Biomechanical study of the fixation stability of broken pedicle screws and subsequent strategies.
Pedicles are often broken when screws are inserted into hard pedicles with small diameters or when the diameter of the screw itself is inadequate. However, there is a lack of biomechanical literature that addresses screw loosening as a result of broken pedicles or the resulting salvage of those screws. We performed a novel in vitro study to compare the pullout strength of screws between intact pedicles and two different types of broken pedicles; strategies to prevent screw loosening were also compared. Thirty L4 Sawbones were designed to represent intact pedicles, semi-pedicles, and nonpedicles and were prepared for screw insertion. Three sizes of polyaxial screws (diameter × length dimensions of 6.0 mm × 45 mm, 6.0 mm × 50 mm and 6.5 mm × 45 mm) were independently and randomly distributed into the intact-pedicle group (IP group, n = 30), the semi-pedicle group (SP group, n = 15), or the nonpedicle group (NP group, n = 15). The experiments were conducted across a minimum of five trials for each of the chosen screw sizes. We then analyzed the results of the imaging, pullout testing, and embedded bone volume. Any fractures or defects of the vertebrae caused by screw insertion were excluded from the study. The appropriate screw trajectory and insertional depth were confirmed using axial and sagittal X-ray imaging prior to screw pullout testing. A pullout strength of only 41% to 45% for the SP group and 29% to 39% for the NP group was retained following a broken pedicle. The use of longer or larger-diameter screws appears to be an effective salvaging procedure for the NP group (p < 0.05). The embedded bone volume percentage analysis indicated that, compared to the IP group, 68% to 76% of effective bone embedded into the screw threads in the SP group, and 58% to 65% in the NP group. There was no direct correlation between the pullout strength and the embedded bone volume; however, less effective embedded bone volume was associated with lower pullout strength. This study describes the evolution of the well-established screw pullout test being applied to the broken pedicle Sawbone testing model. The pedicle plays an important role in determining the pullout strength of a screw. However, a salvage procedure that utilizes a longer or larger-diameter screw might be a reliable clinical approach to address broken pedicles.


Highly Efficient Copper-Indium-Selenide Quantum Dot Solar Cells: Suppression of Carrier Recombination by Controlled ZnS Overlayers.
Copper-indium-selenide (CISe) quantum dots (QDs) are a promising alternative to the toxic cadmium- and lead-chalcogenide QDs generally used in photovoltaics due to their low toxicity, narrow band gap, and high absorption coefficient. Here, we demonstrate that the photovoltaic performance of CISe QD-sensitized solar cells (QDSCs) can be greatly enhanced simply by optimizing the thickness of ZnS overlayers on the QD-sensitized TiO2 electrodes. By roughly doubling the thickness of the overlayers compared to the conventional one, conversion efficiency is enhanced by about 40%. Impedance studies reveal that the thick ZnS overlayers do not affect the energetic characteristics of the photoanode, yet enhance the kinetic characteristics, leading to more efficient photovoltaic performance. In particular, both interfacial electron recombination with the electrolyte and nonradiative recombination associated with QDs are significantly reduced. As a result, our best cell yields a conversion efficiency of 8.10% under standard solar illumination, a record high for heavy metal-free QD solar cells to date.


The Role of Ect2 Nuclear RhoGEF Activity in Ovarian Cancer Cell Transformation.
Ect2, a Rho guanine nucleotide exchange factor (RhoGEF), is atypical among RhoGEFs in its predominantly nuclear localization in interphase cells. One current model suggests that Ect2 mislocalization drives cellular transformation by promoting aberrant activation of cytoplasmic Rho family GTPase substrates. However, in ovarian cancers, where Ect2 is both amplified and overexpressed at the mRNA level, we observed that the protein is highly expressed and predominantly nuclear and that nuclear but not cytoplasmic Ect2 increases with advanced disease. Knockdown of Ect2 in ovarian cancer cell lines impaired their anchorage-independent growth without affecting their growth on plastic. Restoration of Ect2 expression rescued the anchorage-independent growth defect, but not if either the DH catalytic domain or the nuclear localization sequences of Ect2 were mutated. These results suggested a novel mechanism whereby Ect2 could drive transformation in ovarian cancer cells by acting as a RhoGEF specifically within the nucleus. Interestingly, Ect2 had an intrinsically distinct GTPase specificity profile in the nucleus versus the cytoplasm. Nuclear Ect2 bound preferentially to Rac1, while cytoplasmic Ect2 bound to RhoA but not Rac. Consistent with nuclear activation of endogenous Rac, Ect2 overexpression was sufficient to recruit Rac effectors to the nucleus, a process that required a functional Ect2 catalytic domain. Furthermore, expression of active nuclearly targeted Rac1 rescued the defect in transformed growth caused by Ect2 knockdown. Our work suggests a novel mechanism of Ect2-driven transformation, identifies subcellular localization as a regulator of GEF specificity, and implicates activation of nuclear Rac1 in cellular transformation.


Promotive effect of ginsenoside Rd on proliferation of neural stem cells in vivo and in vitro.
Ginseng, the root of Panax ginseng C. A. MEYER (Araliaceae), is reputedly known for its nootropic and anti-aging functions and has been widely used to treat various diseases and enhance health for thousands of years in Asia. Recent studies revealed that ginsenoside, responsible for the pharmacological effects of ginseng, can prevent memory loss and improve spatial learning in mice, but underlying mechanisms are still largely unknown. Active neurogenesis in adult hippocampus is closely related to animals' learning and memory ability. The present study aimed to investigate the possible effects of ginsenoside Rd, one of the most effective ingredients in ginseng, on neurogenesis in vivo and in vitro. Adult rats and cultured neural stem cells were treated with ginsenoside Rd at different doses, and the changes in the proliferation and differentiation of neural stem cells were examined by immunohistochemistry and immunocytochemistry. Ginsenoside Rd significantly increased the numbers of BrdU(+) and DCX(+) cells in the hippocampal dentate gyrus but did not affect the ratio of NeuN/BrdU double-labeled cells to the total number of BrdU(+) cells. For cultured neural stem cells, ginsenoside Rd promoted the size and number of neurospheres, increased the number of BrdU(+) and Ki67(+) cells but did not affect the differentiation of neural stem cells into neurons, astrocytes and oligodendrocytes. These results indicate that ginsenoside Rd can enhance the proliferation but not affect the differentiation of neural stem cells in vivo and in vitro.


OPTICAL COHERENCE TOMOGRAPHY FEATURES OF POLYPOIDAL LESION CLOSURE IN POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH AFLIBERCEPT.
To evaluate whether optical coherence tomography (OCT) can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy eyes after 12 months of aflibercept monotherapy. Polypoidal lesion perfusion status, assessed by indocyanine green angiography, is an important anatomical outcome in polypoidal choroidal vasculopathy management. Post hoc data from a prospective randomized, open-label, study in eyes with polypoidal choroidal vasculopathy undergoing monotherapy with aflibercept evaluated PL perfusion status based on indocyanine green angiography (gold standard) and OCT features from baseline to 12 months. Individual PLs (110 in total) from 48 eyes (48 patients) showed at 12 months; 57/110 PLs (51.8%) were closed on indocyanine green angiography. At 12 months, eyes with closed PLs were more likely to have the following OCT features: 1) no subretinal fluid (67.1% vs. 32.9%), 2) smaller pigment epithelial detachment height (67.2 [±43.8] vs. 189.2 [±104.9] μm), 3) densely hyperreflective pigment epithelial detachment contents (84.0% vs. 16.0%), 4) an absence of a hyperreflective ring(64.0% vs. 36.0%), and a 5) indistinct overlying retinal pigment epithelial (71.4% vs. 28.6%) (all P < 0.05). The three highest performing OCT features that differentiated perfused from closed PLs were (1), (3), and (4) (area under the receiver operating characteristic curve 0.85, 0.73, and 0.70, respectively). A combination of these three features achieved an area under the receiver operating characteristic curve of 0.90. Polypoidal lesion closure, an important anatomical treatment outcome in polypoidal choroidal vasculopathy typically defined by indocyanine green angiography, can be accurately detected by specific OCT features.


[Tissue migration of neutrophil granulocytes in the course of antiproliferative treatment in Hodgkin's disease].
The ability of neutrophil granulocytes to mobilization in sterile inflammatory focus was studied in patients with Hodgkin's disease during treatment. Plastic chambers filled with patient's serum were used for this purpose. The migration ability of granulocytes in the group of patients was reduced already before beginning of treatment. It decreased even more 3 days after beginning of cytostatic treatment but on the 7th day the number of cells passing into the inflammatory exudate increased to values observed in healthy subjects. The observed changes were not correlated with fluctuations in the granulocyte count in the peripheral blood observed on the same days. It is suggested that the evaluation of migration ability of granulocytes to the inflammatory focus may provide better information about the defensive mechanisms of the organism than determination of the count of these cells in the peripheral blood.


An active pseudopeptide analog of the leucokinin insect neuropeptide family.
A pseudopeptide analog of the active core of the leucokinin insect neuropeptide family was synthesized and found to retain myotropic activity. No reports of active pseudopeptide analogs of an insect or other invertebrate neuropeptide have previously appeared in the literature. The pseudopeptide (Phe psi [CH2-NH] Phe-Ser-Trp-Gly-NH2) contains a reduced-amide linkage between the two N-terminal Phe residues. Unlike its amide-bond containing counterpart, the activity of the pseudopeptide was not destroyed upon exposure to aminopeptidase M.


