial scar. After epicardial ablation no sustained VT was induced. She had been doing well without VT occurrence but died 1 year later unexpectedly at home.


[Intracranial pressure monitoring as a complementary tests for diagnosing brain death. Preliminary observation through the report of 2 cases].
The clinical evolution of two patients with continuous intracranial pressure (ICP) monitoring, admitted to the Intensive Care Unit of Neurology, University Hospital of Botucatu, and followed until irreversible cardiac failure (ICF) was studied retrospectively. The evolution of ICP showed that it reached a maximum 5 to 12 hours before a decrease in wave amplitude occurred (this was observed approximately 47 to 60 hours before ICF). The tracing became linear approximately 30 hours before ICF in both cases. The clinical diagnosis of brain death (BD) was obtained 3 to 28 hours after the tracing had become linear. The authors suggest that, in absence of sedation, the diagnosis of BD may be made early with the use of ICP monitoring even before the clinical diagnosis, and emphasize the need for more observations in a larger number of patients.


MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia.
The microcephalin gene (MCPH1) [also known as inhibitor of human telomerase reverse transcriptase (hTERT) expression] is a tumor suppressor gene that is functionally involved in the DNA damage response. Angiopoietin 2 (ANGPT2) is a crucial factor regulating tumor angiopoiesis. Deregulation of angiogenesis is one of the hallmarks of many cancers, including chronic lymphocytic leukemia (CLL). In CLL, ANGPT2 is a well-studied potential prognostic marker. As MCPH1 overlaps with the ANGPT2 transcription unit on the same chromosome but in the opposite orientation, we wanted to study the functional role of MCPH1 in regulation of ANGPT2 in CLL. The mRNA expression levels of MCPH1 and ANGPT2, including the MCPH1 target gene hTERT, showed significant differences between two prognostic groups, i.e. IGHV-mutated and IGHV-unmutated (P = 0.007 for MCPH1, P = 0.0002 for ANGPT2, and P = 0.00001 for hTERT), in which the expression level of MCPH1 was inversely correlated with the expression levels of hTERT and ANGPT2. Downregulation of MCPH1 resulted in upregulation of ANGPT2, accompanied by loss of its promoter methylation. Using chromatin immunoprecipitation and coimmunoprecipitation assays, we found that MCPH1 binds to the ANGPT2 promoter and recruits DNA methyltransferases, thereby silencing ANGPT2. Thus, our data suggest a novel function for MCPH1 in regulating and maintaining ANGPT2 silencing in CLL through regulation of promoter DNA methylation.


COVID-19 infection analysis framework using novel boosted CNNs and radiological images.
COVID-19, a novel pathogen that emerged in late 2019, has the potential to cause pneumonia with unique variants upon infection. Hence, the development of efficient diagnostic systems is crucial in accurately identifying infected patients and effectively mitigating the spread of the disease. However, the system poses several challenges because of the limited availability of labeled data, distortion, and complexity in image representation, as well as variations in contrast and texture. Therefore, a novel two-phase analysis framework has been developed to scrutinize the subtle irregularities associated with COVID-19 contamination. A new Convolutional Neural Network-based STM-BRNet is developed, which integrates the Split-Transform-Merge (STM) block and Feature map enrichment (FME) techniques in the first phase. The STM block captures boundary and regional-specific features essential for detecting COVID-19 infectious CT slices. Additionally, by incorporating the FME and Transfer Learning (TL) concept into the STM blocks, multiple enhanced channels are generated to effectively capture minute variations in illumination and texture specific to COVID-19-infected images. Additionally, residual multipath learning is used to improve the learning capacity of STM-BRNet and progressively increase the feature representation by boosting at a high level through TL. In the second phase of the analysis, the COVID-19 CT scans are processed using the newly developed SA-CB-BRSeg segmentation CNN to accurately delineate infection in the images. The SA-CB-BRSeg method utilizes a unique approach that combines smooth and heterogeneous processes in both the encoder and decoder. These operations are structured to effectively capture COVID-19 patterns, including region-homogenous, texture variation, and border. By incorporating these techniques, the SA-CB-BRSeg method demonstrates its ability to accurately analyze and segment COVID-19 related data. Furthermore, the SA-CB-BRSeg model incorporates the novel concept of CB in the decoder, where additional channels are combined using TL to enhance the learning of low contrast regions. The developed STM-BRNet and SA-CB-BRSeg models achieve impressive results, with an accuracy of 98.01%, recall of 98.12%, F-score of 98.11%, Dice Similarity of 96.396%, and IOU of 98.85%. The proposed framework will alleviate the workload and enhance the radiologist's decision-making capacity in identifying the infected region of COVID-19 and evaluating the severity stages of the disease.


