The effect of pessary treatment on puborectalis muscle function.
The objective was to assess if puborectalis muscle (PRM) function changes in women with pelvic organ prolapse (POP) undergoing pessary treatment. This was a prospective cohort study of women with symptomatic POP choosing pessary treatment. An interview, clinical examination and 3D/4D transperineal ultrasound were performed at baseline and at 3-month follow-up. POP was assessed using the Pelvic Organ Prolapse Quantification system (POPQ). Parameters compared between baseline and follow-up were: hiatal area at rest (HArest), maximal contraction (HActx), and maximal Valsalva maneuver (HAVal), displacement in contraction (DISPL-ctx, i.e., relative difference between HArest and HActx), and displacement in Valsalva (DISPL-Val, i.e., relative difference between and HAVal and HArest). Parameters were compared in women with and those without complete avulsion. A total of 162 women were assessed and 34 were included. Mean age was 64 years (SD 11.4), and mean BMI 24 kg/m2 (SD 3.1). Thirty-one women had a cystocele, 8 a uterine prolapse, and 12 had a posterior compartment prolapse. Twenty-one women (61.8%) had a POP stage II, and 13 (38.2%) a POP stage III. Ring pessaries were most frequently used (97%). In the entire group a statistically significant increase in DISPL-ctx was observed (mean difference 2.1%, p = 0.017). In the no avulsion group HArest and DISPL-ctx increased significantly (mean difference 4.1%, p = 0.016 and 2.7%, p = 0.016 respectively) and the increase in DISPL-ctx was higher than in the avulsion group (mean difference 2.7% vs 0.2%, p = 0.056). Our results show that PRM function changes in women with POP undergoing pessary treatment and suggest that such change occurs mainly in the absence of complete avulsion.


Update on nitric oxide-dependent vasodilation in human subjects.
There currently is great interest in translating findings about the importance of nitric oxide (NO) in vascular biology to the clinical arena. The bioactivity of endothelium-derived NO can readily be assessed in human subjects as vasodilation of conduit arteries or increased flow, which reflects vasodilation of resistance vessels. This chapter provides an update on the available noninvasive methodology to assess endothelium-dependent vasodilation in human subjects.


Sarcolipin provides a novel muscle-based mechanism for adaptive thermogenesis.
The sarco(endo)plasmic reticulum Ca-ATPase (SERCA) transports Ca into the sarcoplasmic reticulum lumen and contributes significantly to skeletal muscle metabolic rate. Sarcolipin (SLN) has been shown recently to uncouple Ca transport from adenosine triphosphate hydrolysis by SERCA. We have hypothesized that SLN provides a novel mechanism of adaptive thermogenesis within skeletal muscle and protects against diet-induced obesity.


A 168-year temperature recording based on tree rings and latitude differences in temperature changes in northeast China.
A ring-width series was developed from Dahurian larch (Larix gmelinii) in the northeastern forest area of Inner Mongolia, China. By analyzing the relationships between tree-ring data and climate records, an August-September mean maximum temperature (T89) series during 1845 and 2012 was reconstructed based on a simple linear regression equation. This reconstructed series explained 40.9% variance of the observed temperature from 1959 to 2012. The reconstructed T89 series was consistent with the historical disaster events caused by extreme climate (e.g., flood, frost disaster, and cold damage). Besides, the temperature comparisons showed that the year in which the warm months (April-September) in northeast China began to warm up has latitude differences. It started with a gradual delay from north to south, starting 1980 in the south region, after 1950 AD in the central region and after 1940 in the north region. Our study can enrich high-resolution temperature series in Northeast China and help clarify the characteristic of recent warming in northeast China.


Human lymphocyte proliferation kinetics in Hanks' BSS supplemented with autologous plasma and in synthetic medium.
Human lymphocyte proliferation kinetics was studied in different culture conditions including synthetic medium, Hanks' BSS and Hanks' supplemented with autologous plasma at several culture times. Even though mitotic indices (MI) were low, lymphocytes were able to divide for a few cycles in BSS alone, with a cycling time of around 24 h. Similar cell proliferation patterns with similar MIs, replication indices and cell cycle times of approximately 12 h were obtained with RPMI 1640 and with autologous plasma-supplemented BSS, although lymphocytes exhibited a more uniform MI distribution curve in synthetic medium. The findings mentioned above suggest that Hanks' with autologous plasma may represent a suitable and inexpensive culture condition to avoid undesirable side effects related to synthetic media and heterologous sera, for diagnostics as well as research cytogenetics.


Coordinated activation of muscle fibres by different conduction velocities in branches of a crustacean motor axon.
Higher conduction velocities in branches of the fast excitor axon to distal muscle fibres ensure that these fibres are activated almost simultaneously with proximal fibres in the claw closer muscle of lobsters, producing a contraction of maximal force.


An emm-type specific qPCR to track bacterial load during experimental human Streptococcus pyogenes pharyngitis.
Streptococcus pyogenes causes a profound global burden of morbidity and mortality across its diverse clinical spectrum. To support a new controlled human infection ('challenge') model seeking to accelerate S. pyogenes vaccine development, we aimed to develop an accurate and reliable molecular method for quantifying bacterial load from pharyngeal swabs collected during experimental human pharyngitis. Combined sequential RNA + DNA extraction from throat swabs was compared to traditional separate RNA-only and DNA-only extractions. An emm-type specific qPCR was developed to detect the emm75 challenge strain. Results from the qPCR were compared to culture, using throat swab samples collected in a human challenge study. The qPCR was 100% specific for the emm75 challenge strain when tested against a panel of S. pyogenes emm-types and other respiratory pathogens. Combined RNA + DNA extraction had similar yield to traditional separate extractions. The combined extraction method and emm75 qPCR had 98.8% sensitivity compared to culture for throat swabs collected from challenge study participants. We have developed a reliable molecular method for measuring S. pyogenes bacterial load from throat swabs collected in a controlled human infection model of S. pyogenes pharyngitis. NCT03361163 on 4th December 2017.


Correlation of fatigue during the acute stage of stroke with serum uric acid and glucose levels, depression, and disability.
To clarify the correlation of fatigue during the acute stage of stroke with serum uric acid (UA) and glucose levels, depression, and disability. Cross-sectional descriptive study. A stroke group of 312 patients and a reference group of 312 healthy controls were recruited during the same period. Fatigue was assessed using the Fatigue Severity Scale (FSS). Patients with an FSS score ≥4 points were defined as having fatigue. Depression was assessed using the Self-rating Depression Scale (SDS). Patients with an SDS score ≥50 points were defined as having depression. Stroke severity and the level of disability were assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Modified Rankin Scale (MRS). The prevalence of fatigue in the stroke group was higher than that in the reference group (p < 0.001). Within the stroke group, low serum UA level, high MRS score, high serum glucose level, and high SDS score were associated with increased FSS score. The MRS score was associated most consistently with the FSS score (B = 0.411, 95% CI: 0.297, 0.525). Age, gender, chronic disease history, and NIHSS score were not associated with FSS score. Serum UA and glucose levels, depression, and disability are closely related to fatigue during the acute stage of ischaemic stroke.


Trimalleolar fracture and associated Achilles tendon rupture: Ten year follow up of an unusual water-skiing injury.
A 49 year old professional fitness instructor sustained a high velocity rotational injury to his right ankle while waterski-ing. The ski bindings did not release, exacerbating the injury. This resulted in a trimalleolar fracture and a rupture of his Achilles tendon. A trimalleolar fracture in association with a rupture of the Achilles tendon has not been previously reported. This combination of injuries posed a dilemma in treatment options and postoperative management. The authors felt that ensuring that the Achilles tendon healed with no shortening was the priority for future function in this professional athlete. It was decided to treat the Achilles tendon rupture by open repair and to place the ankle in equinus postoperatively. It was also decided to openly reduce and internally fix the medial and lateral malleolar fractures before immobilising the ankle in equinus. Any residual stiffness in the ankle, subtalar and midtarsal joints would be treated with aggressive physiotherapy. It was felt that the rotational forces may have resulted in a degree of degloving around the ankle. Care was therefore taken in the choice and placement of the surgical incisions. In spite of this, the lateral surgical wound broke down postoperatively, needing treatment with a fasciocutaneous flap. When reviewed at ten years following the injury, the patient was continuing to work as a fitness instructor with a view to continuing to retirement in five years at the age of 65. There was a slight decrease in dorsiflexion of the right ankle but flexion was full and movement of the subtalar and midtarsal joints were also full. There remained 1 cm of wasting of the right calf. Radiology of the ankle showed no joint space narrowing or evidence of degenerative change at ten years following the injury.


alpha-L-iduronidase activity in leukocytes: diagnosis of homozygotes and heterozygotes of the Hurler syndrome.
The activity of alpha-L-iduronidase was determined in leukocytes from two patients with the Hurler syndrome, five obligatory heterozygotes, one patient with the Hunter syndrome, and ten normal individuals. It was found that the determination of alpha-L-iduronidase in leukocytes was a useful method for differential diagnosis between the Hurler and Hunter syndromes. Heterozygotes of the Hurler syndrome showed approximately 50% level of alpha-L-iduronidase activity in leukocytes as compared with that of normal individuals. This suggests that the determination of alpha-L-iduronidase activity may be available for the carrier detection of the Hurler syndrome.


[Postradiation recovery of hematopoiesis in mice administered cell-free tissue extracts from the central Asiatic turtle].
It was shown on mice exposed to 8 Gy radiation that a spleen extract from T. horsfieldi has a high therapeutic effect. Bone marrow cellularity is restored as early as 8 days following irradiation and injection of the extract; the survival rate is 71.2% against 4.2 in the control.


Biochemical Methods for Assessing Gasdermin D Inactivation in Macrophages.
Gasdermin D is an essential mediator of pyroptosis. Under resting conditions gasdermin D is inactive in the cytosol. Following inflammasome activation, gasdermin D undergoes processing and oligomerization to create membrane pores and induce pyroptosis to release mature IL-1 and IL-18. Biochemical methods for the analysis of gasdermin D activation states are important for assessing gasdermin D function. Here we describe the biochemical methods for assessing gasdermin D processing and oligomerization and its inactivation using small molecule inhibitors.