Trends and predictions of perioperative transfusion and venous thromboembolism in hepatectomy using a North American Registry.
Studies indicate a link between allogeneic blood transfusion and venous thromboembolism (VTE) post-major surgery. Analyzing trends and predictors of these outcomes after hepatectomy can inform risk management. The American College of Surgeons National Surgical Quality Improvement Program database was used for a retrospective analysis. Primary outcomes were perioperative red blood cell (RBC) transfusion and VTE events within 30 days of hepatectomy. Seven-year trends and predictors were evaluated. Among 29,131 hepatectomy patients, transfusion rates showed no statistically significant decreasing trends (p = .122) from 2014 to 2020 (18.13%-16.71%), while VTE rates showed a downward trend over the 7 years (p = .021); 17.2% received RBC transfusion, with higher rates in surgeries lasting ≥282 min (median: 220 min). Calculated RBC mass [hematocrit (%) × body weight (kg) × 10-5 × 70/ √ (body mass index/22)] at or below 1.5 L substantially increased transfusion odds. VTE was reported postoperatively in 2.6% of cases more frequently in longer cases involving transfusions. The adjusted odds ratio (aOR) of VTE escalated from the shortest operative time to the longest (3.17; 95% confidence interval [CI], 2.37-4.22). The adjusted odds of VTE doubled for transfused patients compared to non-transfused patients (aOR, 2.19; 95% CI, 1.86-2.57). Rates of RBC transfusion and VTE rates hepatectomy have minimally changed in the recent years. VTE prevention is challenging in extended surgeries at increased risk of bleeding and RBC transfusions. Patient-level data on coagulation and thromboprophylaxis can potentially refine risk assessment for postoperative VTE.


Being creative during lockdown: The relationship between creative potential and COVID-19-related psychological distress in narcolepsy type 1.
The national lockdown imposed in several countries to counteract the coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented situation with serious effects on mental health of the general population and of subjects affected by heterogeneous diseases. Considering the positive association between narcoleptic symptoms and creativity, we aimed at exploring the psychological distress associated with COVID-19 restrictions and its relationship with depressive symptoms and creativity in patients with narcolepsy type 1 (NT1). A total of 52 patients with NT1 and 50 healthy controls, who completed a previous study on creativity, were contacted during the first lockdown period to complete an online survey evaluating psychological distress related to the COVID-19 outbreak, sleep quality, narcolepsy and depressive symptoms, and creative abilities. The patients with NT1 showed an improvement in subjective sleepiness while controls reported worsening of sleep quality during the lockdown. Depression and NT1 symptom severity proved significant predictors of COVID-19-related distress. Creative performance, namely generative fluency, turned out to be a favourable moderator in the relationship between depression and patients' distress, reducing the detrimental effect of depression on the patients' wellbeing. On the contrary, creative originality proved to be a disadvantageous moderator in the relationship between NT1 symptom severity and the distress associated with this traumatic event indicating a higher vulnerability to developing COVID-19-related distress, particularly evident in patients displaying higher originality. Overall, these results highlight a crucial role of creativity in patients with NT1, suggesting that creative potential could be used as a protective factor against the development of distress associated with the lockdown.


The commissural pathway and cochlear nucleus bushy neurons: an in vivo intracellular investigation.
A direct commissural connection formed between cochlear nuclei allows information from the contralateral ear to rapidly influence the processing of the ascending auditory signal. Among the neuronal groups proposed to both receive, and contribute to, commissural input is the bushy cell population in the ventral cochlear nucleus (VCN). In this in vivo electrophysiological study we examine the intracellular recordings of bushy neurons during electrical stimulation of the contralateral cochlear nucleus (CN) for evidence of both their contribution to, and input from commissural projections. Activation of the commissural pathway revealed short-latency fast hyperpolarisation in 19.5% of the 41 bushy neurons examined. The hyperpolarising potentials were small in amplitude, displayed a highly variable time course between neurons, and in some cases were eliminated with injection of depolarising current. There was no indication of antidromic activity, or short-latency excitatory potentials. These results suggest that i) bushy neurons do not contribute projections to the commissural connection, and ii) a small portion of bushy neurons are hyperpolarised following commissural stimulation.


The role of Pax-6 in lens regeneration.
Pax-6 is a master regulator of eye development and is expressed in the dorsal and ventral iris during newt lens regeneration. We show that expression of Pax-6 during newt lens regeneration coincides with cell proliferation. By knocking down expression of Pax-6 via treatment with morpholinos, we found that proliferation of iris pigment epithelial cells was dramatically reduced both in vitro and in vivo, and, as a result, lens regeneration was significantly retarded. However, induction of dedifferentiation in the dorsal iris was not inhibited. Pax-6 knockdown early in lens regeneration resulted in inhibition of crystallin expression and retardation of lens fiber induction. Once crystallin expression and differentiation of lens fibers has ensued, however, loss of function of Pax-6 did not affect crystallin expression and lens fiber maintenance, even though the effects on proliferation persisted. These results conclusively show that Pax-6 is associated with distinct early events during lens regeneration, namely control of cell proliferation and subsequent lens fiber differentiation.


[Zheng Classification in Chinese Medicine: from Its Integration with Disease Diagnosis to Clinical Effectiveness Assessment and Combinational New Drug Discovery].
As the core of traditional Chinese medicine theory, Zheng (syndrome, or pattern) classification will promote personalized medicine by changing the clinical diagnosis into a more precise mode when integrating Zheng classification with disease diagnosis approaches. The author adopted rheumatoid arthritis (RA) as a disease model, to explore the scientific fundamentals of Zheng classification based on disease diagnosis using systemic biological approaches and evidence-based medicine design, as well as developed novel approaches on the methodology of clinical effectiveness evaluation on Chinese medicine and R&D of combinational drugs design based on Fu Fang (Chinese herbal formula). Some unique research design and methods are herein introduced.


Development-related mitochondrial properties of retinal pigment epithelium cells derived from hEROs.
To explore the temporal mitochondrial characteristics of retinal pigment epithelium (RPE) cells obtained from human embryonic stem cells (hESC)-derived retinal organoids (hEROs-RPE), to verify the optimal period for using hEROs-RPE as donor cells from the aspect of mitochondria and to optimize RPE cell-based therapeutic strategies for age-related macular degeneration (AMD). RPE cells were obtained from hEROs and from spontaneous differentiation (SD-RPE). The mitochondrial characteristics were analyzed every 20d from day 60 to 160. Mitochondrial quantity was measured by MitoTracker Green staining. Transmission electron microscopy (TEM) was adopted to assess the morphological features of the mitochondria, including their distribution, length, and cristae. Mitochondrial membrane potentials (MMPs) were determined by JC-1 staining and evaluated by flow cytometry, reactive oxygen species (ROS) levels were evaluated by flow cytometry, and adenosine triphosphate (ATP) levels were measured by a luminometer. Differences between two groups were analyzed by the independent-samples t-test, and comparisons among multiple groups were made using one-way ANOVA or Kruskal-Wallis H test when equal variance was not assumed. hEROs-RPE and SD-RPE cells from day 60 to 160 were successfully differentiated from hESCs and expressed RPE markers (Pax6, MITF, Bestrophin-1, RPE65, Cralbp). RPE features, including a cobblestone-like morphology with tight junctions (ZO-1), pigments and microvilli, were also observed in both hEROs-RPE and SD-RPE cells. The mitochondrial quantities of hEROs-RPE and SD-RPE cells both peaked at day 80. However, the cristae of hEROs-RPE mitochondria were less mature and abundant than those of SD-RPE mitochondria at day 80, with hEROs-RPE mitochondria becoming mature at day 100. Both hEROs-RPE and SD-RPE cells showed low ROS levels from day 100 to 140 and maintained a normal MMP during this period. However, hEROs-RPE mitochondria maintained a longer time to produce high levels of ATP (from day 120 to 140) than SD-RPE cells (only day 120). hEROs-RPE mitochondria develop more slowly and maintain a longer time to supply high-level energy than SD-RPE mitochondria. From the mitochondrial perspective, hEROs-RPE cells from day 100 to 140 are an optimal cell source for treating AMD.


Continuous infusions of B domain-truncated recombinant factor VIII, turoctocog alfa, for orthopedic surgery in severe hemophilia A: first case report.
Continuous infusions (CI) of factor (F)VIII are preferable to the conventional bolus injections for the maintenance of consistent FVIII levels during surgery in patients with severe hemophilia A. A third generation, B domain-truncated recombinant FVIII (turoctocog alfa, Novo Nordisk, NovoEight®), was approved for clinical use in 2014. The hemostatic efficacy and safety of bolus injections of turoctocog alfa in patients undergoing surgery have been reported, but no reports on CI therapy have been published. We describe a 43-year-old patient with severe hemophilia A who required arthroscopic synovectomy of the right elbow and arthrodesis of the right ankle. He was treated with a bolus injection of turoctocog alfa (36 IU/kg) immediately before operation, followed by CI (infusion rate; 2.9 IU/kg/h) to maintain FVIII activity > 80 IU/dl throughout the perioperative period. Surgery was completed successfully with uncomplicated hemostatic control. CIs were continued until post-operative day (POD) 4. Further bolus injections were given from POD5. No anti-FVIII inhibitor has been detected post-operation. This case provides important information on CI therapy using turoctocog alfa during surgery for patients with severe hemophilia A.


Machine learning-based analysis of CT radiomics model for prediction of colorectal metachronous liver metastases.
Early identification of patients at risk of developing colorectal liver metastases can help personalizing treatment and improve oncological outcome. The aim of this study was to investigate in patients with colorectal cancer (CRC) whether a machine learning-based radiomics model can predict the occurrence of metachronous metastases. In this multicentre study, the primary staging portal venous phase CT of 91 CRC patients were retrospectively analysed. Two groups were assessed: patients without liver metastases at primary staging, or during follow-up of ≥ 24 months (n = 67) and patients without liver metastases at primary staging but developed metachronous liver metastases < 24 months after primary staging (n = 24). After liver parenchyma segmentation, 1767 radiomics features were extracted for each patient. Three predictive models were constructed based on (1) radiomics features, (2) clinical features and (3) a combination of clinical and radiomics features. Stability of features across hospitals was assessed by the Kruskal-Wallis test and inter-correlated features were removed if their correlation coefficient was higher than 0.9. Bayesian-optimized random forest with wrapper feature selection was used for prediction models. The three predictive models that included radiomics features, clinical features and a combination of radiomics with clinical features resulted in an AUC in the validation cohort of 86% (95%CI 85-87%), 71% (95%CI 69-72%) and 86% (95% CI 85-87%), respectively. A machine learning-based radiomics analysis of routine clinical CT imaging at primary staging can provide valuable biomarkers to identify patients at high risk for developing colorectal liver metastases.