Microbial safety and sanitary quality of strawberry primary production in Belgium: risk factors for Salmonella and Shiga toxin-producing Escherichia coli contamination.
Strawberries are an important fruit in Belgium in both production and consumption, but little information is available about the presence of Salmonella and Shiga toxin-producing Escherichia coli (STEC) in these berries, the risk factors in agricultural production, and possible specific mitigation options. In 2012, a survey was undertaken of three soil and three soilless cultivation systems in Belgium. No Salmonella spp. were isolated. No STEC was detected in the strawberry samples (0 of 72), but STEC was detected by PCR in 11 of 78 irrigation water and 2 of 24 substrate samples. Culture isolates were obtained for 2 of 11 PCR-positive irrigation water samples and 2 of 2 substrate samples. Multivariable logistic regression analysis revealed elevated generic E. coli numbers (the odds ratio [OR] for a 1 log increase being 4.6) as the most important risk factor for STEC, together with the berry-picking season (elevated risk in summer). The presence of generic E. coli in the irrigation water (≥1 CFU per 100 ml) was mainly influenced by the type of irrigation water (collected rainfall water stored in ponds was more often contaminated than groundwater pumped from boreholes [OR = 5.8]) and the lack of prior treatment (untreated water versus water subjected to sand filtration prior to use [OR = 19.2]). The follow-up study in 2013 at one of the producer locations indicated cattle to be the most likely source of STEC contamination of the irrigation water.


A human YAC transgene rescues craniofacial and neural tube development in PDGFRalpha knockout mice and uncovers a role for PDGFRalpha in prenatal lung growth.
The platelet-derived growth factor alpha-receptor (PDGFRalpha) plays a vital role in the development of vertebrate embryos, since mice lacking PDGFRalpha die in mid-gestation. PDGFRalpha is expressed in several types of migratory progenitor cells in the embryo including cranial neural crest cells, lung smooth muscle progenitors and oligodendrocyte progenitors. To study PDGFRalpha gene regulation and function during development, we generated transgenic mice by pronuclear injection of a 380 kb yeast artificial chromosome (YAC) containing the human PDGFRalpha gene. The YAC transgene was expressed in neural crest cells, rescued the profound craniofacial abnormalities and spina bifida observed in PDGFRalpha knockout mice and prolonged survival until birth. The ultimate cause of death was respiratory failure due to a defect in lung growth, stemming from failure of the transgene to be expressed correctly in lung smooth muscle progenitors. However, the YAC transgene was expressed faithfully in oligodendrocyte progenitors, which was not previously observed with plasmid-based transgenes containing only upstream PDGFRalpha control sequences. Our data illustrate the complexity of PDGFRalpha genetic control, provide clues to the location of critical regulatory elements and reveal a requirement for PDGF signalling in prenatal lung growth, which is distinct from the known requirement in postnatal alveogenesis. In addition, we found that the YAC transgene did not prolong survival of Patch mutant mice, indicating that genetic defects outside the PDGFRalpha locus contribute to the early embryonic lethality of Patch mice.


Use of Continuous Glucose Monitoring in Youth-Onset Type 2 Diabetes.
Continuous glucose monitoring (CGM) technology has long been accepted as a tool for managing glycemia in type 1 diabetes (T1D) and is receiving increased attention as a tool for monitoring glucose patterns in patients with other forms of diabetes, in particular type 2 diabetes (T2D). Recent studies in adults with T2D have shown benefits of CGM in the investigation of glycemic variability, as well as utility as a tool for improving glycemic control. The literature on CGM use in youth-onset T2D, however, is sparse. This paper reviews the various roles for CGM in T2D, with a focus on published reports of CGM use in youth-onset T2D. The gaps in knowledge are highlighted, along with a discussion regarding need for future studies of potential applications for CGM in this younger population. CGM systems provide insight into glycemic abnormalities in obese youth with and at risk for T2D. This technology has enabled examination of the relationship between free-living glycemic profiles and traditional diabetes screening tests, as well as markers of cardiometabolic risk in this high-risk population. Investigators are incorporating CGM technology into the study of T2D in youth, but interventional studies of CGM as a tool for glycemic control in youth-onset T2D are limited. Youth with T2D face a more aggressive disease than adults with T2D, and further studies utilizing advances in glucose monitoring technology to improve outcomes in this population are needed.


Magnetic resonance imaging measurement of knee cartilage volume in a multicentre study.
To investigate the variability between different high-field scanners in magnetic resonance imaging (MRI) measurement of knee cartilage volume in healthy female volunteers. Five volunteers had both knees scanned using three different MRI scanners. Cartilage volume in each compartment was measured from the images by image segmentation. The data were analysed using analysis of variance models. The mean total cartilage volume of the 10 knees scanned at three different centres was 16.15, 16.40 and 15.63 ml for the Siemens, GE and Philips scanners respectively. Small systematic differences were seen in the total knee cartilage volume results. Although there were small systematic differences in knee cartilage volume, the three MRI scanners gave broadly similar results.