Ivermectin-treated cattle reduces blood digestion, egg production and survival of a free-living population of Anopheles arabiensis under semi-field condition in south-eastern Tanzania.
Anopheles arabiensis feed on cattle and contributes to residual transmission of malaria in areas with high coverage of long-lasting insecticide-treated nets and indoor residual spraying in East Africa. This study aimed to evaluate the effects of ivermectin-treated cattle as a complementary vector control tool against population of An. arabiensis under the semi-field conditions in south-eastern Tanzania. The free-living population of An. arabiensis was allowed to forage on untreated or ivermectin-treated cattle in alternating nights within the semi-field system in south-eastern Tanzania. Fresh blood fed mosquitoes were collected in the morning using mouth aspirators and assessed for their blood meal digestion, egg production, and survivorship. The residual activity of ivermectin-treated cattle was also determined by exposing mosquitoes to the same treatments after every 2 days until day 21 post-treatments. These experiments were replicated 3 times using different individual cattle. Overall, the ivermectin-treated cattle reduced blood meal digestion in the stomach of An. arabiensis, and their subsequent egg production and survival over time. The ivermectin-treated cattle halved blood meal digestion in mosquitoes, but reduced their egg production for up to 15 days. The ivermectin-treated cattle reduced the survival, and median survival times (1-3 days) of An. arabiensis than control cattle. The daily mortality rates of mosquitoes fed on ivermectin-treated cattle increased by five-fold relative to controls in the first week, and it gradually declined up to 21 days after treatment. This study demonstrates that long-lasting effects of ivermectin-treated cattle on egg production and survival of An. arabiensis may sustainably suppress their vector density, and reduce residual transmission of malaria. This study suggests that ivermectin-treated non-lactating cattle (i.e. calves, heifers and bulls) could be suitable option for large-scale malaria vector control without limiting consumption of milk and meat by communities in rural settings. Furthermore, simulation models are underway to predict the impact of ivermectin-treated cattle alone, or in combination with LLIN/IRS, the frequency of treatment, and their coverage required to significantly suppress population of An. arabiensis and reduce residual transmission of malaria.


Biochar induced improvement in root system architecture enhances nutrient assimilation by cotton plant seedlings.
Raising nitrogen use efficiency of crops by improving root system architecture is highly essential not only to reduce costs of agricultural production but also to mitigate climate change. The physiological mechanisms of how biochar affects nitrogen assimilation by crop seedlings have not been well elucidated. Here, we report changes in root system architecture, activities of the key enzymes involved in nitrogen assimilation, and cytokinin (CTK) at the seedling stage of cotton with reduced urea usage and biochar application at different soil layers (0-10 cm and 10-20 cm). Active root absorption area, fresh weight, and nitrogen agronomic efficiency increased significantly when urea usage was reduced by 25% and biochar was applied in the surface soil layer. Glutamine oxoglutarate amino transferase (GOGAT) activity was closely related to the application depth of urea/biochar, and it increased when urea/biochar was applied in the 0-10 cm layer. Glutamic-pyruvic transaminase activity (GPT) increased significantly as well. Nitrate reductase (NR) activity was stimulated by CTK in the very fine roots but inhibited in the fine roots. In addition, AMT1;1, gdh3, and gdh2 were significantly up-regulated in the very fine roots when urea usage was reduced by 25% and biochar was applied. Nitrogen assimilation efficiency was significantly affected when urea usage was reduced by 25% and biochar was applied in the surface soil layer at the seedling stage of cotton. The co-expression of gdh3 and gdh2 in the fine roots increased nitrogen agronomic efficiency. The synergistic expression of the ammonium transporter gene and gdh3 suggests that biochar may be beneficial to amino acid metabolism.


Notch signaling pathway regulates proliferation and differentiation of immortalized Müller cells under hypoxic conditions in vitro.
Previous studies have indicated that Müller glia in chick and fish retinas can re-enter the cell cycle, express progenitor genes, and regenerate neurons via the Notch signaling pathway in response to retinal damage or growth factors. Here, we investigated the role of Notch signaling and the effect of hypoxia, as a means to induce retinal damage, on the proliferation of an immortalized Müller cell line (rMC-1 cells). Our data showed that rMC-1 cells expressed Müller glia and neural and retinal progenitor markers but did not express neuronal or retinal markers. Hypoxia increased rMC-1 cell proliferation by activating the positive cell-cycle regulators, cyclins A and D1, as well as the neural and retinal progenitor markers, Notch1, Hes1, nestin, Sox2, Msi1, Pax6, and NeuroD1. However, hypoxia did not significantly influence the expression of Müller glial markers GS, CRALBP, and cyclin D3 or the death of the rMC-1 cells. The increase in cell proliferation induced by hypoxia was greatly attenuated by blocking Notch signaling with the inhibitor DAPT, resulting in the reduced expression of positive cell-cycle regulators (cyclins A and D1) and neural and retinal progenitor markers (Notch1, Hes1, Sox2, Pax6, and NeuroD1). Blockade of the Notch signaling pathway by DAPT after hypoxia promoted the differentiation of rMC-1 cells to neurons, as demonstrated by the induction of neural marker (Tuj1), retinal amacrine (Syntaxin1), and retinal ganglion cell (Brn3b) markers, although the expression of the latter marker was low. Taken together, our data indicate that Notch signaling is required for proliferation under hypoxic conditions either by activating the positive cell-cycle regulators or by skewing their de-differentiation towards a neural progenitor lineage. These findings indicate that the Notch signaling pathway regulates hypoxia-induced proliferation and differentiation of Müller glia.


[Biologic therapies different from the anti-TNFα therapy in psoriasis and psoriatic arthritis].
Psoriasis and psoriatic arthritis (PsA) are common conditions in the clinical practice of both dermatologists and rheumatologists. Both entities may cause an important loss in quality of life, and in the case of PsA, joint structural damage may arise over time. For these reasons, clinicians may be faced with the need for treating these cases with highly effective therapies, such as TNFα blocking agents, although these drugs may be paradoxically related with de novo onset (or exacerbation of previous lesions) of psoriasis or psoriasiform lesions. In spite of the clinical efficacy of these therapies, recent registry studies show that up to 25% of PsA cases exposed to anti-TNF therapies are withdrawn from these drugs within the first year of therapy. Therefore, there is a need for the use of alternative biologic therapies in this context. The present review deals with this subject.


Novel thrombospondin-1 transcript exhibits distinctive expression and activity in thyroid tumorigenesis.
Thrombospondin 1 (TSP1) is known for its cell-specific functions in cancer progression, such as proliferation and migration. It contains 22 exons that may potentially produce several different transcripts. Here, we identified TSP1V as a novel TSP1-splicing variant produced by intron retention (IR) in human thyroid cancer cells and tissues. We observed that TSP1V functionally inhibited tumorigenesis contrary to TSP1 wild-type, as identified in vivo and in vitro. These activities of TSP1V are caused by inhibiting phospho-Smad and phospho-focal adhesion kinase. Reverse transcription polymerase chain reaction and minigene experiments revealed that some phytochemicals/non-steroidal anti-inflammatory drugs enhanced IR. We further found that RNA-binding motif protein 5 (RBM5) suppressed IR induced by sulindac sulfide treatment. Additionally, sulindac sulfide reduced phospho-RBM5 levels in a time-dependent manner. Furthermore, trans-chalcone demethylated TSP1V, thereby preventing methyl-CpG-binding protein 2 binding to TSP1V gene. In addition, TSP1V levels were significantly lower in patients with differentiated thyroid carcinoma than in those with benign thyroid nodule, indicating its potential application as a diagnostic biomarker in tumor progression.


An innovative arrangement for in-vial membrane-assisted liquid-liquid microextraction: application to the determination of esters of phthalic acid in alcoholic beverages by gas chromatography-mass spectrometry.
A new arrangement for membrane-assisted liquid-liquid microextraction is presented. The extracting organic solvent was placed into a chromatographic microvial, compatible with the chromatograph autosampler, whose septum was replaced by a disc of porous hydrophobic membrane. This extraction device was completely immersed into the analytical sample contained in a cylindrical container subjected to rotary and basculant movement. Then, the extraction of analytes took place from the sample to the organic solvent contained in the vial through the membrane. Esters of the phthalic acid have been selected as model analytes to determine the performance characteristics of the extraction system. The limits of detection, limits of quantification and relative standard deviations (%) were in the range 0.1-0.4, 0.3-1 and 4-7, respectively. Esters of phthalic acid have been successfully analysed in alcoholic beverages. The main operational advantages of this arrangement consisted of minimal required handling, minimal risk of cross contamination and its simplicity.


Impact forces of plyometric exercises performed on land and in water.
Aquatic plyometric programs are becoming increasingly popular because they provide a less stressful alternative to land-based programs. Buoyancy reduces the impact forces experienced in water. To quantify the landing kinetics during a range of typical lower limb plyometric exercises performed on land and in water. Crossover design. Eighteen male participants performed ankle hops, tuck jumps, a countermovement jump, a single-leg vertical jump, and a drop jump from 30 cm in a biomechanics laboratory and in a swimming pool. Land and underwater force plates (Kistler) were used to obtain peak impact force, impulse, rate of force development, and time to reach peak force for the landing phase of each jump. Significant reductions were observed in peak impact forces (33%-54%), impulse (19%-54%), and rate of force development (33%-62%) in water compared with land for the majority of exercises in this study (P < 0.05). The level of force reduction varies with landing technique, water depth, and participant height and body composition. This information can be used to reintroduce athletes to the demands of plyometric exercises after injury.