Group Ia synaptic input to fast and slow twitch motor units of cat triceps surae.
1 The characteristics of the group Ia synaptic input to triceps surae motoneurones have been examined in pentobarbitone-anaesthetized cats, using intracellular recording techniques. The mechanical properties of the muscle units innervated by the cells were determined and the motoneurone input resistance values were also measured.2. A significant positive correlation was found between the maximum amplitudes of homonymous composite (electrically evoked) monosynaptic excitatory post-synaptic potentials (EPSPs) and the motoneurone input resistance values across the entire population of units sampled. The same correlation in the case of heteronymous EPSPs was also significant although somewhat less strong.3. The distribution of the amplitudes of unitary miniature EPSPs (mEPSPs) of presumed group Ia origin, elicited by small static stretches of the homonymous muscles, were also studied. A significant positive correlation was found between the median amplitudes of the mEPSP distributions and the input resistance values in the motoneurones studied. Positive correlation was also observed between the amplitudes of the median mEPSPs and the maximum homonymous composite EPSPs in the cells for which both data points were available.4. In each of these correlations, the synaptic potential amplitudes tended to be larger in the relatively high resistance type S (slow twitch muscle unit) motoneurones from both gastrocnemius and soleus motor pools, than in the lower resistance type F (fast twitch muscle unit) gastrocnemius cells.5. Examination of the shape of the homonymous monosynaptic EPSP wave forms in different motoneurones showed that these tended to be significantly longer in duration in type S cells than in type F. This difference could not be entirely accounted for by the relatively small difference in mean time constant values found in types F and S cells.6. The results suggest that the density of group Ia synaptic terminals tends to be higher on type S motoneurones than on the type F cells. Further, cells receiving a relatively high density of group Ia input apparently tend to have a greater proportion of this input distributed to distal membrane regions than is the case in motoneurones receiving a relatively low input density.


Accumulation of unstable periodic orbits and the stickiness in the two-dimensional piecewise linear map.
We investigate the stickiness of the two-dimensional piecewise linear map with a family of marginal unstable periodic orbits (FMUPOs), and show that a series of unstable periodic orbits accumulating to FMUPOs plays a significant role to give rise to the power law correlation of trajectories. We can explicitly specify the sticky zone in which unstable periodic orbits whose stability increases algebraically exist, and find that there exists a hierarchy in accumulating periodic orbits. In particular, the periodic orbits with linearly increasing stability play the role of fundamental cycles as in the hyperbolic systems, which allows us to apply the method of cycle expansion. We also study the recurrence time distribution, especially discussing the position and size of the recurrence region. Following the definition adopted in one-dimensional maps, we show that the recurrence time distribution has an exponential part in the short time regime and an asymptotic power law part. The analysis on the crossover time T(c)(*) between these two regimes implies T(c)(*) approximately -log[micro(R)] where micro(R) denotes the area of the recurrence region.


Study on Microstructural Evolution and Mechanical Properties of Mg-3Sn-1Mn-xLa Alloy by Backward Extrusion.
Mg-3Sn-1Mn-xLa alloy bars were prepared using backward extrusion, and the effects of the La content on the microstructures and mechanical properties of the alloy were systematically studied using an optical microscope (OM), X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), and tensile tests. The results of this research show that the Mg2Sn phases were mainly formed at the α-Mg grain boundaries and within the grains in the Mg-3Sn-1Mn alloy. After adding a certain amount of La, the plate-shaped MgSnLa compounds consisting of Mg17La2, Mg2Sn, and La5Sn3 gradually disappeared in the α-Mg matrix and grain boundaries. With an increase in La content, the Mg2Sn phase in the crystal was gradually refined and spheroidized. When the content of La reached 1.5%, the tensile strength of the alloy reached 300 Mpa and the elongation reached 12.6%, i.e., 25% and 85% increases, respectively, compared to the Mg-3Sn-1Mn alloy. The plate-shaped compound of Mg-3Sn-1Mn-1.5La had an average length of 3000 ± 50 nm, while the width was 350 ± 10 nm. Meanwhile, the extruded alloy's grain size was significantly refined, and there were many small cleavage steps and dimples in the fracture surface of the alloy. When the La content reached 2%, the alloy performance showed a downward trend due to the coarsening of the grains. The formed plate-shaped MgSnLa compounds and Mg2Sn phases were consistent with the α-Mg matrix. They effectively pinned the dislocations and grain boundaries, which is the main reason for strengthening the mechanical properties of extrusion alloys.


Combined high ligation and stab avulsion for varicose veins in an outpatient setting.
In recent years, the transition from radical surgery for the treatment of primary varicose veins has been modified from the previously described high ligation with complete stripping of the greater or lesser saphenous vein. The purpose of the herewith-described technique is to present a less invasive technique that incorporates saphenofemoral ligation with hook avulsion of branch varicosities. Sapheno-femoral ligation with hook avulsion of branch varicosities is carried out under local anesthesia utilizing the tumescent technique with dissection, ligation, and division of the greater saphenous vein and its tributaries. The hook avulsion procedure removes residual diseased venous segments. Patients treated by this combined ligation-hook avulsion approach achieve excellent functional and clinical results associated with a minimal side effect profile. Combined flush sapheno-femoral ligation of normal saphenous veins (< 8 mm in diameter) and hook avulsion of branch tributaries produces excellent functional and cosmetic results with minimal morbidity.


Channeling of the energy and momentum during energetic-ion-driven instabilities in fusion plasmas.
New features of instabilities driven by energetic ions are revealed. It is found that these instabilities can affect plasma heating and rotation by channeling the energy and momentum of the energetic ions to the region where the destabilized waves are damped. Because of the energy channeling, the plasma core may not be heated by the energetic ions even when these ions have a very peaked radial distribution. It is likely that this new phenomenon can explain experiments on the spherical torus NSTX where a broadening of the temperature profile and even a drop of the temperature at the plasma center with increasing injected power were observed during Alfvén instabilities [D. Stutman, Phys. Rev. Lett. 102, 115002 (2009)10.1103/PhysRevLett.102.115002]. The momentum channeling can lead to plasma rotation and frequency chirping due to the Doppler shift varying in time.


Enhancer-trap detection of expression patterns corresponding to the polar coordinate system in the imaginal discs of Drosophila melanogaster.
We have isolated three classes of "enhancertrap" lines of Drosophila in which lacZ expression patterns in the imaginal discs are consistent with the idea of a polar (radial and angular) coordinate system of positional information. In the first class (HZ76), a circular pattern was expressed transiently during the mid-third instar larval stage when the radial components of the coordinate are probably generated. The expression patterns of the second class (HZ84) were sector-shaped and circular in the leg disc, suggesting a correlation with both radial and angular coordinate values. The expression patterns found in the third class (PZ63 and PZ22) were circular and appeared to reflect radial positional values. Expression in the latter two classes always began in the presumptive dorsal region of the leg disc and gradually spread to the ventral region. These developmental profiles of expression suggested the existence of a centre that initiates patterned gene expression in the presumptive dorsal region of the leg disc. The PZ22 line showed transient expression during tarsal segmentation, suggesting its involvement in tarsal segment formation. We have cloned the PZ22 gene and partially determined its sequence. The deduced amino acid sequence contained a zinc finger motif found in DNA/RNA binding proteins. By in situ hybridization, we determined that the PZ22 gene was transcribed in the leg disc in a pattern identical to that of the lacZ expression. In addition, it was expressed transiently in the embryonic mesoderm during mesoderm segmentation. The PZ22 gene, therefore, may function both in mesodermal segmentation in the embryo and in tarsal segmentation in the imaginal disc.


Quantifying the Race Stratified Impact of Socioeconomics on Graft Outcomes in Kidney Transplant Recipients.
Socioeconomic status (SES) is a significant determinant of health outcomes and may be an important component of the causal chain surrounding racial disparities in kidney transplantation. The social adaptability index (SAI) is a validated and quantifiable measure of SES, with a lack of studies analyzing this measure longitudinally or between races. Longitudinal cohort study in adult kidney transplantation transplanted at a single-center between 2005 and 2012. The SAI score includes 5 domains (employment, education, marital status, substance abuse and income), each with a minimum of 0 and maximum of 3 for an aggregate of 0 to 15 (higher score → better SES). One thousand one hundred seventy-one patients were included; 624 (53%) were African American (AA) and 547 were non-AA. African Americans had significantly lower mean baseline SAI scores (AAs 6.5 vs non-AAs 7.8; P < 0.001). Cox regression analysis demonstrated that there was no association between baseline SAI and acute rejection in non-AAs (hazard ratio [HR], 0.92; 95% confidence interval [95% CI], 0.81-1.05), whereas it was a significant predictor of acute rejection in AAs (HR, 0.89; 95% CI, 0.80-0.99). Similarly, a 2-stage approach to joint modelling of time to graft loss and longitudinal SAI did not predict graft loss in non-AAs (HR, 1.01; 95% CI, 0.28-3.62), whereas it was a significant predictor of graft loss in AAs (HR, 0.23; 95% CI, 0.06-0.93). After controlling for confounders, SAI scores were associated with a lower risk of acute rejection and graft loss in AA kidney transplant recipients, whereas neither baseline nor follow-up SAI predicted outcomes in non-AA kidney transplant recipients.


A 136-amino-acid-residue COOH-terminal fragment of colicin A is endowed with ionophoric activity.
DNA regions encoding the various domains of a protein can be expressed as separate entities by inserting at appropriate sites a 'STOP-Shine-Dalgarno-sequence-ATG' cassette encoding a termination codon, a Shine-Dalgano sequence and an initiation codon within the structural gene. This technique has been used to obtain a 137-amino-acid-residue pore-forming protein designated DA70C comprising the final 136-amino-acid-residue COOH-terminal of colicin A preceded by an NH2-terminal methionine. Da70C was correctly expressed but poorly released to the extracellular medium. Its purification involved, as a final step, a partition in Triton X-114 thus demonstrating that hydrophobic regions are exposed in this protein. The ability of DA70C to form ion channels in planar lipid bilayers was investigated and pore properties were analyzed. The results indicate that helices 1-3 of the 204-amino-acid-residue colicin pore-forming domain (containing 10 alpha-helices) are not involved in ion conduction through the channel. However, they are important in maintaining the stability of the soluble state of the COOH-terminal domain.


Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin.
The Forkhead Box transcription factor FoxM1 regulates expression of genes that promote cell cycle progression, and it plays essential roles in the development of liver, lung, prostate and colorectal tumors. Thiazolidinediones (TZDs) activate the peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated nuclear receptor transcription factor. We found that treatment of the human hepatoma cell lines HepG2 and PLC/PRF/5 cells with TZDs leads to inhibition of FoxM1 gene expression. No PPARγ/retinoid X receptor (RXR) consensus DNA binding sites were detected in the FoxM1 promoter extending to -10 kb upstream, and knockdown of PPARγ had no impact on TZD mediated downregulation of FoxM1 expression. Previously, others showed that PPARγ agonists inhibit the expression and DNA-binding activity of the Sp1 transcription factor. Here we show that Sp1 binds to the FoxM1 promoter region and positively regulates FoxM1 transcription, while mithramycin, a chemotherapy drug that specifically binds GC rich sequences in the DNA and inhibits activities of Sp1, inhibits expression of FoxM1. Our data suggest that TZD mediated suppression of Sp1 is responsible for downregulation of FoxM1 gene expression. Inhibition of FoxM1 expression by TZDs provides a new mechanism for TZD mediated negative regulation of cancer cell growth. FoxM1 expression and activity in cancer cells can be targeted using PPARγ agonists or the anti-neoplastic antibiotic mithramycin.


Gene-diet interaction and plasma lipid responses to dietary intervention.
Strategies for disease prevention can have a major impact on people's health. However, major gaps exist in our knowledge with regard to nutritional adequacy, nutrient-disease interactions, nutrient-gene interactions, and effective strategies for implementation of dietary recommendations which have the potential to decrease the disease burden and to contribute to successful aging of the population. Coronary heart disease is one of the major causes of mortality in the world. We have sound evidence that high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease. Lipoprotein concentrations are associated with environmental variables such as diet and lifestyle, but genetics also play a significant role. We have examined polymorphisms at candidate loci to determine their usefulness as markers for dietary responses. A G/A polymorphism 75 bp upstream from the gene encoding apolipoprotein AI (APOA1) has been described in approximately 30% of the population. Our studies show that this polymorphism is associated with variability in the HDL-C response to dietary fat, specifically to polyunsaturated fatty acids (PUFA) in the diet. Carriers of the A allele respond to increases in dietary PUFA with elevations in HDL-C levels, probably due to altered interactions of transcription factors with the mutated promoter. Therefore carriers of the A allele can potentially decrease their atherogenic risk by consuming high-PUFA diets. Likewise, we have examined the interaction between other dietary habits, such as alcohol drinking, and variability at the APOE locus, and have demonstrated that the classical associations between APOE polymorphism and LDL-C levels are observed primarily in those subjects who consume alcohol. Moreover, we have found a subgroup of the population, APOE4 carriers, for whom drinking alcohol may exert detrimental effects on lipid metabolism. This knowledge will contribute towards the development of more effective personalized dietary recommendations.


Functional Mitochondria Are Important for the Effect of Resveratrol.
Resveratrol (Resv) is a polyphenol reported to modulate mitochondrial activity. The aim was to use HeLa and 143B cells to characterize the action of Resv on mitochondrial activity, cell size and proliferation using wild type (WT) and Rho 0 cells deficient in mitochondrial DNA. In both HeLa WT and Rho 0 cells, the oxygen consumption rate (OCR) was increased at 20 µM Resv after 24 h, whereas only a non-significant increase of OCR was observed in 143B WT cells. Resv decreased cell number concentration-dependently in both WT and Rho 0 cell types. An increased cell diameter was observed in HeLa WT, but not in Rho 0 when treated with Resv. Overall, the findings presented indicate that functional mitochondria are a prerequisite for cell enlargement by Resv.


Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcoma in vitro and in vivo.
Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin-like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e., IGF binding proteins (IGFBPs), thereby setting free IGFs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA is associated with various cancers. It is overexpressed and required for proliferation in ES. PAPPA also stimulates normal bone growth. We isolated HLA-A*02:01+/peptide-restricted T cells from A*02:01- healthy donors directed against PAPPA, generated by priming with A*02:01+ PAPPA peptide loaded dendritic cells. After TCR identification, retrovirally TCR transduced CD8+ T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2-/-γc-/- mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity toward HLA-A*02:01+/PAPPA+ ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2-/-γc-/- mice and in vivo engraftment in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells in contrast to controls. Tumors of treated mice revealed tumor-infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a first-rate target for TCR-based immunotherapy of ES.


Leu309 plays a critical role in the encapsulation of substrate protein into the internal cavity of GroEL.
In the crystal structure of the native GroEL.GroES.substrate protein complex from Thermus thermophilus, one GroEL subunit makes contact with two GroES subunits. One contact is through the H-I helices, and the other is through a novel GXXLE region. The side chain of Leu, in the GXXLE region, forms a hydrophobic cluster with residues of the H helix (Shimamura, T., Koike-Takeshita, A., Yokoyama, K., Masui, R., Murai, N., Yoshida, M., Taguchi, H., and Iwata, S. (2004) Structure (Camb.) 12, 1471-1480). Here, we investigated the functional role of Leu in the GXXLE region, using Escherichia coli GroEL. The results are as follows: (i) cross-linking between introduced cysteines confirmed that the GXXLE region in the E. coli GroEL.GroES complex is also in contact with GroES; (ii) when Leu was replaced by Lys (GroEL(L309K)) or other charged residues, chaperone activity was largely lost; (iii) the GroEL(L309K).substrate complex failed to bind GroES to produce a stable GroEL(L309K).GroES.substrate complex, whereas free GroEL(L309K) bound GroES normally; (iv) the GroEL(L309K).GroES.substrate complex was stabilized with BeF(x), but the substrate protein in the complex was readily digested by protease, indicating that it was not properly encapsulated into the internal cavity of the complex. Thus, conformational communication between the two GroES contact sites, the H helix and the GXXLE region (through Leu(309)), appears to play a critical role in encapsulation of the substrate.


Low-molecular-weight heparin prophylaxis 24 to 36 hours after degenerative spine surgery: risk of hemorrhage and venous thromboembolism.
Retrospective review. To assess the safety and efficacy of prophylactic low-molecular-weight heparin (LMWH) started 24 to 36 hours after degenerative spine surgery. Venous thromboembolism (VTE) is a significant postoperative complication best averted with dual mechanical/pharmacological prophylaxis. Pharmacological prophylaxis is widely used in patients with spinal cord injury, but there is no consensus on its role in degenerative spine surgery, particularly after laminectomy with the concurrent risk of epidural hematoma. The literature suggests a small but potentially devastating hemorrhage risk when LMWH is started within 24 hours of spine surgery. An intermediate strategy is delayed LMWH initiation to minimize hemorrhage risk and retain benefits of dual prophylaxis. Operative reports of the senior author were retrospectively reviewed for all cases of cervical and lumbar laminectomy from 2007 to 2011. Single-level decompressions without fusion and all nondegenerative cases were excluded. Baseline and operative details were recorded. Mechanical prophylaxis was used throughout admission, and prophylactic LMWH was started postoperative day 1 at 10 PM. All cases of postoperative hemorrhage (epidural hematoma, superficial hematoma, persistent wound drainage), deep venous thrombosis, and pulmonary embolism were noted. A total of 367 patients underwent multilevel laminectomy or laminectomy and fusion for degenerative disease. VTE risk factors (age >60 yr, smoking, obesity) were common. No patients receiving LMWH 24 to 36 hours after surgery developed postoperative hemorrhage (95% confidence interval: 0-0.8%). Nearly half of the study population underwent lower extremity ultrasonography or chest computed tomography, and acute VTE was diagnosed in 14 patients (3.8%; 95% confidence interval: 2.1-6.3). LMWH prophylaxis seems to carry a very low hemorrhage risk when started 24 to 36 hours after spine surgery. Larger, prospective studies are needed to assess the safety of early delayed LMWH administration more definitively. Even with aggressive prophylaxis, patients undergoing fusion or multilevel laminectomy for degenerative disease are at significant risk for VTE.


The dynamic natural history of cerebral aneurysms from cardiac myxomas: A review of the natural history of myxomatous aneurysms.
We describe two contrasting patients with multiple cerebral aneurysms and a previous history of resected cardiac myxomas with no cardiac recurrence on follow-up echocardiography. Both patients presented with stroke- like symptoms; one with a left visual defect and the other with right hemiplegia. Magnetic resonance imaging of the brain of both patients showed the presence of multiple cerebral aneurysms that was later confirmed on conventional angiography. Both patients' aneurysms were managed conservatively. Serial angiograms were performed during their follow-up, which spanned several years. One patient's aneurysms remained static while the evolution of the other patient's aneurysms displayed a dynamic quality with some increasing in size while others diminished. This is the first description in which some aneurysms progressed while others regressed simultaneously in the same patient. Aneurysms in patients with a history of cardiac myxoma can be active years after primary tumor resection and it is difficult to predict how they will develop. We reviewed the literature of all patients with multiple myxomatous aneurysms who were treated conservatively to better understand the natural history of this rare disease. Long-term follow-up of these patients may be necessary.