Factors causing release of ribosomal subunits from isolated nuclei of regenerating rat liver in vitro.
Incubation medium II causes release of ribosomal subunits from isolated prelabeled nuclei of regenerating rat liver in vitro (Sato, T., Ishikawa, K. and Ogato, K. (1976) Biochim. Biophys. Acta 000, 000-000). The effects of individual components of this medium on release of subunits were studied and the following results were obtained. 1. Dialyzed cytosol was effective in causing release of total labeled RNA, but its effect on release of labeled ribosomal subunits was rather lower than that of low molecular yeast RNA. Spermidine inhibited the release of total labeled RNA as well as that of labeled ribosomal subunits. 2. Low molecular yeast RNA was the most effective component for inducing release of labeled ribosomal subunits. Homologous ribosomal RNA was as effective as yeast RNA. Cytoplasmic ribosomes, prepared by washing with solution of high salt concentration, and their subunits were also effective. 3. Transfer RNA was not so effective as yeast RNA and ribosomal RNA and even after heat treatment it had little effect. 4. Among the homopolyribonucleotides tested, polyuridylic acid had a strong effect but polyadenylic acid, polycytidylic acid and polyinosinic acid had no effect. 5. The effects of yeast RNA and polyuridylic acid in causing release of labeled ribosomal subunits were dependent upon their concentrations in the reaction mixture. The characteristics of the factors which cause release of labeled ribosomal subunits in vitro are discussed on the basis of the results.


The evidence for technical considerations in pancreatic resections for malignancy.
The surgeon who wishes to perform successful resections for malignant processes involving the pancreas has to be conversant with a broad range of topics. There are extensive collections of data that usually give excellent guidance, but sometimes also provide conflicting advice. No matter what the data suggest might work best, the surgeon and local collaborators must be able to deliver the quality care cited in some of these reports; usually it is the best results that are published. There is a difference between results that are statistically significant, clinically significant, and important to the patient, and these concepts should never be confused.


A bioluminescent probe for in vivo imaging of pyroglutamate aminopeptidase in a mouse model of inflammation.
Pyroglutamate aminopeptidase (PGP) specifically cleaves the peptide bond of pyroglutamic acid linked to the N-terminal end of a polypeptide or protein. Previous studies showed that PGP was associated with several physiological processes and diseases especially those involving inflammation. Utilizing a 'caging' strategy, we designed and synthesized a bioluminescence probe (PBL) with a limit-of-detection of 3.7 * 10-4 mU/mL. In vivo imaging in a mouse model of inflammatory liver disease revealed that the probe has excellent sensitivity and selectivity and provides a powerful tool for studying the physiological and pathological processes involving PGP.


Influence of change of tunnel axis angle on tunnel length during double-bundle ACL reconstruction via the transportal technique.
Commercially available flexible reamer and curved guide systems allow a certain degree of control over intra-articular tunnel orientation, therefore allows a wide range of intra-osseous femoral tunnel orientations, contrary to the femoral tunneling technique using a straight guide pin, which are determined by knee flexion angle. We sought to find the clinical relevance of intra-osseous femoral tunnel orientations in the respect of tunnel length. To evaluate the relationship between the tunnel axis angle in three orthogonal planes and tunnel length in the anteromedial (AM) and posterolateral (PL) femoral tunnels in patients who underwent anatomic double-bundle anterior cruciate ligament reconstruction (DB-ACLR) using the transportal (TP) technique with a 42o curved guide. A total of 40 patients who underwent primary DB-ACLR with the TP technique using a curved guide were evaluated retrospectively. The tunnel axis angle in three orthogonal planes were evaluated on a three-dimensional surface model constructed using an axial computed tomography scan obtained after reconstruction. Then, correlations with tunnel length were analyzed. In the AM tunnel, tunnel axis angles in the coronal (β = 0.0252, p = 0.022) and sagittal (β = 0.0168, p = 0.029) plane showed significant correlations with tunnel length, while the axial plane did not (p = 0.493) (adjusted R2 = 0.801). In the PL tunnel, only tunnel axis angles in the axial plane (β = 0.0262, p = 0.008) showed a significant relationship with tunnel length (adjusted R2 = 0.700). Drilling at a higher angle in the coronal and sagittal planes in AM tunnels and at a higher angle in the axial plane in PL tunnels decreases the incidence of short femoral tunnels.


Incident reports may or may not be privileged information.
Whether incident reports are discoverable depends on the purpose of the reports and the laws of the state where the reports are filed. Subtle differences in state laws and/or how reports are used can make major differences in the determination. These differences are for hospital attorneys to study and consider. In addition to anticipating litigation, hospitals may use incident reports to promote hospital safety and prevent general losses. The hospital, not the nurse, decides if incident reports will be used in a manner more likely to protect the reports from discovery or if protection from discovery is of less concern (either because of state law or corporate philosophy). These decisions will determine how the forms are printed, when reports should be filed, what information is required, how many copies are made, and to whom the copies are distributed. Perioperative nurses need only follow the facility's policy and procedure for completing and filing incident reports. If the hospital attempts to protect reports from discovery, it is especially important that the procedure be followed precisely.


Effect of APOE ε4 on multimodal brain connectomic traits: a persistent homology study.
Although genetic risk factors and network-level neuroimaging abnormalities have shown effects on cognitive performance and brain atrophy in Alzheimer's disease (AD), little is understood about how apolipoprotein E (APOE) ε4 allele, the best-known genetic risk for AD, affect brain connectivity before the onset of symptomatic AD. This study aims to investigate APOE ε4 effects on brain connectivity from the perspective of multimodal connectome. Here, we propose a novel multimodal brain network modeling framework and a network quantification method based on persistent homology for identifying APOE ε4-related network differences. Specifically, we employ sparse representation to integrate multimodal brain network information derived from both the resting state functional magnetic resonance imaging (rs-fMRI) data and the diffusion-weighted magnetic resonance imaging (dw-MRI) data. Moreover, persistent homology is proposed to avoid the ad hoc selection of a specific regularization parameter and to capture valuable brain connectivity patterns from the topological perspective. The experimental results demonstrate that our method outperforms the competing methods, and reasonably yields connectomic patterns specific to APOE ε4 carriers and non-carriers. We have proposed a multimodal framework that integrates structural and functional connectivity information for constructing a fused brain network with greater discriminative power. Using persistent homology to extract topological features from the fused brain network, our method can effectively identify APOE ε4-related brain connectomic biomarkers.


Semi-supervised mp-MRI data synthesis with StitchLayer and auxiliary distance maximization.
The availability of a large amount of annotated data is critical for many medical image analysis applications, in particular for those relying on deep learning methods which are known to be data-hungry. However, annotated medical data, especially multimodal data, is often scarce and costly to obtain. In this paper, we address the problem of synthesizing multi-parameter magnetic resonance imaging data (i.e. mp-MRI), which typically consists of Apparent Diffusion Coefficient (ADC) and T2-weighted (T2w) images, containing clinically significant (CS) prostate cancer (PCa) via semi-supervised learning and adversarial learning. Specifically, our synthesizer generates mp-MRI data in a sequential manner: first utilizing a decoder to generate an ADC map from a 128-d latent vector, followed by translating the ADC to the T2w image via U-Net. The synthesizer is trained in a semi-supervised manner. In the supervised training process, a limited amount of paired ADC-T2w images and the corresponding ADC encodings are provided and the synthesizer learns the paired relationship by explicitly minimizing the reconstruction losses between synthetic and real images. To avoid overfitting limited ADC encodings, an unlimited amount of random latent vectors and unpaired ADC-T2w Images are utilized in the unsupervised training process for learning the marginal image distributions of real images. To improve the robustness for training the synthesizer, we decompose the difficult task of generating full-size images into several simpler tasks which generate sub-images only. A StitchLayer is then employed to seamlessly fuse sub-images together in an interlaced manner into a full-size image. In addition, to enforce the synthetic images to indeed contain distinguishable CS PCa lesions, we propose to also maximize an auxiliary distance of Jensen-Shannon divergence (JSD) between CS and nonCS images. Experimental results show that our method can effectively synthesize a large variety of mp-MRI images which contain meaningful CS PCa lesions, display a good visual quality and have the correct paired relationship between the two modalities of a pair. Compared to the state-of-the-art methods based on adversarial learning (Liu and Tuzel, 2016; Costa et al., 2017), our method achieves a significant improvement in terms of both visual quality and several popular quantitative evaluation metrics.


Moderate noise associated oxidative stress with concomitant memory impairment, neuro-inflammation and neurodegeneration.
Noise, a disturbing and unwanted sound is currently being perceived as a widespread environmental stressor. In the present study we investigated the activation of oxidative stress as a mechanism involved in cognitive impairment through changes in neuro-inflammation. Sprague Dawley rats (200-220  g m) were exposed to moderate (100dB) sound pressure level (SPL) noise daily for 2 h s over a period of 15 and 30 days and the consequence on brain regions of hippocampus observed through behavioral studies by Morris Water Maze to assess effects on spatial memory coupled with biochemical evaluation of markers of oxidative stress and inflammation. Further, the underlying mechanism pertaining to apoptosis was investigated by immuno-histological studies through assessment of Caspase-3 and TUNEL assay as well as morphological parameters, namely Nissl bodies in CA1, CA3 and DG regions of hippocampus. Poorer performance in the MWM indicative of decrement in concept formation, attention, working memory, and reference memory was observed on 15 and 30 days of noise exposures. At the cellular level, increased oxidative stress and inflammation was noticed as evinced by elevated levels of TNF-α, IL-6, IL-1α and IFN-γ in both hippocampus and plasma. Exposure to noise also led to a gradual increase in the number of pyknotic and apoptotic neurons together with the increase in DNA fragmentation in hippocampus. Increased levels of inflammatory genes (i.g.) ccl2, ccr5, ifng, il13, il1a, tnfa coupled with decreased levels of bmp2 and il3 genes were found in both the noise exposure groups. Our findings revealed that moderate intensity noise exposure impaired early memory changes in expression of several gene families including genes associated with regulation of transcription, inflammatory response, and, response to oxidative stress.


The transformation-related protein p53 is not bound to the SV40 T antigen in BALB 3T12 cells expressing T antigen.
In most murine cells transformed by the SV40 virus, virtually all of the cellular phosphoprotein p53 is in a complex with the SV40 T antigen. Here, we report that, in SV40-infected T-antigen-positive Balb 3T12 mouse cells, most (approximately 80%) of the p53 is not in complex. Complex formation was determined by measuring the amounts of [35S]methionine-labeled p53 which coprecipitated with T antigen when using monoclonal antibody to T antigen. The amount of complex formation was expressed as a percentage of total p53 present, measured by the amount of p53 precipitated with the monoclonal antibody to the p53. The values were confirmed by Western blotting procedure, in which the steady-state levels of the proteins were measured. In these measurements after complete precipitation with antibody to T antigen, the residual p53 in the supernatant was precipitated by antibody to p53, and this amount was denoted as free p53. There was no significant difference seen between the [35S]methionine-labeled tryptic peptides of complexed and the free p53 (or between complexed and free T antigens) as determined by two-dimensional gel electrophoresis and chromatography. Virus rescue experiments and retransformation by the rescued virus showed that there was no mutation in the SV40 DNA coding for the T antigen which could account for the lack of complex formation. Both p53 and T antigen were underphosphorylated in cells which exhibited reduced complex formation. Tumorigenicity in syngeneic mice and anchorage-independent cell growth in culture of various cloned mouse cells with or without T antigen expression was compared. The changes in the biologic properties were explainable solely on the basis of known or expected effects of expression of the T antigen and were independent of complex formation or of absence of complex formation between p53 and T antigen.


Circadian variation of diazepam acute toxicity in mice.
The LD50 of i.p. injected diazepam was determined every 4 h over a 24-h period in albino mice adapted to a 12-h dark/12-h light programmed illumination cycle. Results show that diazepam is more toxic during the light phase of the cycle than during the dark phase and demonstrate circadian variation in the toxicity of the compound in mice.


Resistant pathogens, fungi, and viruses.
Although originally described in Staphylococcus aureus, resistance among bacteria has now become a race to determine which classes of bacteria will become more resistant. Availability of antibacterial agents has allowed the development of entirely new diseases caused by nonbacterial pathogens, related largely to fungi that are inherently resistant to antibacterials. This article presents the growing body of knowledge of the herpes family of viruses, and their occurrence and consequences in patients with concomitant surgical disease or critical illness. The focus is on previously immunocompetent patients, as the impact of herpes viruses in immunosuppressed patients has received thorough coverage elsewhere.


Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels.
The assumption that antidepressants may reduce suicide risk by reducing depressive symptoms is not based on data. Further, it is unclear if the retrospectively based anti-suicidal effects of lithium can be prospectively evaluated using lithium as an augmenting agent to antidepressants. To verify our hypothesis, we designed and conducted an exploratory proof of concept trial of four weeks duration using a randomized, double-blind, parallel group method. Forty patients were assigned to citalopram + lithium and 40 were assigned to citalopram + placebo. The primary dependent measures were the Sheehan-Suicidality Tracking Scale (S-STS) and the Montgomery-Asberg Depression Rating Scale (MADRS). The reduction of S-STS scores was large (43%) and twice that seen in MADRS scores (25%) among the eighty patients included in the trial. Both response (χ(2) = 8.8, p < 0.01) and remission (χ(2) = 4.6, p = 0.03) rates showed similar patterns. There were no significant differences in mean total S-STS change scores among patients assigned to citalopram with placebo (4.8 ± 5.1) and patients assigned to citalopram with lithium (5.1 ± 5.2). When explored further, a subgroup of the patients assigned to citalopram and lithium achieved therapeutic serum levels and had significantly higher S-STS remission rates (45% compared to 19%, p < 0.05). There were no deaths by suicide or other causes indicating that trials enrolling acutely suicidal patients are feasible. These results suggest that citalopram may have a direct therapeutic effect on suicidal thoughts and behaviors. Further, lithium when used in therapeutic doses may augment such effects. These data warrant further exploration of lithium and an antidepressant combination for anti-suicidal effects.


Whole-cell oxidation of omeprazole sulfide to enantiopure esomeprazole with Lysinibacillus sp. B71.
Production of enantiopure esomeprazole by biocatalysis is of great demand by pharmaceutical industry. A Gram-positive bacterium oxidizing omeprazole sulfide 1a (5-methoxy-2-[((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio]-1H-benzoimidazole) to (S)-sulfoxide esomeprazole 2a (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl]-3H-benzoimidazole was isolated from soil polluted with elemental sulfur. The strain exhibited the highest identity with the genus Lysinibacillus and catalyzed oxidation of 1a into enantiopure esomeprazole with conversion of 77% in a stirred bioreactor, fed-batch culture. No consecutive oxidation of (S)-sulfoxide to sulfone was observed during whole-cell catalysis. The unique characteristics of the catalyst provide a solid basis for further improvement and development of sustainable green bioprocess.


Systems-based approach to examine the cytokine responses in primary mouse lung macrophages infected with low pathogenic avian Influenza virus circulating in South East Asia.
Influenza A virus (IAV) is a major public health concern, being responsible for the death of approximately half a million people each year. Zoonotic transmissions of the virus from swine and avian origin have occurred in the past, and can potentially lead to the emgergence of new IAV stains in future pandemics. Pulmonary macrophages have been implicated in disease severity in the lower airway, and understanding the host response of macrophages infected with avian influenza viruses should provide new therapeutic strategies. We used a systems-based approach to investigate the transcriptome response of primary murine lung macrophages (PMФ) infected with the mouse-adapted H1N1/WSN virus and low pathogenic avian influenza (LPAI) viruses H5N2 and H5N3. The results showed that the LPAI viruses H5N2 and H5N3 can infect PMФ with similar efficiency to the H1N1/WSN virus. While all viruses induced antiviral responses, the H5N3 virus infection resulted in higher expression levels of cytokines and chemokines associated with inflammatory responses. The LPAI H5N2 and H5N3 viruses are able to infect murine lung macrophages. However, the H5N3 virus was associated with increased expression of pro-inflammatory mediators. Although the H5N3 virus it is capable of inducing high levels of cytokines that are associated with inflammation, this property is distinct from its inability to efficiently replicate in a mammalian host.


[Microvascular injury in hyperthermia by injecting warm water using noradrenaline into tumor feeding artery-induced tumor necrosis of Walker-256].
Wistar rats were injected sc, with cells from Walker-256, which is resistant to hyperthermia. When hyperthermia was achieved by immersing the tumor at 44 degrees C for 60 minutes after injecting MMC (0.5 mg/kg), tumor growth was markedly suppressed in D-8 group, which formed many tumor vessels, but was not suppressed in D-4 group, which did not still form them. In D-8 group, 10 ml of warmed water at 44 degrees C using 0.001% of noradrenaline injected into tumor feeding artery after chemotherapy showed enhanced anti tumor effects in established vascularized tumor. These two methods of hyperthermia caused vascular endothelial cell damage that preceded tumor necrosis. These results suggest that hyperthermia exerted an antitumor effect in this tumor model by damaging tumor blood vessels, which led to ischemic tumor necrosis.


Meta-analysis of the efficacy and safety of tirofiban in patients with acute ischaemic stroke undergoing mechanical thrombectomy.
Mechanical thrombectomy is now widely used in acute ischaemic stroke, but its adjunctive antiplatelet aggregation regimen is controversial. This study aimed to investigate the safety and efficacy of tirofiban in patients with acute ischaemic stroke (AIS) who underwent mechanical thrombectomy. We systematically searched Pubmed, Embase, Cochrane Library, and Web of science. Randomized controlled studies and cohort studies comparing the tirofiban group and non-tirofiban group (control group) in patients with AIS who underwent mechanical thrombectomy. The primary safety outcomes were symptomatic intracranial hemorrhage (sICH), 3-month mortality, and re-occlusion rate. The primary efficacy outcomes were good functional outcome (mRS 0-2), excellent functional outcome (mRS 0-1), and successful recanalization (mTICI≥2b). We included 22 studies with a total of 6062 patients. For safety outcomes, the tirofiban group had a non-significantly higher rate of sICH (OR = 0.90, 95 % CI = 0.73-1.10, P = 0.29) and a significantly lower rate of re-occlusion (OR = 0.40, 95 % CI = 0.19-0.82, P = 0.01) and 3-month mortality (OR = 0.71, 95 % CI = 0.61-0.82, P < 0.00001) compared to the control group. In terms of efficacy outcomes, significant improvement in good functional outcomes (mRS 0-2) (OR = 1.24, 95 % CI = 1.11-1.39, P = 0.0002) and recanalization rate (OR = 1.38, 95% CI = 1.17-1.62, P = 0.0001) compared to tirofiban, but not significant improvement in excellent functional outcomes(OR = 1.14, 95 % CI = 0.93-1.39, P = 0.21). In addition, compared with cardiogenic stroke, the large atherosclerotic stroke had a higher rate of good functional outcome (OR = 1.58, 95 % CI = 1.18-2.11, P = 0.002) and a lower rate of 3-month mortality (OR = 0.58, 95 % CI = 0.39-0.85, P = 0.005). Subgroup analysis by route of administration showed a significant improvement in good functional outcome in the intravenous group (OR = 1.27, 95 % CI = 1.08-1.50, P = 0.004), while no significant difference was found between the arterial and arteriovenous groups. Treatment with tirofiban in patients with AIS with mechanical thrombectomy is effective in improving functional prognosis, arterial recanalization rates, and reducing 3-month mortality and re-occlusion rates, particularly in patients with large atherosclerotic stroke, without increasing the rate of symptomatic intracranial hemorrhage. Intravenous administration of tirofiban significantly improves the clinical prognosis compared to arterial administration. Tirofiban is effective and safe in patients with AIS.