[Comparative analysis via data mining on the clinical features of Western medicine and Chinese medicine in diagnosing rheumatoid arthritis].
To compare the clinical characteristics of traditional Chinese medicine (TCM) and Western medicine (WM) in diagnosing rheumatoid arthritis (RA). A total of 85 clinical RA related messages were enacted and classified into 5 sets as pathological locations, quantitative diagnosis, symptomatic descriptions, general status and environment factors. The respective frequency of their presence in the TCM or WM data sets for RA diagnosis collected from MEDLINE and China National Knowledge Infrastructure (CNKI) were analyzed statistically by Chi-square test, and the relationship of some TCM diagnostic factors/conditions with the RA related biological factors was analyzed by co-occurrence-based literature approach of mining. There was significant difference between the diagnostic pattern of WM and TCM (P < 0.01). Compared with that of WM, TCM diagnosis on RA paid more attention to environmental factors and symptomatic descriptions, which showed definite association with the cytokines and neuro-endocrine factors in RA. Examination of environmental factors and symptomatic descriptions for RA diagnosis is one of the important characteristics of TCM treatment in accordance to syndrome differentiation, it has its potential biologic basis. A novel approach is proposed for exploring the characteristics of TCM in diagnosis and observation.


'Optimal' participation: a reflective look.
There is mounting interest by professionals working in the rehabilitation sciences related to the concept of participation, especially given the increasing numbers of individuals worldwide living with chronic illnesses. It is now internationally agreed that participation level is influenced by both personal and environmental factors. The question arises as to the meaning of 'optimal' participation. The main objective of this article is to provide a reflective look at the concept of participation and the meaning of 'optimality' for individuals with and without disability and to explore both in relation to response shift. Similarities in definitions of participation are first examined. Normal participation level is discussed leading to an 'optimal' level based on normality. Cases are used to illustrate normality as well as how 'optimal' participation can be achieved through a transition period despite disabilities caused by a health condition such as a stroke. 'Optimal' participation would rely on a perfect fit between an individual's reality (how activities and roles are actually realised) and expectations of how activities and roles should be accomplished. A transition period, including a response shift, following an acute event or onset of a chronic condition can lead to an optimal participation level despite persisting disabilities. A better understanding of the meaning of optimal participation and its association to response shift is important to clinical practice. Interventions aimed at optimizing participation through assisting clients who are experiencing a response shift can then be designed to maximize participation and concomitantly, quality of life in those with chronic health conditions.


[Relationship between aortic arch shape and blood pressure response after coarctation repair].
The mechanisms of secondary hypertension after repair of coarctation of the aorta are not well understood. Abnormalities of the architecture of the aortic arch and their consequences on blood pressure have not been studied. In order to study the relationship between abnormalities or aortic arch architecture and resting blood pressure ninety-four patients without re-coarctation were followed up prospectively from 1997 to 2004 (mean age 16.9 +/- 8.1 years; mean weight 57.5 +/- 18.3 Kg; interval since surgery 16.3 +/- 5.4 years). All underwent MRI angiography of the thoracic aorta which enabled the abnormalities to be classified in 3 groups: gothic arch, crenellated arch and roman arch. Twenty-four patients (25.5%) were hypertensive and 70 (74.4%) normotensive. There were 40 gothic arches (42.5%). 14 crenellated arches (15%) and 40 roman arches (42.5%). Gothic arches were more commonly observed in the hypertensive patients (18/40, [45%, 95% CI 31-62]) than the crenellated arches (4/14, [28.5%, 95% CI 7-48]) or the roman arches (2/40, [5%, 95% CI 2-12]). Only the gothic arch was independently correlated with hypertension on multivariate analysis. The authors conclude that gothic deformation of the aortic arch is an independent predictive factor of hypertension in patients operated for coarctation with an excellent result on the isthmic region. Patients with a gothic appearance of their aortic arch should be followed up closely.


The diverse expression of the WT1 gene in patients with acquired bone marrow failure syndromes.
Acquired bone marrow failure syndromes (aBMFS) encompass a wide range of diseases. A study to investigate WT1 expression in BM was conducted in 387 patients with aBMFS in China. The WT1 level in patients with aplastic anemia (AA) was significantly lower than that in patients with paroxysmal nocturnal hemoglobinuria (PNH, p = .023) and myelodysplastic syndrome (MDS, p < .001). In addition, the WT1 level in patients with MDS significantly increased as the disease progressed to an advanced stage. Patients with hypoplastic MDS had a differentiated expression level of WT1 compared with that of NSAA (p < .001). Furthermore, post-treatment patients of AA with partial response (PR) or complete response (CR) status had relatively higher WT1 levels than those with naive AA (p = .017, p = .003, respectively). Thus, the WT1 expression level could be a useful genetic marker for routine clinical work in aBMFS.


Buparlisib in combination with tamoxifen in pretreated patients with hormone receptor-positive, HER2-negative advanced breast cancer molecularly stratified for PIK3CA mutations and loss of PTEN expression.
The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor-positive (HR+ ), HER2-negative advanced breast cancer patients after failure of prior endocrine therapy. In this open-label, single-arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100 mg) and tamoxifen (20 mg) once daily on a continuous schedule (28-day cycle) until progression or unacceptable toxicity. Primary endpoint was overall 6-month progression-free survival (PFS) rate. Key secondary endpoints included the 6-month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety. Overall, the 6-month PFS rate was 33.3% (n/N = 7/21, one-sided 95% CI 16.8-100) and median PFS was 6.1 (CI 2.6-10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA-mutated subgroup consistently showed the highest 6-month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk-benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR+ breast cancer. Further biomarker-stratified studies with isoform-specific PI3K inhibitors are warranted. EudraCT No: 2014-000599-24.


Effect of Optical Wedge Rotary on Ablation Efficiency of Femtosecond Laser on Dental Hard Tissue and Restorative Materials.
Objective: Femtosecond laser (fs-laser) is a novel tooth preparation tool but its ablation efficiency is insufficient. The purpose is to establish a new fs-laser tooth ablation method based on a dual-wedges path ablation system, and explore the efficiency of tooth hard tissue and dental restorative materials ablation. Materials and methods: Extracted third molars, pure titanium, cobalt-chromium alloy, gold alloy, and 3Y-zirconia were prepared into samples. These samples were rotary ablated by an fs-laser with dual-wedges. The wavelength was 1030 nm and the pulse duration was 250 fsec. Laser parameters were set as a repetition frequency of 25 kHz, the power percentages as 50% for dental tissues, and 60% for restorative materials. The optical wedge angle was set as 0°, 20°, 40°, 60°, and 80° for restorative materials, 0°, 20°, 30°, 40°, and 60° for enamel, and 0°, 10°, 20°, 30°, and 40°for dentin. Three times of ablation was processed at each parameter to obtain total 90 ablation microcavities of 6 kinds of materials. The diameter, depth, and volume of microcavities were measured by confocal laser microscopy and plotted against optical-wedge-angle in curves of different materials. One-way analysis of variance (ANOVA) was used to test whether the ablation efficiency between different angles was statistically significant. Results: The ablation efficiency of each material at different optical-wedge-angle was statistically significant (p < 0.05) and tends to be correlated. For dental hard tissue, the enamel ablation efficiency was 208.1 times and dentin ablation efficiency were 65.2 times than before when the wedge angle was 40°. For pure titanium, zirconia, cobalt-chromium, and gold alloys, the ablation efficiencies were 3.1, 10.7, 81.5, and 128.8 times than before when the rotation angle was 80°. Conclusions: The ablation efficiency of dental hard tissues and restorative materials was significantly increased with the increase of laser oblique incidence angle. Clinical Trial Registration number: PKUSSIRB-201949124.


A randomized, double-blind study to evaluate the acid-inhibitory effect of vonoprazan (20 mg and 40 mg) in patients with proton-pump inhibitor-resistant erosive esophagitis.
Standard treatment for patients with erosive esophagitis (EE) is proton-pump inhibitors (PPIs), but some patients are resistant to PPIs. We aimed to evaluate the acid-inhibitory effects and efficacy of a novel potassium-competitive acid blocker (vonoprazan) in patients with PPI-resistant EE. This randomized, double-blind, multicenter study of vonoprazan evaluated gastric and esophageal pH over a 24-hour period as the primary endpoint and EE healing rate as the secondary endpoint. Following a 7 to 14-day run-in period (lansoprazole 30 mg treatment), patients with endoscopically confirmed PPI-resistant EE received vonoprazan 20 mg or 40 mg for 8 weeks. Patients were randomized to receive vonoprazan 20 mg (n = 9) or 40 mg (n = 10). Over a 24-hour period; both groups showed a significant increase from baseline in the percentage of time gastric pH ≥ 4, referred to as pH 4 holding time ratio (HTR): an increase from 73.21% to 96.46% in the 20 mg group, and from 69.97% to 100.00% in the 40 mg group. Increases from baseline in esophageal pH 4 HTRs were not significant. The 40 mg group showed greater increases in gastric and esophageal pH 4 HTRs compared with the 20 mg group, but differences between groups were not significant. After 8 weeks' treatment, the healing rate in subjects with baseline EE grades A-D was 60.0% (3/5 patients) in the 20 mg group and 71.4% (5/7 patients) in the 40 mg group. Vonoprazan was generally well tolerated. One patient (40 mg group) experienced four treatment-emergent adverse events (TEAEs) (unrelated to study drug), leading to study discontinuation. Vonoprazan 20 mg and 40 mg effectively inhibited gastric acid secretion over a 24-hour period with significantly increased gastric pH 4 HTR, and resulted in an EE healing rate > 60.0% in this study. Vonoprazan treatment may be valuable for patients with PPI-resistant EE.