Machine learning prediction of sleep stages in dairy cows from heart rate and muscle activity measures.
Sleep is important for cow health and shows promise as a tool for assessing welfare, but methods to accurately distinguish between important sleep stages are difficult and impractical to use with cattle in typical farm environments. The objective of this study was to determine if data from more easily applied non-invasive devices assessing neck muscle activity and heart rate (HR) alone could be used to differentiate between sleep stages. We developed, trained, and compared two machine learning models using neural networks and random forest algorithms to predict sleep stages from 15 variables (features) of the muscle activity and HR data collected from 12 cows in two environments. Using k-fold cross validation we compared the success of the models to the gold standard, Polysomnography (PSG). Overall, both models learned from the data and were able to accurately predict sleep stages from HR and muscle activity alone with classification accuracy in the range of similar human models. Further research is required to validate the models with a larger sample size, but the proposed methodology appears to give an accurate representation of sleep stages in cattle and could consequentially enable future sleep research into conditions affecting cow sleep and welfare.


Isolation and characterization of methylated sugars from the tube of the hydrothermal vent tubiculous annelid worm Alvinella pompejana.
The tube of Alvinella pompejana contains in its carbohydrate fraction, 3 methylated monosaccharides: 2-mono-O-methyl-L-fucose, 3-mono-O-methyl-L-fucose and 2,4-di-O-methyl-L-fucose. The present work appears to be the first report of the occurrence of 2-mono-O-methyl-L-fucose and 3-mono-O-methyl-L-fucose in the animal kingdom. Moreover, it is the first time that 2,4-di-O-methyl-L-fucose is found in nature.


Clinical characteristics, histopathology, and treatment outcomes in adult and pediatric patients with nonspecific orbital inflammation.
To evaluate the clinical characteristics, histopathology, and treatment outcomes in adult and pediatric patients with nonspecific orbital inflammation (NSOI). This retrospective study evaluates 76 patients with NSOI. The patients were categorized in 9 groups according to the site of involvement and histopathology results. These groups included: anterior involvement, dacryoadenitis, myositis, perineural involvement, acute fat involvement, focal mass, orbital apex involvement, diffuse sclerosing form, and multiple tissue involvement. The course of the disease was categorized as acute, subacute, or chronic. The cases with symptom duration of less than 1 week were classified as acute, 1 week to 1 month as subacute, and more than 1 month as chronic. 36 (47.4%) patients were males. The mean age was 41.68 ± 17.62 (6-75) years. The most common signs and symptoms were periorbital pain, periorbital edema, decreased ocular movements or diplopia, and conjunctival injection. The most common group was dacryoadenitis in 29 (38.1%) cases. The most common form of disease was the acute involvement (50% of patients). Most of the patients were treated by oral corticosteroids. Duration of follow-up was 7.17 ± 6.26 months. Recurrence occurred in 9 (11.8%) of patients during the follow-up period. This study presents a new categorization in which multiple tissue involvements were separated. Some of the NSOI features differ between adults and children. In most patients, treatment especially with corticosteroids, resolves the clinical findings.


Cytokine-secreting follicular T cells shape the antibody repertoire.
High-affinity antibodies are critical for host protection and underlie successful vaccines. The generation of such antibodies requires T cell-dependent help, which mediates germinal center reactions in which mutation and selection of B cells occurs. Using an interleukin 4-reporter system, we show here that CD4(+) follicular helper T cells constituted essentially all of the cytokine-secreting T cells in lymph nodes and were functionally distinct from T cells secreting the same cytokine in peripheral tissues. Follicular helper T cells with different cytokine profiles could be isolated as conjugates with B cells undergoing cytokine-specific immunoglobulin class switching with evidence of somatic hypermutation. Our findings support a model in which B cells compete for cytokines produced by follicular helper T cells that shape the affinity and isotype of the antibody response.


Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine.
The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.


Cost-effectiveness analysis of sorafenib, lenvatinib, atezolizumab plus bevacizumab and sintilimab plus bevacizumab for the treatment of advanced hepatocellular carcinoma in China.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, especially in China. According to the 2021 Chinese Society of Clinical Oncology guidelines, sorafenib, lenvatinib, atezolizumab combined with bevacizumab, and sintilimab combined with bevacizumab are recommended as first-line treatment options for advanced HCC. This study provides a cost-effectiveness analysis of these treatments from the patient perspective. A partitioned survival model was established using the TreeAge 2019 software to evaluate the cost-effectiveness. The model includes three states, namely progression-free survival, progressive disease, and death. Clinical data were derived from three randomized controlled studies involving patients with advanced HCC who received the following treatment: sorafenib and lenvatinib (NCT01761266); atezolizumab in combination with bevacizumab (NCT03434379); and sintilimab in combination with bevacizumab (NCT03794440). Cost and clinical preference data were obtained from the literature and interviews with clinicians. All compared with sorafenib therapy, lenvatinib had an incremental cost-effectiveness ratio (ICER) of US$188,625.25 per quality-adjusted life year (QALY) gained; sintilimab plus bevacizumab had an ICER of US$75,150.32 per QALY gained; and atezolizumab plus bevacizumab had an ICER of US$144,513.71 per QALY gained. The probabilistic sensitivity analysis indicated that treatment with sorafenib achieved a 100% probability of cost-effectiveness at a threshold of US$36,600/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the medical insurance reimbursement ratio and drug prices. In this economic evaluation, therapy with lenvatinib, sintilimab plus bevacizumab, and atezolizumab plus bevacizumab generated incremental QALYs compared with sorafenib; however, these regimens were not cost-effective at a willingness-to-pay threshold of US$36,600 per QALY. Therefore, some patients may achieve preferred economic outcomes from these three therapies by tailoring the regimen based on individual patient factors.


Usage of Digital Twins Along a Typical Process Development Cycle.
Digital methods for process design, monitoring, and control can convert classical trial-and-error bioprocess development to a quantitative engineering approach. By interconnecting hardware, software, data, and humans currently untapped process optimization potential can be accessed. The key component within such a framework is a digital twin interacting with its physical process counterpart. In this chapter, we show how digital twin guided process development can be applied on an exemplary microbial cultivation process. The usage of digital twins is described along a typical process development cycle, ranging from early strain characterization to real-time control applications. Along an illustrative case study on microbial upstream bioprocessing, we emphasize that digital twins can integrate entire process development cycles if the digital twin itself and the underlying models are continuously adapted to newly available data. Therefore, the digital twin can be regarded as a powerful knowledge management tool and a decision support system for efficient process development. Its full potential can be deployed in a real-time environment where targeted control actions can further improve process performance.


Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials.
Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24. EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels. EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.


Post-whaling shift in mating tactics in male humpback whales.
Recent studies have shown behavioural plasticity in mating strategies can increase a population's ability to cope with anthropogenic impacts. The eastern Australian humpback whale population was whaled almost to extinction in the 1960s (~200 whales) and has recovered to pre-whaling numbers (>20,000 whales). Using an 18-year dataset, where the population increased from approximately 3,700 to 27,000 whales, we found that as male density increased over time, the use of mating tactics shifted towards more males engaging in non-singing physical competition over singing. Singing was the more successful tactic in earlier post-whaling years whereas non-singing behaviour was the more successful tactic in later years. Together, our study uncovers how changes in both local, and population-level male density resulted in a shift in the frequency, and fitness pay-off, of alternative mating tactics in a wild animal. This individual-level plasticity in male humpback whale mating tactics likely contributed to minimising their risk of extinction following a dramatic change in their social landscape due to whaling.


A new method for the preparation of a purified glucosylceramide and ceramide from shiitake mushroom.
Ingestion of plant and fungal glucosylceramides is known to reduce colon carcinogenesis and skin barrier damage in mice and humans. However, such effects in animal experiments have not been revealed for plant and fungal ceramides because the content of ceramides contained in plants and fungi is so low that the large amount required for animal experiments is difficult to obtain. Noting that the fungus shiitake mushroom (Lentinula edodes) is rich in a glucosylceramide, (4E,8E)-N-d-2'-hydroxypalmitoyl-1-O-β-d-glucopyranosyl-9-methyl-4,8-sphingadienine [Glc-d19:2(4E,8E,9Me)-h16:0], we developed a new method to purify this fungal glucosylceramide using ethanol precipitation and high-performance liquid chromatography. We also developed a new method to produce large amounts of a ceramide [d19:2(4E,8E,9Me)-h16:0] from this purified glucosylceramide using human glycoside hydrolase family 30 glucocerebrosidase (imiglucerase). These methods will be useful for elucidating the physiological function by ingestion of fungal ceramides in animal experiments.


Endoscopic correction of primary vesicoureteric reflux.
One hundred and three children with primary vesicoureteric reflux treated by endoscopic injection of Polytef paste between March 1984 and February 1986 have been followed up for periods ranging from 3 to 23 months. Seventy-five per cent of refluxing ureters showed absence of reflux after one injection of Polytef paste; 14% of ureters required two to four sub-ureteric injections of Polytef paste for the correction of vesicoureteric reflux; 8% of ureters showed improvement in the grade of reflux after the initial injection of Polytef paste. Duplex systems were more difficult to correct and recurrence of reflux was much higher than in primary reflux. Follow-up intravenous urograms showed no evidence of ureteric obstruction in the treated ureters. The procedure is safe, simple and effective in correcting all grades of vesicoureteric reflux. To obtain best results, attention should be paid to minute details of the technique and the injection made with pinpoint accuracy.


Laparoscopy-assisted repair with Ventralex ST Hernia Patch for a small subcostal hernia: A case report.
A 55-year-old woman with a history of right hepatic lobectomy via a Benz incision presented for evaluation of a new abdominal bulge in the right upper quadrant. We diagnosed an incisional hernia, but because we could neither reduce the hernia contents nor locate the orifice, we performed a laparoscopic evaluation. Laparoscopy revealed subcostal herniation of the greater omentum via a 2-cm defect on the caudal side of the right ribs, which we repaired using a Ventralex ST Hernia Patch. Laparoscopic placement of this mesh with straps allowed for reliable deployment, fixation, and confirmation of defect closure, including the cranial aspect-often a major challenge in subcostal hernia repair.


Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.


Prognostic significance of soluble interleukin-2 receptor levels in patients with dilated cardiomyopathy.
Activation of T lymphocytes is thought to mediate myocardial dysfunction in dilated cardiomyopathy (CMP), probably through cytotoxic cytokines, but its value as a prognostic factor has not been evaluated. For 2 years we prospectively followed 76 patients (65 males, 11 females, age 49 +/- 7 years) with CMP and New York Heart Association(NYHA) Class II-III heart failure; left ventricular (LV) function was assessed echocardiographically. Thirty-three patients (28 males, five females, age 52 +/- 6 years) with ischaemic heart disease (IHD) and similar NYHA and LV function characteristics were used as controls. Serum sIL-2R levels, peripheral blood lymphocyte proliferation (basal, + concanavalin A) and HLA-DQB1 genotyping was carried out in all patients. The CMP patients had increased sIL-2R levels (1259 +/- 130 pg mL-1) compared with the IHD patients (703 +/- 80 pg mL-1, P < 0.01, only 3 > 800 pg mL-1). In the CMP patients, there was a significant (r = +0.45, P= 0.04) correlation between sIL-2R and the LV end-diastolic diameter but not with the LV ejection fraction or NYHA Class. During the 24-month follow up, 17 of the CMP patients had an adverse clinical course (death, need for cardiac transplantation, or worsening heart failure). Of these, 14 (75%) had elevated (>or= 800 pg mL-1) sIL-2R levels (Group I) compared with only five (6%) with a stable clinical course (Group II). Neither [3H] thymidine incorporation into the peripheral blood lymphocytes nor the excess of HLA-DQB1-30 histidine homozygotes in the Group I patients (38% vs. 17%, P < 0.05) could predict the clinical outcome. Increased sIL-2R levels in CMP patients are an independent predictor of a more aggressive clinical course.


Hypercalcemia with ovarian carcinoma: evidence of a pathogenetic role for prostaglandins.
A 70-year-old white woman had a lower abdominal mass and hypercalcemia. Physical and radiologic evidence was found for the presence of nonmetastatic pelvic tumor. Biochemical tests confirmed the presence of hypercalcemia with evidence of active bone resorption. Plasma parathyroid hormone (PTH) and the nephrogenic urinary cyclic AMP excretion were low; levels of plasma prostaglandins were elevated. Bone biopsy revealed histologic evidence of extensive osteoclastic bone resorption. At operation, a papillary serous cystadenocarcinoma of the ovary was removed. Postoperatively, the serum calcium fell to normal, and plasma prostaglandins became undetectable. Short-term incubation of ovarian tumor fragments demonstrated the production by tumor tissue of a substance causing bone resorption in an in vitro bioassay. The production of this substance was blocked by indomethacin. Radioimmunoassay of the incubation medium revealed significant amounts of prostaglandins of the E + F series. Parathyroid hormone was not detected in the medium. These data implicate tumor-produced prostaglandins as mediators of the hypercalcemia in this patient.


Past adult lead exposure is linked to neurodegeneration measured by brain MRI.
To determine whether cumulative lead dose in former organolead workers was associated with MRI measures of white matter lesions (WML) and global and structure-specific brain volumes. MRIs, tibia lead, and other measures were obtained from 532 former organolead workers with a mean age of 56 years and a mean of 18 years since last occupational exposure to lead. Cumulative lead dose was measured by tibia lead, obtained by X-ray fluorescence, and expressed as microg lead per gram of bone mineral (microg Pb/g). WML were evaluated using the Cardiovascular Health Study grading scale. A total of 21 global and specific brain regions were evaluated. A total of 36% of individuals had WML grade of 1 to 7 (0 to 9 scale). Increasing peak tibia lead was associated with increasing WML grade (p = 0.004). The adjusted OR for a 1 microg Pb/g increase in tibia lead was 1.042 (95% CI = 1.021, 1.063) for a CHS grade of 5+ (> or = 5 vs < 5). In linear regression, the coefficient for tibia lead was negative for associations with all structures. Higher tibia lead was significantly related to smaller total brain volume, frontal and total gray matter volume, and parietal white matter volume. Of nine smaller specific regions of interest, higher tibia lead was associated with smaller volumes for the cingulate gyrus and insula. These data suggest that cumulative lead dose is associated with persistent brain lesions, and may explain previous findings of a progressive decline in cognitive function.


Rapid reductive-carboxylation of secondary amines, one pot synthesis of N'-(4-11C-methyl)imipramine.
A new rapid high yield synthesis of radiolabeled N'-(4-11C-methyl)imipramine has been developed using a reductive-carboxylation approach, in which 11CO2 is reacted with either N'-trimethylsilyldesimipramine or N'-lithium derivative of desimipramine, followed by lithium aluminum hydride reduction, to give no carrier added or carrier added 11C-labeled imipramine respectively. The final product is characterized by chromatographic and spectroscopic methods.


Psychiatric Comorbidities Are Highly Prevalent in Nonesophageal Eosinophilic Gastrointestinal Diseases.
The prevalence of psychiatric comorbidity in nonesophageal eosinophilic gastrointestinal disorders (EGIDs) has not been studied. We aimed to ascertain the prevalence of psychiatric diagnoses and psychiatric medication use in children, adolescents, and adults with EGIDs and to assess whether psychiatric comorbidity affects clinical presentation. This was a retrospective cohort study of newly diagnosed patients with a nonesophageal EGID at the University of North Carolina from 2008 to 2020. Psychiatric diagnoses and medications were extracted from medical records. We compared the clinical and demographic features of EGID patients with and without psychiatric diagnoses. Of 79 patients (mean 23.3 years of age, 53% male, 78% White) with a nonesophageal EGID diagnosis, 40 (51%) were diagnosed with a comorbid psychiatric disease. Anxiety (37%) and depression (28%) were most common. There were also 40 (51%) patients treated medically for a psychiatric diagnosis. Patients with a psychiatric diagnosis were more commonly ≥18 years of age at the time of EGID diagnosis (odds ratio [OR], 3.95, 95% confidence interval [CI], 1.20-13.02) and had endorsed symptoms of nausea (OR, 5.31; 95% CI, 1.33-21.22) and dysphagia (OR, 4.24; 95% CI, 1.18-15.26). Psychiatric diagnoses were very common in nonesophageal EGID patients with approximately 7 in 10 adults and one-third of children diagnosed. Similar proportions were found for psychiatric medication use. We also found that psychiatric illness may influence age of clinical presentation and symptoms. Providers should assess for concomitant psychiatric comorbidities in EGID patients.


Separation of the enantiomers of some potassium channel activators using an alpha 1-acid glycoprotein column.
The separations of the enantiomers of some 3,4-dihydro-2,2'-dimethyl-2H-1-benzopyrans and a related tetrahydronaphthalene on alpha 1-acid glycoprotein (Chiral-AGP) are presented, together with the results from an investigation of the effects of organic modifier and pH on the separations achieved. The general utility of Chiral-AGP in separating the enantiomers of compounds from this class of antihypertensive agents is demonstrated in this paper.


Photodynamic therapy of choroidal hemangioma in sturge-weber syndrome, with a review of treatments for diffuse and circumscribed choroidal hemangiomas.
We report three new cases of patients with Sturge-Weber Syndrome and symptomatic retinal detachments from diffuse choroidal hemangiomas successfully treated with photodynamic therapy (PDT) and review medical literature on the available treatment options for choroidal hemangiomas. All patients were treated with a single session of PDT with verteporfin infused at a concentration of 6 mg/m(2) and treated for 83 seconds with 689-nm Zeiss laser that was delivered with total energy level of 50 J/cm(2) with an intensity of 600 mW/cm(2). The exudative retinal detachment (RD) and macular edema completely resolved in all cases by 1-4 months after PDT treatment. Visual acuity improved in all three cases with diminished tumor size in the areas of treatment. One case was followed for 5 months, another for 2 years, and the third case for 6 years, with no recurrence of exudative RD. PDT is an effective treatment option for visual deterioration from exudative retinal detachment in patients with diffuse choroidal hemangiomas.


Comparative evaluation of 5 different selective media for Group B Streptococcus screening in pregnant women.
We compared the performances and the cost-effectiveness of 5 selective media for Group B Streptococcus (GBS) screening in vaginal samples from pregnant women. The usefulness of these media is unquestionable for GBS screening; the choice will depend largely on the laboratory organization.


A preliminary observation on auto-cholinergic synapse dysfunction in patients with different types of epilepsy.
Serum anti-acetylcholine receptor antibodies (A AchR Ab) and anti-synaptic premembrane antibodies (A PrM Ab) were measured in 21 patients with absence epilepsy, 21 cases with benign childhood epilepsy with centro-temporal spikes (BCECTs) and 13 cases with atypical epilepsy. Respectively, in five (23.8%), eleven (51.2%) and eight (66.7%) of the above mentioned groups of patients both A AchR Ab and A PrM Ab were found.


Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation.
Middle east respiratory syndrome coronavirus (MERS-CoV) is a fatal pathogen that poses a serious health risk worldwide and especially in the middle east countries. Targeting the MERS-CoV 3-chymotrypsin-like cysteine protease (3CLpro) with small covalent inhibitors is a significant approach to inhibit replication of the virus. The present work includes generating a pharmacophore model based on the X-ray crystal structures of MERS-CoV 3CLpro in complex with two covalently bound inhibitors. In silico screening of covalent chemical database having 31,642 compounds led to the identification of 378 compounds that fulfils the pharmacophore queries. Lipinski rules of five were then applied to select only compounds with the best physiochemical properties for orally bioavailable drugs. 260 compounds were obtained and subjected to covalent docking-based virtual screening to determine their binding energy scores. The top three candidate compounds, which were shown to adapt similar binding modes as the reported covalent ligands were selected. The mechanism and stability of binding of these compounds were confirmed by 100 ns molecular dynamic simulation followed by MM/PBSA binding free energy calculation. The identified compounds can facilitate the rational design of novel covalent inhibitors of MERS-CoV 3CLpro enzyme as anti-MERS CoV drugs.


Accuray CyberKnife image-guided radiosurgical system.
Radiosurgery is the application of radiation therapy in an extremely precise manner. These techniques apply large bioequivalent doses of radiation to a small area in order to destroy tumor cells, while sparing surrounding normal tissues. Radiosurgery has been available for intracranial abnormalities since the 1950s but it has only recently become available to treat tumors outside of the brain and skull base. This article outlines the authors experience with CyberKnife in the treatment of spinal and spine-associated abnormalities.