Recurrent insulinoma in a 10-year-old boy with Down's syndrome.
An insulinoma is a rare tumour with an incidence of four cases per million per year in adults. The incidence in children is not established. There is limited literature available in children with insulinoma, and only one case is reported in association with Down's syndrome in adults. Insulinoma diagnosis is frequently missed in adults as well as in children. The Whipple triad is the most striking feature although it has limited application in young children. Hypoglycaemia with elevated insulin, C-peptide and absent ketones is highly suggestive of hyperinsulinism. We present a case of 10-year-old boy with Down's syndrome with recurrent insulinoma. He was initially misdiagnosed as having an adrenal insufficiency and developed cushingoid features and obesity secondary to hydrocortisone treatment and excessive sugar intake. The tumour was successfully localised in the head of the pancreas with an MRI and octreotide scan on first presentation. Medical treatment with diazoxide and octreotide could not achieve normal blood glucose levels. The insulinoma was laparoscopically enucleated and pathological examination confirmed a neuroendocrine tumour. Subsequently, he had complete resolution of symptoms. He had a recurrence after 2 years with frequent episodes of hypoglycaemia. The biochemical workup was suggestive of hyperinsulinism. MRI and PET scan confirmed the recurrence at the same site (head of the pancreas). He had an open laparotomy for insulinoma resection. The pathology was consistent with benign insulinoma, and subsequently, he had complete resolution of symptoms. Insulinoma is a very rare tumour in children; it should be considered in the differential diagnosis of hypoglycaemia with absent ketones.Refractory neurological symptoms like seizure, migraine, mood changes and regression of learning abilities should suggest evaluation for hypoglycaemia.MRI with contrast and PET scan would localise the majority of pancreatic beta islet cell lesions.Medical treatment with diazoxide, octreotide and the addition of corn starch in feeds is not curative but can be supportive to maintain normoglycemia until the surgical resection.Surgical resection is the only curative treatment. The surgical procedure of choice (laparoscopic/open laparotomy) depends on local expertise, preoperative localisation, tumour size and number.Surgical treatment results in complete resolution of symptoms, but all cases should be closely followed up to monitor for recurrence. The recurrence rate is four times higher in MEN1 cases.


[Hip replacement].
Total hip replacement is widely in use all over the world. It is an extremely beneficial procedure. But some requirements must be fulfilled: an excellent indication, a good technique and a special choice of the material in use. For elderly patients less demanding, regular metal on polyethylene cemented implants are still in use. For younger patients, more sophisticated materials like ceramic on ceramic, or metal on metal seem to be more appropriate. The way the prosthesis is stabilized, using or not cement, is also of marked importance. Many other details are relevant: the approach, the surgical technique, the way the patients are followed, the survivorship analysis which can predict partially the outcome in the future for a given prosthesis.


Full-spectrum volumetric solar thermal conversion via photonic nanofluids.
Volumetric solar thermal conversion is an emerging technique for a plethora of applications such as solar thermal power generation, desalination, and solar water splitting. However, achieving broadband solar thermal absorption via dilute nanofluids is still a daunting challenge. In this work, full-spectrum volumetric solar thermal conversion is demonstrated over a thin layer of the proposed 'photonic nanofluids'. The underlying mechanism is found to be the photonic superposition of core resonances, shell plasmons, and core-shell resonances at different wavelengths, whose coexistence is enabled by the broken symmetry of specially designed composite nanoparticles, i.e., Janus nanoparticles. The solar thermal conversion efficiency can be improved by 10.8% compared with core-shell nanofluids. The extinction coefficient of Janus dimers with various configurations is also investigated to unveil the effects of particle couplings. This work provides the possibility to achieve full-spectrum volumetric solar thermal conversion, and may have potential applications in efficient solar energy harvesting and utilization.


Self-esteem before and after treatment in children with nocturnal enuresis and urinary incontinence.
A case control study was designed to study self-esteem in children with nocturnal enuresis and daytime incontinence. The patients and the controls were recruited from the normal population in the town of Umeå, Sweden. Medical and psychological examinations were performed before the start of treatment. Follow up investigations were carried out at 3 and 6 months after starting treatment. Self-esteem was measured using a Swedish self-answering questionnaire that was known to have good psychometric properties. Statistically significant impairment of self-esteem was observed between patients and control children before starting treatment (P < 0.001). After 6 months treatment, the patients had the same levels of self-esteem as the control group. Self-esteem was significantly better in patients that were totally dry at 6 months follow up compared with the patients with persisting urinary problems (P < 0.01). Children from lower socioeconomic groups were found to have lower self-esteem than children from higher socioeconomic groups; boys were also found to have lower self-esteem than girls.


Presence of natural anti-Galalpha1-4GalNAcbeta1-3Gal (anti-NOR) antibodies in animal sera.
Rare polyagglutinable NOR erythrocytes contain unusual globoside extention products terminating with a Galalpha1-4GalNAcbeta1-3Gal- unit. This trisaccharide epitope is recognized by recently characterized antibodies naturally occurring in most human sera (Duk et al., Glycobiology, 15, 109, 2005). These antibodies represent two major types of fine specificity. All these antibodies are most strongly inhibited by Galalpha1-4GalNAcbeta1-3Gal (NOR-tri), and weakly by Galalpha1-4Gal. However, the type 1 antibodies are strongly inhibited by Galalpha1-4Galbeta1-3Gal-R and weakly by Galalpha1-4GalNAc, while the type 2 antibodies show the opposite reactivities with these two oligosaccharides. Similar antibodies have now been found in horse, rabbit and pig sera. The antibodies were purified from animal sera by affinity chromatography on Galalpha1-4GalNAcbeta1-3Gal-human serum albumin(HSA)-Sepharose 4B conjugate. The specificity of the antibodies was determined by binding to ELISA plates coated with several alpha-galactosylated oligosaccharide-polyacrylamide (PAA) or -HSA conjugates and by inhibition with synthetic oligosaccharides. The purified antibodies bound specifically to conjugates containing NOR-tri. The inhibition of binding showed that the animal sera also contain two types of anti-NOR antibodies: type 2 was found in the horse serum, and a mixture of both types was present in rabbit and pig serum. These results indicate that anti-NOR, a new and distinct kind of anti-alphaGal antibody, are present in animal sera and show similar specificties and diversity as their counterparts found in human sera.


Characteristics of patients with Banff borderline changes in renal allograft biopsies.
The aim of this retrospective study was to characterize the patients who experienced borderline rejection. Patients with a minimum follow-up of 2 years were enrolled in this study. Forty-seven patients out of 106 patients with borderline rejection (after exclusion of those with associated chronic interstitial fibrosis) were compared with patients with acute cellular rejection grade 1 (n = 650), and patients free of rejection episodes (n = 444) regarding the different characteristics. Patients aged 20 years or younger were frequently in borderline rejection group than other groups (which was statistically significant) (P = .001). Significant differences were found in recipient and donor ages, consanguinity, pretransplant blood transfusion, and immunosuppression plan. Most patients in borderline rejection group received triple immunosuppression therapy than other groups (P = .001). Univariate and multivariate regression analysis of different variables on graft survival in borderline rejection patients revealed that none of them was statistically significant. Borderline rejection is a frequent finding in biopsy-proven acute rejection after kidney transplant. Time of occurrence, frequency, treatment or not, and response to therapy were not predictors to graft survival.


Increase of cardiac M2-muscarinic receptor gene expression in type-1 but not in type-2 diabetic rats.
Changes of cardiac M2-muscarinic receptor (M2-mAChR) gene expression was investigated in type-1 like diabetic rats induced by intravenous injection of streptozotocin (STZ) and type-2 like diabetic rats induced by fed with fructose-rich chow. Systolic blood pressure (SBP) in STZ-diabetic rats was significantly lower than that in age-matched non-diabetic rats, while the SBP in type-2 like diabetic rats was higher than in non-diabetic rats. Also, the mRNA or protein level of cardiac M2-mAChR in STZ-diabetic rats was markedly higher than non-diabetic rats, but it was not observed in type-2 like diabetic rats as compared to age-matched non-diabetic rats. Arecaidine propargyl ester (APE), the agonist of M2-mAChR, produced a marked reduction of heart rate in STZ-diabetic rats but made less influence on heart rate in fructose-fed rats or non-diabetic rats. The results suggest that cardiac M2-mAChR gene expression is raised in type-1 like diabetic rats but not in type-2 like diabetic rats, this difference mainly due to hyperglycemia, for the production of hypotension in diabetic disorders.


Interdisciplinary approach for treating a large through-and-through periapical defect using guided tissue regeneration: a case report.
A number of diagnostic and management challenges exist for achieving complete regeneration of large through-and-through periapical lesions. An unfavorable endodontic outcome may occur as a result of uncontrolled infection or unpredictable bone healing. This article presents a case with a 15 × 15-mm through-and-through periapical lesion and persistent gingival swelling. Endodontic microsurgery and guided tissue regeneration were performed using a resorbable membrane and osseous substitute. A 2-year postoperative radiograph revealed complete resolution of the periapical radiolucency. Seven-year clinical and radiographic follow-up showed that the tooth was asymptomatic and a long-term successful outcome had been maintained.


Relationship between Metabolic Syndrome Components and Severity of Asthma in Outpatients Referring to Alzahra Hospital Clinic.
Metabolic syndrome is the most common problem worldwide associated with numerous complications. Some studies indicated that metabolic syndrome is associated with asthma; therefore, this study aimed to investigate the possible relationship between metabolic syndrome components and severity of asthma in outpatients referring to Alzahra Hospital in Isfahan, Iran. This descriptive cross-sectional study was performed on 200 patients with asthma referring to Alzahra Lung Clinic in Isfahan, Iran, within 2018-2020. The severity of asthma was evaluated by the Guidelines for the Diagnosis and Management of Asthma by the National Institutes of Health. The association between different categories of asthma severity and metabolic syndrome was investigated. The patients were divided into four categories according to the severity of asthma, including intermittent (n=63), mild (n=63), moderate (n=56), and severe (n=18). Moreover, 38.5% (n=77) of patients had metabolic syndrome, and there was no significant relationship between different categories of asthma severity and metabolic syndrome (P=0.73). The prevalence of metabolic syndrome is high among patients with asthma; however, there was no significant relationship between metabolic syndrome and different categories of asthma severity.


[Diagnostic and therapeutic approach to progressive sensorineural hearing loss].
Progressive sensorineural hearing loss (PSNHL) is an important clinical entity that can develop rapidly and evolve to deafness. The causes of PSNHL can be divided into hereditary, developmental, infectious, autoimmune, metabolic, vascular, neoplastic, toxic and degenerative, even if the origin of the hearing impairment often remains unknown and a diagnosis of idiopathic PSNHL is made. In order to establish the etiology of the hypoacusia or to rule out any known etiology of PSNHL and to diagnose an idiopathic form, a detailed family, physiological and medical history has to be obtained, including history of pregnancies. A careful audiological and otoneurological evaluation should also be carried out, followed by laboratory tests. Furthermore, a complete otoneurological evaluation is required, with puretone audiometry, speech audiometry, impedance audiometry and study of the stapedial reflex, brainstem auditory evoked potentials and vestibular examination. Finally, patients with PSNHL must undergo neuroradiological examination (computerized tomography of petrosal bone, cerebral magnetic resonance and inner ear magnetic resonance); ophthalmological, rheumatological and neuropsychiatric (in childhood) advices should be sought, while other advices may be required on the basis of a particular clinical suspicion. When the etiology is established, therapy must be based on specific treatment for the cause of the hearing deficit; for example, hormonal therapy in alterations of thyroid function, antibiotic treatment in bacterial infections, calcium-antagonist and antiaggregant drugs in the vascular forms, corticosteroids or cyclophosphamide or other immunosuppressive drugs in PSNHL associated with systemic autoimmune diseases. In idiopathic hearing loss, treatment must be started in the absence of important contraindications. The therapeutic protocol that we use in such cases is the following: methylprednisolone boluses, 500 mg/day for three consecutive days, and subsequently oral treatment gradually tapering off in association with a cycle of hyperbaric therapy. Patients showing clinical and historical indications are also treated with intravenous glicerolo, calciparina and/or antiaggregant and calcium-antagonist drugs.


Cephalometric assessment of patients with adenoidal faces.
To evaluate the dentofacial morphology of adenoidal faces via linear and angular measurements on lateral cephalometric tracings and compare the extent of changes with control group. A cross sectional study was conducted from January to July 2007 at the Department of Orthodontics, de'Montmorency Institute of Dental Sciences/Punjab Dental Hospital, Lahore (tertiary health center). As a non probability purposive sampling, total of 90 cephalometric radiographs of subjects (12 to 17 years of age) 45 with adenoidal faces and 45 subjects having normal class I and orthognathic profile were collected and utilized in the study. Subject with cranio-facial anomalies and syndromes, history of previous orthodontic treatment or trauma to the head and neck region were excluded. The collected data was entered on SPSS version 10 and analyzed by using, Paired 't' test. Significant difference is seen among the readings showing a drastically vertical pattern of growth in dentofacial complex, except the palatal inclination angle. The findings suggest that the subjects with upper airway obstruction display excessive vertical dentofacial development, leading to a long face appearance. The condition needs to be prevented by early recognition and treatment of the causative factor.


Pd-Xantphos-catalyzed direct arylation of nucleosides.
Direct arylation of the exocyclic amino groups of nucleosides represents a simple approach to N-aryl nucleoside derivatives. To date, one limitation has been that only electron-deficient aryl bromides and triflates possessed adequate reactivity for efficient, direct N-arylation of nucleosides. We demonstrate herein that Pd-Xantphos catalytic systems lead to successful N-arylation of suitably protected 2'-deoxyadenosine and 2'-deoxyguanosine with a wide range of aryl bromides.


Therapy for unresectable recurrent and in-transit extremity melanoma.
Unresectable recurrent and in-transit extremity melanoma presents a dilemma for the treating physician. While the disease is confined to the involved limb, the survival mimics that of multiple nodal metastases, with a 10-year survival rate of approximately 40%. This represents late-stage disease for which curative treatment options are limited. To review the current treatment strategies for stage IIIB (N2c) in-transit and recurrent melanoma focusing on the options for unresectable disease, MEDLINE was searched for studies of known and experimental treatments for in-transit and recurrent extremity melanoma. Further results were obtained after review of the initial citations. For unresectable recurrences and in-transit metastases, therapies are limited to palliative (radiation), local (intratumoral injection, laser ablation and electroporation), regional (isolated limb perfusion/infusion), and systemic (chemotherapy) when local or regional techniques are not feasible. In this patient population, intratumoral techniques have a limited role with current treatment regimens, but with the development of new drugs, these techniques may have more utility. If not contraindicated, regional techniques provide the greatest control and have minimal operative morbidity. Until new regimens are available, systemic therapy continues to be associated with considerable toxicity and only marginal response rates.


Phonognatha vicitra Sherriffs, 1928-a taxonomic misidentification of the orb-weaving spider Acusilas coccineus Simon, 1895 (Araneae, Araneidae).
The species described as Phonognatha vicitra Sherriffs, 1928 is the only representative of the genus Phonognatha Simon, 1894 in India (World Spider Catalog 2018). The type locality of this species was a coffee estate named Charlotte estate/division, which is located adjacent to the Cauvery River in the Siddapura/ Sidapur village in the Kodagu (Coorg) district of the southwest Indian state of Karnataka (Sherriffs 1928). The species is still known from its original description, which is based on seven female specimens, and its male genitalia remained unveiled. For redescribing this species, we had visited the Charlotte estate/division and collected topotype materials of P. vicitra. However, while examining the materials, we found that the specimens from the Charlotte estate/division indeed belong to the South East Asian orb-weaving spider genus Acusilas Simon, 1895, indicating that Sherriffs misplaced his species in Phonognatha. In the present paper, we propose to transfer P. vicitra to Acusilas and synonymise it with Acusilas coccineus Simon, 1895.


The gut microbiome modulates gut-brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression.
Emerging research demonstrates that microbiota-gut-brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut-brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axis' role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism.


Fragmentation of propionitrile (CH3CH2CN) by low energy electrons.
Propionitrile (CH3CH2CN, PN) is a molecule relevant for interstellar chemistry. There is credible evidence that anions, molecules, and radicals that may originate from PN could also be involved in the formation of more complex organic compounds. In the present investigation, dissociative electron attachment to CH3CH2CN has been studied in a crossed electron-molecular beam experiment in the electron energy range of about 0-15 eV. In the experiment, seven anionic species were detected: C3H4N-, C3H3N-, C3H2N-, C2H2N-, C2HN-, C2N-, and CN-. The anion formation is most efficient for CN- and anions originating from the dehydrogenation of the parent molecule. A discussion of possible reaction channels for all measured negative ions is provided. The experimental results are compared with calculations of thermochemical thresholds of the detected anions.


Photoreceptor cells of the pike pineal organ as cellular circadian oscillators.
In the pike pineal, the rhythm of melatonin (MEL) secretion is driven by a population of cellular circadian oscillators, synchronized by the 24 h light/dark (LD) cycle. Because the pineal photoreceptor contains both the input and output pathways of the clock, this cell is likely to be a cellular circadian system by itself. To support this idea, we have dissociated and cultured pike pineal cells as well as purified photoreceptors. In culture, the pineal cells reassociated in follicles, surrounded by collagen fibres. At the electron microscopic level, they appeared well preserved. Total cells consisted mainly of photoreceptors and glia. Purified cells corresponded exclusively to photoreceptors. Under LD, MEL production was rhythmic. Under constant darkness (DD), the rhythm was well sustained for at least six 24 h cycles (tau = 24/27 h) with 1 x 10(6) total cells/well or below; with 2 x 10(6) total cells/well, a strong damping occurred towards high levels as soon as after the second cycle. At the density of 0.5 x 10(6) cells/well, purified photoreceptors produced less MEL than an equivalent amount of total cells. However, the pattern of the oscillations was similar to that observed with 2 x 10(6) total cells, i.e. a damping occurred rapidly. Decreasing the density to 0.125 x 10(6) photoreceptors/well resulted in a loss of homogeneity among replicates. The production of melatonin by single photoreceptors was monitored by means of the reverse haemolytic plaque assay. Both under LD and under DD, the number of photoreceptors releasing melatonin was higher during the (subjective) dark than during the (subjective) light. The results provide strong support to the idea that the pike pineal photoreceptor is a cellular circadian system. Expression of the oscillations seemed to depend on several factors, including cell to cell contacts between photoreceptors. There is indication that also MEL and glia might be involved.


Prevalence of HIV, syphilis, HCV and their high risk behaviors among migrant workers in eastern China.
The goal of this study was to understand the knowledge about AIDS, identify the correlates and determine the prevalence of HIV infection, syphilis, HCV among migrant workers in Zhejiang, China. A cross-sectional study using face-to-face anonymous questionnaire interviews was conducted and blood samples were collected for HIV, syphilis and Hepatitis C infection screening. 17,377 (92.8%) of 18,730 migrant workers approached were interviewed. Among 17,377 participants, the HIV/AIDS knowledge rate was 66.2%. A total of 12,694 (73%) of the participants reported having ever had sexual intercourse, with 30.1% of single participants reporting having had sexual intercourse. Among those respondents with sexual experiences, 7.5% admitted they had two or more sexual partners and 4.9% reported having had sex with casual (unpaid) partners in the previous 12 months, whilst 3.7% had paid for sex. More than half of those who had paid for sex (59.4%) had not used a condom every time in their sexual acts with the sex workers. Multiple logistic regression analysis indicated that high risk sexual behavior (defined as sex with a casual or commercial sex partner without using a condom consistently) was associated with being divorced or widowed (P<0.05 for single); male gender; shorter duration of stay in Zhejiang; working in factory, market or domestic service (P<0.05 for odd job); having a province of origin inside Zhejiang; and drug use. The prevalence of HIV and HCV infections were 0.02% (95% CI: 0.01%-0.06%) and 0.40% (95%CI: 0.31%-0.51%), respectively. The prevalence of syphilis among those who were sexually active was 0.55% (95% CI: 0.43%-0.70%). Risk factors for syphilis included shorter duration of stay in Zhejiang, ethnic minority status, being divorced or widowed and having had multiple sex partners. Much greater efforts are needed to promote safer sex, and programs for the control of syphilis need to be tailored for migrant workers in China.