[Albright's type II osteodystrophy and hypothyroidism due to TSH deficiency. Apropos of a case in a child].
The report is dealing with a 10 year-old girl. The diagnosis of Albright's type II osteodystrophy relied on clinical, radiological and biological symptoms: evocative dysmorphic syndrome and absence of disturbances in the phosphocalcic metabolism. Hypothyroidism was secondary to an isolated defect in TSH, and a TRH stimulation test did not induce an increase in plasma TSH.


A dye-dilution method for the determination of blood flow in Cimino-Brescia arteriovenous fistulae.
In 15 patients with large Cimino-Brescia fistulae, arm blood flow and cardiac output were determined by a dye-dilution technique. The mean blood flow through the arm with the shunt open was 1600 ml per min. On compression of the shunt the appearance time increased by 10 sec and there was a moderate decrease in cardiac output.


The Impact of COVID-19 on Sexual Behavior and Psychosocial Functioning in a Clinical Sample of Men who have Sex with Men Using HIV Pre-exposure Prophylaxis.
The purpose of this study was to evaluate the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on sexual behavior, mental health, and substance use among men who have sex with men (MSM) engaged in pre-exposure prophylaxis (PrEP) care. Generalized linear mixed models and logistic mixed-effect models examined change over time for number of sexual partners, mood, and alcohol consumption. From February 29, 2020 to July 31, 2020, 177 MSM actively engaged in PrEP care were evaluated. The median age was 37 [interquartile range (IQR 30, 51]. Patients in the sample were largely representative of the clinic population and identified as White (73.0%), Black/African American (9.2%), and other race (17.2%), and 11.8% identified as Hispanic/Latino ethnicity. Men reported an average of 2.60 fewer sexual partners (95% CI -4.04, -1.40) during the pandemic compared to pre-COVID-19. Rates of depressive symptoms and alcohol use remained stable and few patients reported substance use. The reduced number of sexual partners may be explained by patients' efforts to reduce risk of exposure to COVID-19 and low rates of psychosocial symptoms may be indicative of only the highest functioning patients continuing to engage in care. Reductions in sexual partners may offset reduced engagement in care and help mitigate risk of HIV and other sexually transmitted infections (STIs).


Long-term cost-effectiveness of weight management in primary care.
As obesity prevalence and health-care costs increase, Health Care providers must prevent and manage obesity cost-effectively. Using the 2006 NICE obesity health economic model, a primary care weight management programme (Counterweight) was analysed, evaluating costs and outcomes associated with weight gain for three obesity-related conditions (type 2 diabetes, coronary heart disease, colon cancer). Sensitivity analyses examined different scenarios of weight loss and background (untreated) weight gain. Mean weight changes in Counterweight attenders was -3 kg and -2.3 kg at 12 and 24 months, both 4 kg below the expected 1 kg/year background weight gain. Counterweight delivery cost was pound59.83 per patient entered. Even assuming drop-outs/non-attenders at 12 months (55%) lost no weight and gained at the background rate, Counterweight was 'dominant' (cost-saving) under 'base-case scenario', where 12-month achieved weight loss was entirely regained over the next 2 years, returning to the expected background weight gain of 1 kg/year. Quality-adjusted Life-Year cost was pound2017 where background weight gain was limited to 0.5 kg/year, and pound2651 at 0.3 kg/year. Under a 'best-case scenario', where weights of 12-month-attenders were assumed thereafter to rise at the background rate, 4 kg below non-intervention trajectory (very close to the observed weight change), Counterweight remained 'dominant' with background weight gains 1 kg, 0.5 kg or 0.3 kg/year. Weight management for obesity in primary care is highly cost-effective even considering only three clinical consequences. Reduced healthcare resources use could offset the total cost of providing the Counterweight Programme, as well as bringing multiple health and Quality of Life benefits.


[Hypoxic tumor cells--target for directed modification of radiosensitivity in radiotherapy].
Two peculiarities of tumor hypoxic cell metabolism developing during adaptation to hypoxia--the lowering of respiratory intensity and a change-over from respiration to glycolysis were considered. They form the basis for tissue radiosensitivity modification in different directions in tumor radiation therapy. The first peculiarity of metabolism makes it possible to use hypoxic gaseous mixtures for the predominant protection of normal tissues, and the second artificial hyperglycemia for a selective enhancement of tumor radiation injuries.


Acute leukemia in children.
Advances in the molecular characterization of leukemic cells have greatly improved the precision of diagnosis and treatment assignment as well as the monitoring of residual disease in both acute lymphoblastic leukemia and acute myeloid leukemia. Currently, specific genetic rearrangements can be identified in as many as 50% of children with either acute lymphoblastic leukemia or acute myeloid leukemia. The genes p16 (or MTS1) and TEL/AML1 are now respectively recognized as the most common tumor suppressor and fusion genes in childhood acute lymphoblastic leukemia. Increasingly, contemporary protocols for the acute leukemias are relying on genetic information to guide treatment decisions. Examples include the use of allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia with the BCR-ABL fusion gene or MLL rearrangement, and for acute myeloid leukemia with monosomy 7; antimetabolite-based therapy for acute lymphoblastic leukemia cases with hyperdiploidy of more than 50 chromosomes (DNA index > or = 1.16); and retinoic acid and anthracycline-containing regimens for the acute promyelocytic acute myeloid leukemia subtype with PML-RARA fusion. Other efforts are being made to reduce the long-term sequelae of treatment. Indeed, extended intrathecal therapy and intensive systemic chemotherapy will, in all likelihood, replace cranial irradiation as subclinical central nervous system therapy for patients with intermediate-risk acute lymphoblastic leukemia, and perhaps even for those with high-risk acute lymphoblastic leukemia. The challenge now is to identify specific treatments for other genetically defined subtypes of leukemia. This goal will be realized only through protocol-based studies employing uniform criteria for defining risk status.


Evaluation of root resorption in the lower incisors after orthodontic treatment of skeletal Class III malocclusion by three-dimensional volumetric measurement with cone-beam computed tomography.
To investigate the volumetric changes of the lower incisor roots in skeletal Class III orthodontic patients with anterior crossbite after premolar extraction therapy. Thirty-six adults, aged 18-28 years, had four-premolar extraction treatment. Pre- and posttreatment cone-beam computed tomography (CBCT) images were used to assess the thickness and height of alveolar bone, root volume, and length. A paired t-test was used to detect changes in root volume and length before and after treatment. Pearson's correlation analysis was applied to estimate the correlation between root volume and dentoskeletal morphology. Both the central and lateral incisors had intrusion and tipping movement after treatment. Compared with pretreatment data, root length decreased significantly. The lingual root volume of root cervical, apical third, and the labial root volume of the root apical third decreased significantly (P < .05), among which the percentage of tooth loss at the tip volume was the highest. The pretreatment height of the alveolar ridge crest, thickness of the alveolar bone, and type of incisor movement were related to the volume and length loss. Volume and length loss in the apical third of the lower incisor roots in skeletal Class III patients treated with a Class III bicuspid extraction pattern is common. The pretreatment height of the alveolar ridge crest, thickness of the alveolar bone, and type of tooth movement are related to the loss.


Stone-built heritage as a proxy archive for long-term historical air quality: A study of weathering crusts on three generations of stone sculptures on Broad Street, Oxford.
Black crusts on historic buildings are mainly known for their aesthetic and deteriorative impacts, yet they also can advance air pollution research. Past air pollutants accumulate in distinct layers of weathering crusts. Recent studies have used these crusts to reconstruct pollution to improve our understanding of its effects on stone-built heritage. However, the majority of the studies provide only coarse resolution reconstruction of pollution, able to distinguish between 'inner = old' and 'outer = modern' crust layers. In contrast, very few studies have linked distinct periods of exposure to pollution variations in the composition of these crusts. Here we address this research gap by developing a finer-scale resolution pollution record. Our study explored the unique configuration of limestone sculptures in central Oxford, which have been exposed over the last 350 years to three different periods of atmospheric pollution; the early Industrial Revolution, the Victorian period and the 20th century. When the first two generations of sculptures were moved to less polluted areas, their 'pollution clocks' were stopped. Here we discuss the potential of investigating the 'pollution clock' recorded in the geochemical makeup of each sculpture generation's weathering crust layers. We found the analysed crusts record clear changes related to the evolution of modes of transport and industrial and technological development in Oxford. Higher levels of Arsenic (As), Selenium (Se) are linked to pollution from coal burning during Victorian times and Lead (Pb) indicated leaded petrol use in modern times. Our work shows that stone-built heritage with a known history of air pollution exposure allows improving the pollution reconstruction resolution of these weathering crusts. The results provide the basis for calibrating long-term geochemical archives. This approach may be used to reconstruct past air quality and has the potential to inform stone weathering research and conservation, in addition to improving the reconstruction of historical pollution.


Anisotropic lattice distortions in biogenic aragonite.
Composite biogenic materials produced by organisms have a complicated design on a nanometre scale. An outstanding example of organic-inorganic composites is provided by mollusc seashells, whose superior mechanical properties are due to their multi-level crystalline hierarchy and the presence of a small amount (0.1-5 wt%) of organic molecules. The presence of organic molecules, among other characteristics, can influence the coherence length for X-ray scattering in biogenic crystals. Here we show the results of synchrotron high-resolution X-ray powder diffraction measurements in biogenic and non-biogenic (geological) aragonite crystals. On applying the Rietveld refinement procedure to the high-resolution diffraction spectra, we were able to extract the aragonite lattice parameters with an accuracy of 10 p.p.m. As a result, we found anisotropic lattice distortions in biogenic aragonite relative to the geological sample, maximum distortion being 0.1% along the c axis of the orthorhombic unit cell. The organic molecules could be a source of these structural distortions in biogenic crystals. This finding may be important to the general understanding of the biomineralization process and the development of bio-inspired 'smart' materials.