The influence of socio-demographic and clinical factors on sick leave and return to work after open-heart surgery: a nationwide registry-based cohort study.
To estimate sick leave (SL) duration after first-time elective open-heart surgery and identify factors contributing to increased SL. A retrospective nationwide cohort study combined data from the Norwegian Register for Cardiac Surgery and SL data from the Norwegian Labour and Welfare Administrations. All able-bodied adults who underwent first-time elective open-heart surgery in Norway between 2012 and 2021 were followed until one year after surgery. The impact of socio-demographic and clinical factors on SL after surgery was analysed using logistic regression and odds ratios. Of 5456 patients, 1643 (30.1%), 1798 (33.0%), 971 (17.8%), 1035 (18.9%), and 9 (0.2%) had SL of <3, 3-6, 6-9, and 9-12 months, and one year, respectively. SL > 6 months was associated with female gender, primary education only, and average annual income. Postoperative stroke, postoperative renal failure, New York Heart Association Functional Classification system (NYHA) score > 3, earlier myocardial infarction, and diabetes mellitus increased the odds of SL > 6 months. This study demonstrates that socio-demographic and clinical factors impact SL after first-time elective open-heart surgery. Patients who experience a stroke or develop renal failure after surgery have the highest odds of SL > 6 months. Females and patients with low education levels, earlier myocardial infarction, or NYHA scores III-IV have a twofold chance of SL > 6 months. The findings allow for future investigations of pre- and post-surgery interventions that can most effectively reduce SL and aid return to work.


Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid.
The case of a 12-year-old boy with anaplastic astrocytoma of the left thalamus is reported. Postoperative irradiation and chemotherapy could not repress tumor progression; therefore, treatment was undertaken with an oncolytic virus, MTH-68/H, an attenuated strain of Newcastle disease virus (NDV), and valproic acid (VPA), an antiepileptic drug, which also has antineoplastic properties. This treatment resulted in a far-reaching regression of the thalamic glioma, but 4 months later a new tumor manifestation, an extension of the thalamic tumor, appeared in the wall of the IVth ventricle, which required a second neurosurgical intervention. Under continuous MTH-68/H - VPA administration the thalamic tumor remained under control, but the rhombencephalic one progressed relentlessly and led to the fatal outcome. In the final stage, a third tumor manifestation appeared in the left temporal lobe. The possible reasons for the antagonistic behavior of the three manifestations of the same type of glioma to the initially most successful therapy are discussed. The comparative histological study of the thalamic and rhombencephalic tumor manifestations revealed that MTH-68/H treatment induces, similar to in vitro observations, a massive apoptotic tumor cell decline. In the rhombencephalic tumor, in and around the declining tumor cells, NDV antigen could be demonstrated immunohistochemically, and virus particles have been found in the cytoplasm of tumor cells at electron microscopic investigation. These findings document that the oncolytic effect of MTH-68/H treatment is the direct consequence of virus presence and replication in the neoplastic cells. This is the first demonstration of NDV constituents in an MTH-68/H -treated glioma.


Modulation of oxidative and glycolytic skeletal muscle fibers Na+/H+ exchanger1 (NHE1) and Na+/HCO3- co-transporter1 (NBC1) genes and proteins expression in type 2 diabetic rat (Streptozotocin + high fat diet) following long term endurance training.
Diabetes is known to alter both oxidative and glycolytic pathways in a fiber type-dependent manner. The aim of present study was to investigate the effects of endurance training on muscle NHE1 and NBC1 genes and proteins expression in type 2 diabetic rats. Male wistar rats (n=30), 4 weeks old and 95.7±10.8g, were randomly selected and divided into control, diabetic without training and diabetic with training groups. Diabetes was induced by injection of low dose of streptotozin and feeding with high-fat diet. The Endurance training was performed for 7 weeks that started with relatively low speed and duration of 20 m min-1 for 20 min in the first week and gradually reached to 30 m min-1 for 35min in the last week. NHE1 and NBC1 genes and proteins expression were determined by Real time-PCR and western blotting techniques, respectively, in Soleus as an oxidative and EDL (Extensor digitorum longus) as a glycolytic muscle preparation. NHE1 mRNA and protein expression reduced significantly in EDL and Soleus in the diabetic without training group compared with the control group. However, reduction in the expression of NBC1 gene and protein in the diabetic without training group compared to controls did not significant. Endurance training increased NHE1 and NBC1 genes and proteins expression in both EDL and Soleus in the diabetic training group compared to control groups. In conclusion, endurance training may improve the capacity of pHi regulation in muscles by lactate-independent pathway.


Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress.
The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease. We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells. Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines. We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.


[Clinical diagnosis of genetic liver disease].
The clinical phenotype of genetic liver disease is significantly different. Although the incidence of disease is low, because of the wide spectrum of diseases, the overall affected population is not rare. Therefore, clinical concern is a matter of alarm. Additionally, these diseases rarity in clinical practice has covered the recognition, causing increased problem of clinical misdiagnosis. In accordance with the problems encountered in clinical practice of our hospital, we explore the clinical diagnosis of genetic liver disease.


[Allergy testing in children].
Allergy testing in children can be reduced, since it should have no consequences in most cases of asthma and allergic rhinitis. In atopic dermatitis, it should be done, only when food allergy is suspected. Food allergy must be confirmed by provocation except from allergy to peanuts, which may be diagnosed by component resolved testing. Screening with skin prick test or specific immunoglobulin E is meaningless, since it reveals different results and in most cases tests for, what is consumed without reactions. In our opinion provocation with penicillin can be done without prior testing in case of suspected allergy.


Building a reduced model for nonlinear dynamics in Rayleigh-Bénard convection with counter-rotating disks.
A reduced model to decrease the number of degrees of freedom of the discretized Navier-Stokes equations to a small set that nevertheless captures the essential dynamics of the flow is proposed. The Rayleigh-Bénard convection problem in a cylinder of aspect ratio one where the lower and upper disks, maintained at hot and cold temperatures, respectively, rotate at equal and opposite angular velocities has been chosen to test the technique. The nonlinear dynamics is rich and complex when the temperature difference between disks and their angular velocity is varied. Representatives states--stationary, periodic near sinusoidal, and near heteroclinic--are presented. In each case, the reduced model is compared with temporal integration, and we show that 41 degrees of freedom are sufficient to reproduce the signal. We discuss the strengths and weaknesses of the algorithm by which we build our reduced model.


Human organotypic brain slice culture: a novel framework for environmental research in neuro-oncology.
When it comes to the human brain, models that closely mimic in vivo conditions are lacking. Living neuronal tissue is the closest representation of the in vivo human brain outside of a living person. Here, we present a method that can be used to maintain therapeutically resected healthy neuronal tissue for prolonged periods without any discernible changes in tissue vitality, evidenced by immunohistochemistry, genetic expression, and electrophysiology. This method was then used to assess glioblastoma (GBM) progression in its natural environment by microinjection of patient-derived tumor cells into cultured sections. The result closely resembles the pattern of de novo tumor growth and invasion, drug therapy response, and cytokine environment. Reactive transformation of astrocytes, as an example of the cellular nonmalignant tumor environment, can be accurately simulated with transcriptional differences similar to those of astrocytes isolated from acute GBM specimens. In a nutshell, we present a simple method to study GBM in its physiological environment, from which valuable insights can be gained. This technique can lead to further advancements in neuroscience, neuro-oncology, and pharmacotherapy.


ADVERSE DRUG REACTIONS IN THE ORAL CAVITY.
Every medication may lead to adverse effects, even when used in standard doses and mode of application. In the oral cavity, adverse effects may affect every part of oral mucosa and are the result of medications taken either locally or systemically. Oral adverse reactions to drugs are not typical and therefore sometimes not easy to recognize. On diagnosing adverse side effects in the oral cavity, experienced clinician will usually diagnose the condition on the basis of detailed medical history and clinical finding. However, the only objective evidence for the offending drug is 're-challenge', i.e. exposure to the drug after its discontinuation. It carries a huge risk of anaphylactic reaction; therefore it has to be performed in a controlled hospital setting. Therapy is based on immediate exclusion of the offending drug and, if lesions are present in the oral cavity, topical or systemic corticosteroid therapy is prescribed. This article gives a review of patients with oral adverse drug reactions referred to the Department of Oral Medicine in Zagreb.


Changing New Graduate Nurse Profiles and Retention Recommendations for Nurse Leaders.
This study compares and contrasts new graduate nurse attributes and perceptions using findings from a 2010 study and a recent analysis of new graduate nurses participating in the same residency program. As millennials saturate the healthcare work environment, their unique views and needs will influence the evolution of new graduate nurse residencies. This study used previously reported data on new graduate nurses between 1999 and 2009 and compared it with a secondary analysis of data collected on new graduate nurses between 2011 and 2016. This study provides evidence that millennial new graduate nurses' levels of commitment and satisfaction do not moderate turnover intentions in the 1st 2 years of practice as they did in the previous group of new graduate nurses. Job embeddedness, a construct that measures the likelihood of whether a person is going to stay, may be a better measurement among new graduate nurses than commitment or satisfaction because millennials, a generation that is predominant in current new graduate nurses, are more engaged than loyal.