Tissue-type plasminogen activator (t-PA) and dilute blood clot lysis time in nephrotic patients.
When compared to normal weight normolipidemic control subjects, dilute blood clot lysis time was found to be obviously (p less than 0.001) prolonged in hypertriglyceridemic patients without proteinuria and slightly (p less than 0.05) accelerated in hyperlipidemic nephrotic patients in spite of their very high levels of plasma fibrinogen. As a result the ratio plasma fibrinogen (mg/dl) per clot lysis time (minutes) was 1.241 +/- 0.08 (X +/- SEM) in control subjects, 0.574 +/- 0.07 in hypertriglyceridemic patients and 2.69 +/- 0.172 in nephrotic patients. This finding suggesting that a larger amount of fibrin is rather readily dispersed from dilute blood clots of nephrotic patients was associated with higher levels of plasma t-PA:Ag (9.45 ng/ml +/- 1.18 in nephrotic patients versus 5.8 ng/ml +/- 1.23 in controls before venous occlusion and respectively 33.1 ng/ml +/- 3.83 versus 20.3 +/- 3.40 in controls after venous occlusion). Plasminogen activator activity of the euglobulins as assessed by the bovine fibrin-agarose plate was significantly higher in nephrotic patients only after venous occlusion. Plasma samples of nephrotic patients exerted a more potent inhibition of fibrinolysis in a urokinase activated system. This effect was, however, mainly due to the high levels of alpha 2 macroglobulin in nephrotic plasma which apparently have little influence on dilute blood clot lysis time.


Fully Integrated Laser Guidance for CT-Based Punctures: A Study in Phantoms and Patients.
To test the hypothesis of equal or even superior applicability and accuracy of a fully integrated, laser-based computed tomography (CT) navigation system compared with conventional CT guidance for percutaneous interventions. CT-guided punctures were first performed in phantoms. Four radiologists with different experience levels (2 residents (L.B., C.D.) and 2 board-certified radiologists (B.M., K.R.) performed 48 punctures using both conventional image-guided and laser-guided approaches. Subsequently, 12 punctures were performed in patients during a clinical pilot trial. Phantom targets required an in-plane or a single-/double-angulated, out-of-plane approach. Planning and intervention time, control scan number, radiation exposure, and accuracy of needle placement (measured by deviation of the needle tip to the designated target) were assessed for each guidance technique and compared (Mann-Whitney U test and t test). Patient interventions were additionally analyzed for applicability in a clinical setting. The application of laser guidance software in the phantom study and in 12 human patients in a clinical setting was both technically and clinically feasible in all cases. The mean planning time (P = .009), intervention time (P = .005), control scan number (P < .001), and radiation exposure (P = .013) significantly decreased for laser-navigated punctures compared with those for conventional CT guidance and especially in punctures with out-of-plane-trajectories. The accuracy significantly increased for laser-guided interventions compared with that for conventional CT (P < .001). Interventional radiologists with differing levels of experience performed faster and more accurate punctures for out-of-plane trajectories in the phantom models, using a new, fully integrated, laser-guided CT software and demonstrated excellent clinical and technical success in initial clinical experiments.


Propofol allergy: assessing for patient risks.
Allergies to certain foods such as soybeans and eggs contraindicate the use of propofol, a short-acting hypnotic medication used by many anesthesia care providers. Understanding the safe use and handling of propofol and communicating known patient allergies to all surgical team members is crucial to providing safe perioperative care. The perioperative nurse's preoperative assessment supports and improves the plan of care for the patient by identifying the patient's risk factors. Obtaining a correct and precise history of allergies, not only to medication but to food, and concise hand-off reporting are essential for patient safety.


Intracerebral tumor and diffuse central nervous system infiltration complicating acute myelogenous leukemia.
An intracerebral space occupying lesion was found in a 20-year-old woman with acute myelogenous leukemia (AML) when she was in complete hematological remission. Computerized tomography of the brain demonstrated the tumor in the roof of the third ventricle and its subsequent resolution after cranial irradiation and intraventricular cytosine-arabinoside. This form of central nervous system complication in AML has not been previously reported.


Vortex chip incorporating an orthogonal turn for size-based isolation of circulating cells.
Size-based label-free separation of rare cells such as CTCs is attractive due to its wider applicability, simpler sample preparation, faster turnaround and better efficiency. Amongst such methods, vortex-trapping based techniques offer high throughput but operate at high flow velocities where the resulting hydrodynamic shear stress is likely to damage cells and compromise their viability for subsequent assays. We present here an orthogonal vortex chip which can carry out size-differentiated trapping at significantly lower (38% of previously reported) velocities. Composed of entry-exit channels that couple orthogonally to a trapping chamber, fluid flow in such configuration results in formation of a vortex which selectively traps larger particles above a critical velocity while smaller particles get ejected with the flow. We call this phenomenon the turn-effect. Critical velocities and optimal architectures for trapping of cells and particles of different sizes are characterized. We explain how shear-gradient lift, centrifugal and Dean flow drag forces contribute to the turn-effect by pushing particles into specific vortex orbits in a size- and velocity-dependent fashion. Selective trapping of human breast cancer cells mixed with whole blood at low concentration is demonstrated. The device shows promising results for gentle isolation of rare cells from blood.


Impaired primary, but not secondary, immune response in breast cancer patients under adjuvant chemotherapy.
The antibody response after vaccination against tick-borne encephalitis (TBE) was studied in patients with breast cancer. Although sex- and age-matched control persons produced high titers of anti-TBE antibodies 2 to 4 weeks after the second of two consecutive vaccinations, patients with breast cancer who were first vaccinated after the start of adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) failed to do so. The lack of anti-TBE antibody production was found not only in patients under CMF chemotherapy, but also in those primarily vaccinated 6 to 12 months after the termination of CMF treatment. Patients with breast cancer who had been vaccinated either before or after the onset of disease, but before the initiation of chemotherapy, were shown to have developed significant anti-TBE antibody titers which persisted throughout the course of adjuvant treatment and could be boostered by revaccination during the course of CMF administration. The authors conclude that patients with breast cancer undergoing adjuvant chemotherapy experience a serious and prolonged defect in primary antibody production, whereas secondary immune responses remain unimpaired.


Impact of coronary artery bypass grafting on various aspects of quality of life.
To prospectively study the improvement in quality of life (QoL) after coronary artery bypass surgery (CABG). Consecutive patients (n = 2121) who underwent CABG at Sahlgrenska University Hospital between 1988 and 1991 received 3 questionnaires for the study of QoL: the Physical Activity Score, the Nottingham Health Profile and the Psychological General Well-being Index, which were responded both before surgery and at 3 months (n = 1059), 1 year (n = 1045) and 2 years (n = 1027) postoperatively. All differences were tested against baseline. The Physical Activity Score improved (mean 4.3 before CABG, 3.1, 3 months after (P < 0.0001), and 2.8, 2 years postoperatively (P < 0.0001)). The Nottingham Health Profile score improved (mean 20.5 before CABG, 11.4, 3 months (P < 0.0001), and 10.4, 2 years postoperatively (P < 0.0001)). The Psychological General Well-being Index improved (mean 91.1 before CABG, 103.8, 3 months (P < 0.0001), and 105.8 (P < 0.0001), 2 years after CABG). The subscale analyses of the Nottingham Health Profile and the Psychological General Well-being Index 2 years after CABG showed the greatest improvement in areas reflecting physical capacity and pain, to be followed by mental qualities. At 2 years after CABG only sexual problems were still markedly frequent, and independent predictors for sexual problems after surgery were preoperative problems (P < 0.00001), male sex (P < 0.0001), and diabetes mellitus (P = 0.0008). QoL was markedly and significantly improved after CABG. The major improvement was seen already at 3 months, with further slight improvement observed 2 years after surgery. The major improvement was found in areas reflecting physical capacity and pain, which is consistent with symptomatic and objective measurements after CABG. In contrast to the overall improvement in QoL sexual problems were still markedly common 2 years after CABG. The mechanism for this is not fully understood and needs further investigation.


Digital Smile Design-An innovative tool in aesthetic dentistry.
A fundamental objective of an aesthetic treatment is the patient's satisfaction and that the outcome of the treatment should meet the patient's expectation of enhancing his/her facial aesthetics and smile. A patient constantly doubting the end result of the treatment, which is an irreversible procedure, can be motivated and educated through Digital Smile Designing (DSD) technique. DSD is a technical tool which is used to design and modify the smile of patients digitally and help them to visualize it beforehand by creating and presenting a digital mockup of their new smile design before the treatment physically starts. It helps in visual communication and involvement of the patients in their own smile design process, thus ensuring predictable treatment outcome and increasing case acceptance. This article reviews the aspects of digital smile designing in aesthetic dental practice pertaining to its use, advantages, limitations and future prospects.


Live Cell Detection of Poly(ADP-Ribose) for Use in Genetic and Genotoxic Compound Screens.
Poly(ADP-ribose) (PAR) is a molecular scaffold that aids in the formation of DNA repair protein complexes. Tools to sensitively quantify PAR in live cells have been lacking. We recently described the LivePAR probe (EGFP fused to the RNF146-encoded WWE PAR binding domain) to measure PAR formation at sites of laser micro-irradiation in live cells. Here, we present two methods that expand on the use of LivePAR and its WWE domain. First, LivePAR enriches in the nucleus of cells following genotoxic challenge. Image quantitation can identify single-cell PAR formation following genotoxic stress at concentrations lower than PAR ELISA or PAR immunoblot, with greater sensitivity to genotoxic stress than CometChip. In a second approach, we used the RNF146-encoded WWE domain to develop a split luciferase probe for analysis in a 96-well plate assay. We then applied these PAR analysis tools to demonstrate their broad applicability. First, we show that both approaches can identify genetic modifications that alter PARylation levels, such as hyper-PARylation in BRCA2-deficient cancer cells. Second, we demonstrate the utility of the WWE split luciferase assay to characterize the cellular response of genotoxins, PARP inhibitors, and PARG inhibitors, thereby providing a screening method to identify PAR modulating compounds.